Embryology - User contributions [en-gb]

User:Z3418702

2014-10-29T00:35:34Z

Z3418702: /* Lab attendance */

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:45, 6 August 2014 (EST)

==Lab attendance==

Lab 1----[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:57, 6 August 2014 (EST)

http://www.ncbi.nlm.nih.gov/pubmed

[http://www.ncbi.nlm.nih.gov/pubmed Pubmed]

[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]

<pubmed>25084016</pubmed>

Lab 2 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:20, 13 August 2014 (EST)

Lab 3 ----[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 13:08, 20 August 2014 (EST)

Lab 4- --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:34, 27 August 2014 (EST)

Lab 5 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:58, 3 September 2014 (EST)

Lab 6 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:45, 10 September 2014 (EST)

Lab 7 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 11:16, 17 September 2014 (EST)

Lab 9 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:20, 8 October 2014 (EST)

Lab 10 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:11, 15 October 2014 (EST)

Lab 11 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:33, 22 October 2014 (EST)

Lab 12 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 11:35, 29 October 2014 (EST)

==Online Assessments==

===Lab 1===

'''Article 1:''' <pubmed>24592092</pubmed>

This study was conducted by the IVF Center at Kocaeli University, Turkey. It aimed to test the effect of biochemical markers in follicular fluid, such as nitrous oxide (NO), reduced glutathione (GSH) and malondialdehyde (MDA) on the outcome of in vitro fertilisation. The researchers selected 62 infertile women, all of whom were aged between 25 and 32, were non-smokers, had no systemic diseases, and were suffering from unexplained infertility with no signs of hormonal or ovulatory issues.

Ovulation was first induced in the women using long and short agonists along with a microdose flare-up, after which an oocyte was collected. This was followed by intracytoplasmic sperm injection (ICSI) as the preferred method of fertilisation, then the transfer of the embryo took place. To collect the FF samples, the dominant follicles were chosen and samples were centrifuged, supernatants were removed and stored.

To measure MDA levels, MDA was mixed with thiobarbaturic acid (TBA) which reacted to form a red compound. This mixture was incubated, cooled and assayed to read the absorbance of the butanol phase, and results were expressed in micromoles of MDA. Similarly, levels of GSH were measured in micromoles/L after being supplemented with metaphosphoric acid and assayed. However, NO levels were measured indirectly by measuring the nitrate and nitrite sample concentrations, deproteinising the sample, then measuring absorbance at 545nm using Griess reagent, expressing NO levels in nanomoles/L.

The embryos were then graded in terms of the size of the blastomere and degree of fragmentation, into Grades A-C, A being an even blastomere with <10% fragmentation. A single Grade A embryo was then transferred into each woman on Day 3 of the trial, after which they were categorised into 2 groups based on blood concentration of human chorionic gonadotropin; successful pregnancy (Group 1) and unsuccessful pregnancy (Group 2).

Finally, to analyse these results, the researchers used the women’s pregnancy status following IVF as the primary outcome measure. Statistic analysis was carried out according to non-parametric Mann-Whitney U test. The study found that the successful pregnancy group had significantly lower levels of fluid NO and significantly higher levels of fluid MDA than the unsuccessful pregnancy group. In analysing the correlation between IVF parameters and oxidative stress, the findings showed a positive weak correlation of MDA with fertilisation rate and the number of Grade A embryos. Also, ROC curve analysis implicated MDA as a highly sensitive predictor of pregnancy. Due to this significant difference in MDA levels between groups 1 and 2, the study concluded that MDA was the most suitable indicator of IVF success out of the 3 biochemical markers chosen for analysis.

'''Article 2:''' <pubmed>24914407</pubmed>

The objective of this study was to research the possible association between levels of plasma D-dimer, a haemostatic marker, and the success or failure of pregnancy in women undergoing IVF. The researchers selected 105 infertile women from the Ortona General Hospital’s Assisted Reproduction Unit who were undergoing IVF, indicated by factors such as tubal factor, endometriosis, male factor, anovulation and unexplained infertility.

The participants underwent ovarian stimulation by receiving daily subcutaneous injections of recombinant FSH (follicle stimulating hormone) with doses varying based on basal FSH level, the age of the woman and antral follicle count. This stimulation was begun upon complete pituitary suppression on the 3rd day of the menstrual cycle, and throughout the stimulation, hormonal fluctuations of luteinising hormone (LH) were controlled by injecting agonists and antagonists of GnRH.

Following the collection of oocytes, intracytoplasmic sperm injection (ICSI) was used to perform IVF and an embryo transfer was carried out, 14 days after which a pregnancy test was taken. The presence of a gestational sac with a fetal heartbeat after 7 weeks of gestation was the criterion for a clinical pregnancy.This ovarian stimulation protocol was followed by a venous blood sample to test D-dimer concentrations, where a latex quantitative assay was used with 200ng/mL being the threshold level for an abnormal D-dimer level. These assay levels were statistically analysed using a Mann-Whitney U-test and T-test.

The results of the study indicated significantly higher levels of circulating D-dimer in women with a failed pregnancy following IVF in comparison to those with a clinical or successful pregnancy. This difference was statistically valid even when taking age and vascular risk factors into account. It was found that women with concentrations of D-dimer above the threshold had a more dismal pregnancy outcome, and that D-dimer levels increased after the one-week administration of GnRH. Overall, only 38% of the participants had achieved a clinical pregnancy and the study concluded that high D-dimer concentrations are implicated in a higher risk of a failed pregnancy following IVF. This was consistent with previous postulations that a possible mechanism for failure is unsuccessful implantation and placentation, owing to a hypercoagulable vascular state, leading to increased risk of thrombolic events in maternal vessels to the placenta.

--[[User:Z8600021|Mark Hill]] - Both these papers are recent and present interesting findings. It would have helped you summary in the second paper if you had described what plasma D-dimer was. Your summaries are both correct and concise (5/5).

===Lab 2===

[[File:Fertilisation of medusa eggs by spermatozoids in vitro in sea water.png|300px]]

Fertilisation of medusa eggs by spermatozoids in vitro in sea water<ref><pubmed>23185235</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0046542]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:28, 21 August 2014 (EST) This is all correct, I have fixed the reference link below. Please in future use a shorter image title and do not use .jpg in the image description above (I have removed for you). (4/5)

<references/>

===Lab 3===

'''Adrenal gland'''

<pubmed>7011178</pubmed>
<pubmed>24116052</pubmed>

'''Gonad development'''

<pubmed>17237341</pubmed>
<pubmed>7623307</pubmed>

'''Placenta'''

<pubmed>10419690</pubmed>
<pubmed>7673080</pubmed>

--[[User:Z8600021|Mark Hill] These references are appropriate, you should have included some descriptions, even a single line, with the reference (4/5).

===Lab 4===

'''Summary of research article'''

This study by Chang et al. observed the effect of varying the intratracheal transplantation time of umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) on the attenuation of hyperoxic lung injury in neonatal rats. It was concluded that the optimal time window for stem cell transplantation was narrow; efficient only during the early but not late phases of inflammation. The findings were in line with previous research that the anti-inflammatory properties of UCB-derived MSCs play a crucial therapeutic role in the alleviation of bronchopulmonary dysplasia (BPD), through reducing hypoxia-induced injuries including increased apoptosis and impaired alveolarisation.

Tissue sampling and analysis of lung histopathology found that the Hypoxia Control (HC) group showed fewer, larger and more abnormally-sized alveoli compared to the Normoxia Control (NC) group. However, upon transplantation of UCB-derived MSCs, these alveolar impairments and changes in morphology were attenuated, especially when added on post-natal day 3 (HT3) than on post-natal day 10 (HT10).

The study’s comparison of the levels of pro-inflammatory cytokines such as IL-6α, IL-6β and TNF-α before and after the addition of the UCB-derived MSCs found that such molecular markers were significantly lower after HT3 transplantation than HT10 transplantation. These levels were much lower than the initial starting levels exhibited by the NC group, indicating the therapeutic effect of the cord cells. Furthermore, the hypoxia-induced reduction in VEGF and HGF levels and increase in lung collagen levels were both attenuated by the addition of the MSCs.

These findings led to the conclusion that the therapeutic efficacy of UCB-derived MSCs on treating BPD is indeed time-dependent; having potent effects in the early inflammatory process, which is then reduced in later stages. The study also tested any potential synergistic effects of combined early and late MSCs intratracheal transplantation, but none were found.

<pubmed>23349686</pubmed>

'''Vascular shunts'''

The 3 developmental vascular shunts in the fetal circulation that close postnatally are:

''a) Ductus arteriosus (Ductus Botalli):'' Connects the pulmonary artery to the proximal descending part of the aortic arch and prevents the output of the right ventricle from entering the unexpanded fetal lung, which is fluid-filled and non-functioning. This shunt transfers medium oxygen saturated blood and becomes the ligamentum arteriosum after closing at birth.

''b) Ductus venosus:'' Shunts blood from the left umbilical vein to the inferior vena cava. This carries well-oxygenated blood and allows placental blood to bypass the liver ultimately to the fetal brain.

''c) Foramen ovale (Foramen Botalli):'' Shunts blood that is highly saturated with oxygen from the right atrium to the left atrium and becomes the fossa ovalis after closing at birth.

===Lab 5===

'''Bronchogenic Cysts'''

Bronchogenic cysts (BCs) are an unusual and rare congenital abnormality of the bronchial tree; a generally benign type of malformation of the bronchopulmonary foregut. The classification of these cysts is into; those occurring in the mediastinum (65-90%), which have equal prevalence between the sexes, or those of intrapulmonary origin (lung or pleura) which display a slight male predominance <ref name="PMID23762726"><pubmed>23762726</pubmed></ref> Other sites such as intradiaphragmatic and retroperitoneal are rare, and consequently require close attention.

These lesions are characteristically unilocular, mucus field cysts which arise from the posterior walls of airway membranes during embryonic development. They currently account for 20-30% of congenital cystic bronchopulmonary foregut abnormalities and for only 5-10% of paediatric mediastinal masses. <ref name="PMID23762726"><pubmed>23762726</pubmed></ref> Although the exact cause of bronchogenic cysts is yet to be established, current research postulates that that their developmental cause is the abnormal budding of the tracheal diverticulum and proximal bronchial structures during embryogenesis in weeks 4-6. Bronchogenic cysts stem from abnormal buds from the tracheobronchial tree or primitive esophagus which fail to extend to the site of alveolar differentiation. Generally, early separation causes the system to move into the mediastinum, however it is when this separation occurs late that a BC forms <ref name="PMID23762726"><pubmed>23762726</pubmed></ref>. Histologically, these abnormal bronchogenic cysts are lined by pseudostratified, ciliated, columnar or cuboidal secretory respiratory epithelium and their walls comprise typical structural components of the airways such as smooth muscle, cartilage and mucinous glands. Cysts are typically not filled with air as they lack communication with the bronchial tree, but contain fluid comprising blood, proteinaceous fluid and calcium oxalate, resulting in a solid lesion manifesting on radiographic imaging such as MRI and CT scans <ref name="PMID18292738"><pubmed>18292738</pubmed></ref>

BCs are considered to be the most common form of foregut duplication cysts and are a congenital anomaly as they are asymptomatic and rarely arise in infants with diagnosis usually occurring post-natally. The clinical presentation of cysts is usually either asymptomatic or through airway obstruction causing respiratory distress or cystic infection causing compression of central lung parenchyma <ref name="PMID18760579><pubmed>18760579</pubmed></ref>

<references/>

===Lab 7===

'''Research article- Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary gland development'''

This study by Kioussi et al. investigated the role of the transcription factor ''Pax6'' in creating a dorsal-ventral boundary between cell types of the developing pituitary gland. The researchers considered the physical location of the six cell types in the pituitary that originate from a common primordium- corticotropes, thyrotropes, menalotropes, gonadotropes, somatotropes and lactotropes. They specifically focused on the regulation of cell differentiation by ''Pax6'' and the effects of its absence.

Following analysis of mutant mice embryos with a ''Small eye'' (''Sey'') mutation and ''Pax6'' gene deletion, the study found that ''Pax6'' plays a significant role as an early dorsal marker of the pituitary gland’s development. They found that ''Pax6'' transcripts were expressed and present in the nascent Rathke’s pouch, however excluded from the ventral section of the Sonic hedgehog (''Shh'') pouch, leading to the formation of a ventral zone between cells expressing ''Pax6'' and those expressing ''Shh''. A dorsal-ventral gradient for cell differentiation was evident and ''Pax6'' was seen to be excluded from the rostral zone of the pituitary. These two particular findings suggested that ''Pax6'' may be an essential element of the ‘transcriptional apparatus’ responsible for determining the position of the six pituitary cell lineages.

Furthermore, the research concluded that the absence of ''Pax6'' leads to a decrease in dorsal cell types from the ''Pit-1'' lineage (somatotropes and lactotropes) and an increase in cell types with ventral phenotypes such as thyrotropes. This was confirmed by discovering that the expression patterns of four molecular ventral markers such as GATA2 were uniformly dorsalised, leading to further increase in the population of thyrotropes.

Hence, these results implicated that ''Pax6'' functions as a transcriptional regulator in opposition to ventral signalling molecules, thus clearly delineating the developing dorsal cells from ventral cells in the differentiation stage of pituitary gland development. It has a key regulatory role in the formation of a sharp dorsal-ventral cell type margin through the inhibition of ''Shh'' ventral signals.

<pubmed>10588713</pubmed>

'''Tooth development'''

The cells and their layers that contribute to tooth development through odontogenesis (from week 6 of development) include:

*''Odontoblasts'': Mesenchymal cells of neural crest origin that produce predentin, which calcifies forming dentin in the process of dentinogenesis. Enamel epithelium causes odontoblast differentiation and these cells contribute to the outer dental pulp
*''Ameloblasts'': Derived from ectodermal cells of oral epithelium tissue. They differentiate from preameloblasts, activated by ectomesenchymal cells and produce enamel proteins such as amelogenin and enamelin to form enamel, the outer covering of the tooth’s crown.
*''Peridontal ligament'': Composed of connective tissue (bundles of collagen fibres), which secures the root of the tooth in the alveolar socket so it is not displaced. It surrounds the cementum of the tooth root.

===Lab 8===

'''Ovary development'''

Initially, the genital systems of both sexes are morphologically similar and sexual development hence begins as an indifferent stage with an indifferent (‘bipotential’) gonad later forming either the testis or ovary. Both gonads have contributions from; mesothelium of the posterior abdominal wall cavity, mesenchyme beneath this and primordial germ cells (PGCs) that later differentiate to form sex cells.

In Week 5 of development, a thickening of mesothelium forms on the medial portion of the primitive kidney (the mesonephros). The formation of the gonadal ridge results from the proliferation of the mesothelium and mesenchymal tissue beneath it, as a bulge on the medial mesonephros. Projection of finger-like gonadal (epithelial) cords into the mesenchyme follows, segmenting the indifferent gonad into an internal medulla (covered by germinal epithelium) and external cortex. For embryos with a sex chromosome complex of XX, the medulla regresses while the cortex of the indifferent gonad differentiates to form the ovary.

PGCs reside among dorsal endodermal cells of the umbilical vesicle whose dorsal part is incorporated into the embryo during folding. They are the first cell type migrating through the primitive streak in gastrulation (3rd week) and then reside at the junctional region of the hindgut yolk sac. Following this, there is migration of the PGCs to the gonadal ridge along the hindgut’s dorsal mesentery, regulated by BMP-4, fragilis and stella genes. In week 6, these germ cells are incorporated into the gonadal cords and are called oogonia, having entered underlying mesenchyme.

In female embryos, ovary development is a slow process, with the ovary not histologically identifiable until week 10. Ovary development relies on the genes of the XX chromosome along with an autosomal gene. Gonadal cords form a basic rete ovarii (network of canals) by extension into the internal medulla, although the cords are not notable in the embryonic ovary. The rete ovarii and gonadal cords usually degrade and cease to exist.

[[File:Bailey329.jpg|500px]]

'''Transverse section of the ovary of a fox embryo'''

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466385578-2 Moore: The Developing Human, 9th ed. Chapter 12]

===Lab 9===

====Group 1- Respiratory====

Overall, the project at this stage consists of a good integration of text, images and references throughout. The introduction is well-written and gives an overview of the two parts of the respiratory system (conducting and respiratory zones). I think it is a good idea that your group has split this up and explained both parts separately as it helps to orient an unknowing reader, especially as the gross anatomical structures are also described (e.g. trachea, larynx, bronchi). However, in-text referencing is needed in this introductory segment to provide the reader with the source of all information, exactly where it appears. You could refer to Dr Hill’s instructions on how to do this if needed, or see another group’s page on Edit mode. Also, the images used in the introduction should have a small caption beneath them, otherwise it is hard to tell what the images show exactly and how this may be relevant to the complementary text.

In terms of heading and subheading organisation, I like how you have split the content up into 5 main areas of introduction, lung development stages, current research models/findings, historic findings and abnormalities. This makes the page easy to navigate and the subheadings under each section are relevant. The use of a table in the ‘lung development stages’ section is very well done and appropriate, as it segments the information into a clean, readable format that a student could simply refer to if they were learning from scratch. The information in the table is succinct and provides all the main points. The only improvement here I would suggest, is aligning the content to the left, as it may seem more pleasing to the eye to have even spacing rather than centre alignment. Also, the ‘references’ have been placed as subheading 2.1, whereas the other ‘reference’ sections have not been given a separate subheading, so I would consider making this consistent throughout the project page.

The section on current research models and findings is concise and informative, with good use of numbering to make the information easier to read rather than having long and chunky paragraphs. Although a minor detail, there is one part that says “a study conducted last year”. Since these Wiki pages will be left online, it is important to specify the exact year here, and provide an in-text reference to the study mentioned so a reader can easily locate it. I like the use of dot points in this section, making it look appealing, however the image used should also include a caption, as should the others on the page. Be careful of copyright infringement regarding image use, as there appears to be a file with a ‘Permission Error’ in this section, which may need to be manually removed.

The ‘historic findings’ section was also well-done, especially because it used dot points to segment the information and show the exact years of each discovery. Once again though, the image requires a caption and the references for this section seem to be split into 2 parts; one list from 1-14 then another from 1-4. I think the list from 1-4 needs a subheading to show how those sources are different to the ones above it, otherwise both lists need to be integrated into one.There are also some parts that have coding showing </ol> and </li> which just need to be removed with editing.

Lastly, the section on abnormalities is also of a high standard as each abnormality begins with a brief description then goes into details by using dot points. There is good use of in-text referencing followed by a reference list which is correctly formatted too. The image included has a caption which is good, as other sections lack this, however I would consider adding more images to make this part more visually appealing and engaging to the reader. It is evident that a lot of work has been done on this page as each section is detailed and referenced well, with relevant information.

====Group 2- Renal====

The introduction provided by this project is very good and includes in-text citations. Not only does it introduce the renal system’s components but also discusses its development briefly into the embryonic and fetal stages, focusing more on fetal. Also, by having the references as one long list at the very end of the page, this gives the project a clean and tidy look, which some of the others lack. I thought this was a great idea and very orderly.

While some sections are full of information, others are scarce or empty, such as the ‘Historical findings’ section. Some information on the development of knowledge on the renal system throughout history should be included here, maybe making use of dot points detailing specific year dates. The ‘Developmental Timeline’ provides a good overview of the system’s development, although weeks 3-5 may not be necessary as these are during the embryonic period and the focus here is on fetal development. However, it does provide an overall context which is good. This information may also be effectively translated into a table format for easier readability.

The section on ‘current research models’ was nicely written, with solid analysis of 2 research articles. Using any more articles to that level of depth may be too much information, so this is a good balance. It was very good to see the text actually explaining the accompanying image, which was labelled with a caption too. The introduction to the use of animal models and why these are important was effective also.

I particularly thought the sub-sectioning of the page into the main organs of the renal system was a smart idea rather than having the entire system as a clump of information as this way, it is easier to navigate through the information. The ‘kidney’ section was of a very high standard as the information was relevant and nicely split into different processes of fetal development such as nephrogenesis and renin production. It is very helpful as a reader to have explanations of the images used, making the page more interactive and useful. However, this is a file with a ‘Permission error’ present which would need removal due to copyright infringement; this should be sorted out before the project is due.

The following three sections on the urethra, ureter and bladder were also well-written, referenced correctly with in-text citations and the images used were relevant to the text. However, captioning the image in the urethra section would be good to give the reader knowledge of exactly what it shows. The ‘abnormalities’ section was again, well -researched and full of information, however it seems a little cluttered as lengthy references are placed under the text. Integrating these into the overall reference list at the end of the page would look clearer.

Overall, this project has been well done and there is evidence of consistency throughout the section formatting, suggesting the group members have been communicating between each other, which is good to see. Some improvements I would suggest are the use of hand-drawn images to make it easier for a student to learn off the project, and using tables to summarise some information e.g. timeline.

====Group 3- Gastrointestinal====

The introduction part of this project provided a good overview of the gastrointestinal tract and its components, also mentioning briefly the changes that occur in the fetal period. However, care must be taken to not capitalise words that are not needed e.g. Foregut, Midgut, Appendix etc. Although the information in the ‘timeline’ section is relevant, its formatting needs a bit of review as there are inconsistencies between the foregut, midgut and hindgut parts. It also seems that the in-text citations have just been arbitrarily placed in chronological order, with each line having a new reference. Also, this information may be better presented in table format to improve readability. Some simple editing may be needed to fix this.

The section on ‘Recent findings’ has some good information, however the reference needs to be properly cited and maybe a couple more articles would help give this part some substance. I thought it was effective to have the GIT split into the foregut, midgut and hindgut and then detail the fetal development under those titles. This gave the page a good structure. However, adding some images, both from online and student-drawn to the foregut and hindgut sections would help improve the aesthetics of the page. The hand-drawn images on the midgut section are effective learning tools to a student, but maybe could be drawn a little neater with darker colours as the blue labelling is difficult to read. They should also be captioned. The use of a table to show midgut herniation of fetuses was a good tool as it makes the information easier to read also.

Lastly, the section on abnormalities was well-detailed and I liked that the deformities were split into a definition and cause. An image of gastrochisis may be helpful for a reader to visualise the condition though. The in-text citations in this part were properly done and a long list of references being at the end of the page made the project look neat overall. Areas of improvement may be some simple formatting changes and evening out the information across sections, however a solid project so far.

====Group 4- Genital====

Overall, it is evident that a lot of work has been completed on this project as each section has a decent amount of information and there are images throughout the page. However, the addition of an ‘introduction’ section would help to orient the reader and help students gain an overall understanding of the topic.

The section on ‘system development’ seems to be well-researched, however the formatting of the content in short, one-sentence dot points makes it difficult to read and incongruent, so writing this out in small paragraphs would improve the readability. The capitalization of some words is unnecessary in both the dot points and the table, creating inconsistencies in the formatting. Also, some words are unnecessarily bolded which detracts from the aesthetic appeal of the page. However, the inclusion of a table to summarise the timeline information is an effective tool, although there is much more information provided for the male system than female system. It is really good to see the use of an image as it is relevant and clearly compares the male and female system development side-by side. I also think the video inclusion is fantastic as it would be an effective way to learn for a reader with no previous knowledge, making the page more interactive.

The section on ‘current research, models and findings’ contains lots of relevant information, however this is not referenced in-text and it is thus unclear where the information has been derived from. There also seems to be some unevenness between the depth of information between male and female systems, which some more research can easily remedy. In terms of current findings, the listing of the information in dot points makes it easier to read, however there are some parts italicised and capitalized that are not needed. It is great to see some hand-drawn images as these are simplistic, colourful and effective ways to accompany the text, adding to the page’s appeal. Take care to properly include images, as one of them appears as ‘alt text’ and the link does not show the image itself. Although some references appear under a ‘references’ title in this section others appear as a website links; formatting of these could improve neatness.

The following section on ‘historic findings’ contains evidence of extensive research as it is very detailed and well-written. However, I would consider breaking this part up into smaller sections using dot points as large paragraphs seem tedious to read. The hand-drawn image is a good inclusion, but labelling of it would be effective and adding a couple more would break up the long section visually. Also, there seem to only be in-text citations after long chunks of information; perhaps more sources should be used/consulted.

Lastly, the abnormalities section was comprehensive and detailed and enough information was given on some examples. This was just the right amount of content, as any more would seem excessive. Adding some more images with appropriate captioning is advised also. I liked that the references were listed altogether at the end of the page, making it neat and tidy. Overall, a solid project which just needs some formatting to improve further.

====Group 5- Integumentary====

The introduction of this page was good as it provided a great overview and insight into what the project would later go on to discuss. Perhaps a little information on defining the integumentary system itself would be valuable though, to let the reader know the constituents.

The sub-sectioning of the page’s content into ‘introduction, ‘development overview’, ‘recent findings’, ‘historic findings’ and ‘abnormalities’ was clever, as the development section then went on to describe each component such as skin, nails etc. This effectively segmented the information into smaller chunks that could easily be navigated to. I especially liked the use of the table in the ‘skin’ section, showing the week of development, description and image corresponding alongside it, as it provided a holistic approach to that section. However, there were no in-text citations in the ‘skin’, ‘hair’, ‘nail’ or ‘teeth’ sections, hence the source of the information is unclear. To do this correctly, Dr Hill’s Wiki help page should be consulted.

The use of various images with labelled captions was a strength of this project, as the pictures were effective in balancing the text components to make the page more visually appealing. Most of the sections under ‘development overview’ have a decent amount of content, however the ‘nails’ part is a bit lacking and also needs to be correctly cited. The use of the table of images alongside the description of developmental stage in the ‘teeth’ section was very good to include, however the image is captioned ‘The stages of embryonic teeth development’. This may be irrelevant as the project’s focus is on fetal development. Further research into this area may uncover more relevant information.

Although the section on ‘recent findings’ contains a lot of information, the use of chunky paragraphs detracts from the readability of the page and the purple boxes could be summarised into dot points to help the reader understand the content more quickly. The section on historic findings seems concise and relevant, however the image included says it has been removed/deleted, so this requires editing. Lastly, the ‘abnormalities’ section was very well-structured and written, as each example had a captioned image accompanying it to help the reader visualise. This section was also well-done in terms of in-text citations, with an extensive reference list provided at the end. Perhaps consider adding some student-drawn images and possibly a relevant video, but otherwise it is very good as it is. Overall, the project has a good layout and a decent amount of content; with some editing and formatting it can be improved further.

====Group 7- Neural====

Overall, the project contains a decent amount of content as it is, split up into appropriate subheadings, considering the large scope of the nervous system. The introduction provides a succinct description of the CNS, however including an outline of what topics the page intends to cover would be good to orient a reader that approaches the page for the first time. The descriptions of the brain and spinal cord are well-written, however require in-text citations and some words need not be capitalised e.g midbrain, hypothalamus. These can be easily fixed with proof-reading and further editing.

The use of an image to illustrate fetal development was a very good idea; although the diagram is itself seems complicated, it can be explained well with the accompanying text beneath. The segmentation of the timeline into 4 different parts made it easier to follow, although I would consider placing the images on the right hand side of the page to reduce the vertical length of the page and the scrolling required to navigate through it. The section on ‘brain development’ contained some relevant information, formatted in dot points which improves readability, however in-text citations are needed to allow the reader to source the information if required. The use of the table in this part was effective also; it was concise and straight to the point.

Although the brain development section was very well detailed, there was no information in the spinal cord and meninges sections; with further research, these need to be evened out, along with the current findings section which is just references at this stage, but still a good start to finding sources of information. The section on current research is well-detailed and contains a lot of information too, which is good to see. Fiinally, I thought the section on abnormalities was very well done, using subheadings to segment the content. The use of dot points allowed the information to be easily read off the page, and use of images to accompany them helped the reader to visualise the conditions. There is one image however that has been incorrectly uploaded; consulting Dr Hill’s Wiki help page can remedy this. Also, the placement of all references under one list at the end of the page was effective in neatening it up, that was very well done too.

Overall, the project’s content has been well-researched and there is evidence of good teamwork and communication. Perhaps the use of some student-drawn images and inclusion of a relevant video may be areas of improvement.

====Group 8- Musculoskeletal====

Overall, the project has some very detailed sections and some sections where content is scarce. It would be helpful to start off with an introduction of the musculoskeletal system so the reader is aware of its components and what the page intends to cover. The timeline of muscle development has good potential, I understand it is still being planned at this stage and with further research, it could definitely be effective. A table format would be useful to present this information. The following sections on background embryonic development and fetal myogenesis are well-researched and have a lot of content, however I would consider breaking it down into dot points to improve readability. The sections are cited correctly in-text though, which is good to see.

There is much more improvement in the tendon and second trimester development sections, as the chunks of text have been reduced to provide a succinct summary, however these need to have citations also. The use of some images here, either hand-drawn or from online would be beneficial, to have a balance between text and pictures and make the page more visually appealing. Other than the abnormalities section which provides a good, concise summary of Duchenne Muscular Dystrophy, the following sections seem to be only references at this stage. As long as these are used to compose some relevant paragraphs/dot points, this is fine considering there is still time to improve the page.

Overall, this page has good potential as the groundwork has been completed; it is now more a matter of writing up more information, adding images and possibly a relevant video. The part on ‘making gains’ would need to be removed for the final, but otherwise, it is definitely a decent amount of work so far, especially considering the few group members involved.

===Lab 10===

'''Research article- Stage-dependent requirement of neuroretinal Pax6 for lens and retina development'''

'''Methods summary'''

Embryonic mouse stem cells from timed pregnant females were recombined in a homologous fashion to form floxed Pax-6 alleles in the experimental mice. These embryos were then harvested, fixed, PBS-washed, cryopreserved and sectioned for immunohistochemistry staining in which embryos were permeabilized and washed with PBT and incubated. This was followed by RNA in-situ hybridisation, where RNA polymerase was used to create antisense mRNA probes, then X-gal staining occurred.

The study then measured the length of the cell cycle phases of the mice embryos to assess the role of Pax6. Using wild-type littermates as controls, they found the proportion of proliferating retinal progenitor cells (RPCs) by injecting timed pregnant females with BrDU, then fixing, cryopreserving and sectioning them. Following this was a process of antigen retrieval with several incubations to calculate cell proliferation rate.

Finally, the cell cycle rate at embryonic days 11.5 and 13 were found and the cell cycle and S phase lengths were determined, also calculating the total length of the G1, G2 and M phases. These results were then quantified by statistical analysis using a t-test, counting 3 fields for every individual eye.

'''Results summary'''

By combining the findings of the separate sections of the experiment, the study concluded that Pax6 has an essential role in both lens and retinal cell formation. It was found that Pax6 deletion strong hypocellularity in early RPCs. There was high expression of Pax6 in the surface ectoderm (SE) and optic vesicle (OV) control embryos while the levels of Pax6 stayed constant and unchanged even after Pax6 elimination in the OV, lens pit and SE. The hypocellularity of the retina was more pronounced with time, and retinae deficient in Pax6 became smaller progressively.

Another finding was that the population size of the RPCs was reduced by changed cell cycle length and imbalance between cells exiting the cell cycle and proliferation of eye progenitor cells. It was again observed that retinal cells deficient in Pax6 were very hypocellular and cycling cells were centrally localised in the retina. An increased rate of cell death was observed with increasing time and total cell cycle length of Pax6-deficient RPCs was significantly longer than the control embryos. Also, the down-regulation of cyclin D1 in Pax6-deficient mice suggested that absence of Pax6 drives RPCs to cell cycle exit. Together, these findings suggested that positive progression of RPCs through the cell cycle is regulated by Pax6.

Finally, another conclusive result reached by this study was that the absence of Pax6 in RPCs causes a hindrance in their proper differentiation program into retinal cells; indicating the essential role of Pax6 in proliferation of early progenitors. It was also found that deficiency of Pax6 in optic vesicles could lead to the arrest of lens development during the interaction of the OV and SE. As neither the lens nor retina was formed properly in Pax6 deficient embryos, this indicated the importance of Pax6 presence in the optic vesicle for correct eye morphogenesis in the developing embryo.

<pubmed>24523460</pubmed>

[https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Vision_Development#Lens Sensory-Vision development Wiki page]

===Lab 11===

This study by Masumoto et al sought to explore the potential of human induced pluripotent stem cells (hiPSCs) to regenerate damaged cardiac tissue, in particular vascular cells and cardiomyocytes (CMs).

CMs and vascular cells were simultaneously induced using a differentiation protocol wherein the levels of gene expression of cardiac mesoderm and progenitor genes peaked at day 5 of differentiation. They found that mesoderm-to-CM differentiation enhancement occurred during days 5-7 due to Dkk1 addition (an antagonist). When vascular cell induction with CMs using VEGF was attempted instead of Dkk1, this led to induction of ECs and CMs together. The study found that the cell populations had a composition of vascular endothelial cadherin, platelet-derived growth factor receptor beta and positive MCs. These findings collectively suggested that a change from ‘only CMs’ to ‘CMS and vascular cells’ could be induced by selectively controlling the direction of differentiation of cardiovascular cells.

The experiment also tried to develop sheets of cardiovascular cells from hiPSCs by continuous culture, re-plating and incubations. It was found that reducing temperature served to re-assemble self-pulsating sheets of cells after heating and that sheets were composed of 3-4 layers supported by collagen fibres in a stratified manner. These sheets were shown to have CMs evenly distributed throughout them via immunohistochemical techniques. Within the cell sheets were; CMs, MCs and undifferentiated cells and this composition was attributed to possible apoptotic cell death reducing numbers and reduced proliferation efficiency. Together, these results suggested that it was the hiPSCs only that had generated the CMs and vascular cells, forming a structure that resembled cardiac tissue very realistically.

Lastly, Masumoto et al also found that the transplantation of hiPSCs with CTSs could alleviate dysfunctions in the cardiovascular system even after infarction in rats, as all rats had survived the period of post-transplantation without signs of tumours arising. Using echocardiogram technology, it was observed that anterior wall contraction had been brought back to normal, left ventricle systolic function had improved and that there had been reduced thickening of the wall of myocardial infarcts. Furthermore, staining with Sirius red found that the rate and extent of fibrosis was significantly reduced after hiPSC-CTS transplantation.

In conclusion, Masumoto et al concluded that there remained ample scope for hiPSCs to regenerate cardiac tissue and thus restore cardiac function, if their capabilities were studied more widely by other researchers. The replacement ability and biomedical potential of these pluripotent stem cells hold great promise for the future of stem cell therapy.

<pubmed>25336194</pubmed>

User:Z3418702

2014-10-28T23:16:38Z

Z3418702: /* Lab 11 */

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:45, 6 August 2014 (EST)

==Lab attendance==

Lab 1----[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:57, 6 August 2014 (EST)

http://www.ncbi.nlm.nih.gov/pubmed

[http://www.ncbi.nlm.nih.gov/pubmed Pubmed]

[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]

<pubmed>25084016</pubmed>

Lab 2 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:20, 13 August 2014 (EST)

Lab 3 ----[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 13:08, 20 August 2014 (EST)

Lab 4- --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:34, 27 August 2014 (EST)

Lab 5 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:58, 3 September 2014 (EST)

Lab 6 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:45, 10 September 2014 (EST)

Lab 7 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 11:16, 17 September 2014 (EST)

Lab 9 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:20, 8 October 2014 (EST)

Lab 10 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:11, 15 October 2014 (EST)

Lab 11 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:33, 22 October 2014 (EST)

==Online Assessments==

===Lab 1===

'''Article 1:''' <pubmed>24592092</pubmed>

This study was conducted by the IVF Center at Kocaeli University, Turkey. It aimed to test the effect of biochemical markers in follicular fluid, such as nitrous oxide (NO), reduced glutathione (GSH) and malondialdehyde (MDA) on the outcome of in vitro fertilisation. The researchers selected 62 infertile women, all of whom were aged between 25 and 32, were non-smokers, had no systemic diseases, and were suffering from unexplained infertility with no signs of hormonal or ovulatory issues.

Ovulation was first induced in the women using long and short agonists along with a microdose flare-up, after which an oocyte was collected. This was followed by intracytoplasmic sperm injection (ICSI) as the preferred method of fertilisation, then the transfer of the embryo took place. To collect the FF samples, the dominant follicles were chosen and samples were centrifuged, supernatants were removed and stored.

To measure MDA levels, MDA was mixed with thiobarbaturic acid (TBA) which reacted to form a red compound. This mixture was incubated, cooled and assayed to read the absorbance of the butanol phase, and results were expressed in micromoles of MDA. Similarly, levels of GSH were measured in micromoles/L after being supplemented with metaphosphoric acid and assayed. However, NO levels were measured indirectly by measuring the nitrate and nitrite sample concentrations, deproteinising the sample, then measuring absorbance at 545nm using Griess reagent, expressing NO levels in nanomoles/L.

The embryos were then graded in terms of the size of the blastomere and degree of fragmentation, into Grades A-C, A being an even blastomere with <10% fragmentation. A single Grade A embryo was then transferred into each woman on Day 3 of the trial, after which they were categorised into 2 groups based on blood concentration of human chorionic gonadotropin; successful pregnancy (Group 1) and unsuccessful pregnancy (Group 2).

Finally, to analyse these results, the researchers used the women’s pregnancy status following IVF as the primary outcome measure. Statistic analysis was carried out according to non-parametric Mann-Whitney U test. The study found that the successful pregnancy group had significantly lower levels of fluid NO and significantly higher levels of fluid MDA than the unsuccessful pregnancy group. In analysing the correlation between IVF parameters and oxidative stress, the findings showed a positive weak correlation of MDA with fertilisation rate and the number of Grade A embryos. Also, ROC curve analysis implicated MDA as a highly sensitive predictor of pregnancy. Due to this significant difference in MDA levels between groups 1 and 2, the study concluded that MDA was the most suitable indicator of IVF success out of the 3 biochemical markers chosen for analysis.

'''Article 2:''' <pubmed>24914407</pubmed>

The objective of this study was to research the possible association between levels of plasma D-dimer, a haemostatic marker, and the success or failure of pregnancy in women undergoing IVF. The researchers selected 105 infertile women from the Ortona General Hospital’s Assisted Reproduction Unit who were undergoing IVF, indicated by factors such as tubal factor, endometriosis, male factor, anovulation and unexplained infertility.

The participants underwent ovarian stimulation by receiving daily subcutaneous injections of recombinant FSH (follicle stimulating hormone) with doses varying based on basal FSH level, the age of the woman and antral follicle count. This stimulation was begun upon complete pituitary suppression on the 3rd day of the menstrual cycle, and throughout the stimulation, hormonal fluctuations of luteinising hormone (LH) were controlled by injecting agonists and antagonists of GnRH.

Following the collection of oocytes, intracytoplasmic sperm injection (ICSI) was used to perform IVF and an embryo transfer was carried out, 14 days after which a pregnancy test was taken. The presence of a gestational sac with a fetal heartbeat after 7 weeks of gestation was the criterion for a clinical pregnancy.This ovarian stimulation protocol was followed by a venous blood sample to test D-dimer concentrations, where a latex quantitative assay was used with 200ng/mL being the threshold level for an abnormal D-dimer level. These assay levels were statistically analysed using a Mann-Whitney U-test and T-test.

The results of the study indicated significantly higher levels of circulating D-dimer in women with a failed pregnancy following IVF in comparison to those with a clinical or successful pregnancy. This difference was statistically valid even when taking age and vascular risk factors into account. It was found that women with concentrations of D-dimer above the threshold had a more dismal pregnancy outcome, and that D-dimer levels increased after the one-week administration of GnRH. Overall, only 38% of the participants had achieved a clinical pregnancy and the study concluded that high D-dimer concentrations are implicated in a higher risk of a failed pregnancy following IVF. This was consistent with previous postulations that a possible mechanism for failure is unsuccessful implantation and placentation, owing to a hypercoagulable vascular state, leading to increased risk of thrombolic events in maternal vessels to the placenta.

--[[User:Z8600021|Mark Hill]] - Both these papers are recent and present interesting findings. It would have helped you summary in the second paper if you had described what plasma D-dimer was. Your summaries are both correct and concise (5/5).

===Lab 2===

[[File:Fertilisation of medusa eggs by spermatozoids in vitro in sea water.png|300px]]

Fertilisation of medusa eggs by spermatozoids in vitro in sea water<ref><pubmed>23185235</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0046542]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:28, 21 August 2014 (EST) This is all correct, I have fixed the reference link below. Please in future use a shorter image title and do not use .jpg in the image description above (I have removed for you). (4/5)

<references/>

===Lab 3===

'''Adrenal gland'''

<pubmed>7011178</pubmed>
<pubmed>24116052</pubmed>

'''Gonad development'''

<pubmed>17237341</pubmed>
<pubmed>7623307</pubmed>

'''Placenta'''

<pubmed>10419690</pubmed>
<pubmed>7673080</pubmed>

--[[User:Z8600021|Mark Hill] These references are appropriate, you should have included some descriptions, even a single line, with the reference (4/5).

===Lab 4===

'''Summary of research article'''

This study by Chang et al. observed the effect of varying the intratracheal transplantation time of umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) on the attenuation of hyperoxic lung injury in neonatal rats. It was concluded that the optimal time window for stem cell transplantation was narrow; efficient only during the early but not late phases of inflammation. The findings were in line with previous research that the anti-inflammatory properties of UCB-derived MSCs play a crucial therapeutic role in the alleviation of bronchopulmonary dysplasia (BPD), through reducing hypoxia-induced injuries including increased apoptosis and impaired alveolarisation.

Tissue sampling and analysis of lung histopathology found that the Hypoxia Control (HC) group showed fewer, larger and more abnormally-sized alveoli compared to the Normoxia Control (NC) group. However, upon transplantation of UCB-derived MSCs, these alveolar impairments and changes in morphology were attenuated, especially when added on post-natal day 3 (HT3) than on post-natal day 10 (HT10).

The study’s comparison of the levels of pro-inflammatory cytokines such as IL-6α, IL-6β and TNF-α before and after the addition of the UCB-derived MSCs found that such molecular markers were significantly lower after HT3 transplantation than HT10 transplantation. These levels were much lower than the initial starting levels exhibited by the NC group, indicating the therapeutic effect of the cord cells. Furthermore, the hypoxia-induced reduction in VEGF and HGF levels and increase in lung collagen levels were both attenuated by the addition of the MSCs.

These findings led to the conclusion that the therapeutic efficacy of UCB-derived MSCs on treating BPD is indeed time-dependent; having potent effects in the early inflammatory process, which is then reduced in later stages. The study also tested any potential synergistic effects of combined early and late MSCs intratracheal transplantation, but none were found.

<pubmed>23349686</pubmed>

'''Vascular shunts'''

The 3 developmental vascular shunts in the fetal circulation that close postnatally are:

''a) Ductus arteriosus (Ductus Botalli):'' Connects the pulmonary artery to the proximal descending part of the aortic arch and prevents the output of the right ventricle from entering the unexpanded fetal lung, which is fluid-filled and non-functioning. This shunt transfers medium oxygen saturated blood and becomes the ligamentum arteriosum after closing at birth.

''b) Ductus venosus:'' Shunts blood from the left umbilical vein to the inferior vena cava. This carries well-oxygenated blood and allows placental blood to bypass the liver ultimately to the fetal brain.

''c) Foramen ovale (Foramen Botalli):'' Shunts blood that is highly saturated with oxygen from the right atrium to the left atrium and becomes the fossa ovalis after closing at birth.

===Lab 5===

'''Bronchogenic Cysts'''

Bronchogenic cysts (BCs) are an unusual and rare congenital abnormality of the bronchial tree; a generally benign type of malformation of the bronchopulmonary foregut. The classification of these cysts is into; those occurring in the mediastinum (65-90%), which have equal prevalence between the sexes, or those of intrapulmonary origin (lung or pleura) which display a slight male predominance <ref name="PMID23762726"><pubmed>23762726</pubmed></ref> Other sites such as intradiaphragmatic and retroperitoneal are rare, and consequently require close attention.

These lesions are characteristically unilocular, mucus field cysts which arise from the posterior walls of airway membranes during embryonic development. They currently account for 20-30% of congenital cystic bronchopulmonary foregut abnormalities and for only 5-10% of paediatric mediastinal masses. <ref name="PMID23762726"><pubmed>23762726</pubmed></ref> Although the exact cause of bronchogenic cysts is yet to be established, current research postulates that that their developmental cause is the abnormal budding of the tracheal diverticulum and proximal bronchial structures during embryogenesis in weeks 4-6. Bronchogenic cysts stem from abnormal buds from the tracheobronchial tree or primitive esophagus which fail to extend to the site of alveolar differentiation. Generally, early separation causes the system to move into the mediastinum, however it is when this separation occurs late that a BC forms <ref name="PMID23762726"><pubmed>23762726</pubmed></ref>. Histologically, these abnormal bronchogenic cysts are lined by pseudostratified, ciliated, columnar or cuboidal secretory respiratory epithelium and their walls comprise typical structural components of the airways such as smooth muscle, cartilage and mucinous glands. Cysts are typically not filled with air as they lack communication with the bronchial tree, but contain fluid comprising blood, proteinaceous fluid and calcium oxalate, resulting in a solid lesion manifesting on radiographic imaging such as MRI and CT scans <ref name="PMID18292738"><pubmed>18292738</pubmed></ref>

BCs are considered to be the most common form of foregut duplication cysts and are a congenital anomaly as they are asymptomatic and rarely arise in infants with diagnosis usually occurring post-natally. The clinical presentation of cysts is usually either asymptomatic or through airway obstruction causing respiratory distress or cystic infection causing compression of central lung parenchyma <ref name="PMID18760579><pubmed>18760579</pubmed></ref>

<references/>

===Lab 7===

'''Research article- Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary gland development'''

This study by Kioussi et al. investigated the role of the transcription factor ''Pax6'' in creating a dorsal-ventral boundary between cell types of the developing pituitary gland. The researchers considered the physical location of the six cell types in the pituitary that originate from a common primordium- corticotropes, thyrotropes, menalotropes, gonadotropes, somatotropes and lactotropes. They specifically focused on the regulation of cell differentiation by ''Pax6'' and the effects of its absence.

Following analysis of mutant mice embryos with a ''Small eye'' (''Sey'') mutation and ''Pax6'' gene deletion, the study found that ''Pax6'' plays a significant role as an early dorsal marker of the pituitary gland’s development. They found that ''Pax6'' transcripts were expressed and present in the nascent Rathke’s pouch, however excluded from the ventral section of the Sonic hedgehog (''Shh'') pouch, leading to the formation of a ventral zone between cells expressing ''Pax6'' and those expressing ''Shh''. A dorsal-ventral gradient for cell differentiation was evident and ''Pax6'' was seen to be excluded from the rostral zone of the pituitary. These two particular findings suggested that ''Pax6'' may be an essential element of the ‘transcriptional apparatus’ responsible for determining the position of the six pituitary cell lineages.

Furthermore, the research concluded that the absence of ''Pax6'' leads to a decrease in dorsal cell types from the ''Pit-1'' lineage (somatotropes and lactotropes) and an increase in cell types with ventral phenotypes such as thyrotropes. This was confirmed by discovering that the expression patterns of four molecular ventral markers such as GATA2 were uniformly dorsalised, leading to further increase in the population of thyrotropes.

Hence, these results implicated that ''Pax6'' functions as a transcriptional regulator in opposition to ventral signalling molecules, thus clearly delineating the developing dorsal cells from ventral cells in the differentiation stage of pituitary gland development. It has a key regulatory role in the formation of a sharp dorsal-ventral cell type margin through the inhibition of ''Shh'' ventral signals.

<pubmed>10588713</pubmed>

'''Tooth development'''

The cells and their layers that contribute to tooth development through odontogenesis (from week 6 of development) include:

*''Odontoblasts'': Mesenchymal cells of neural crest origin that produce predentin, which calcifies forming dentin in the process of dentinogenesis. Enamel epithelium causes odontoblast differentiation and these cells contribute to the outer dental pulp
*''Ameloblasts'': Derived from ectodermal cells of oral epithelium tissue. They differentiate from preameloblasts, activated by ectomesenchymal cells and produce enamel proteins such as amelogenin and enamelin to form enamel, the outer covering of the tooth’s crown.
*''Peridontal ligament'': Composed of connective tissue (bundles of collagen fibres), which secures the root of the tooth in the alveolar socket so it is not displaced. It surrounds the cementum of the tooth root.

===Lab 8===

'''Ovary development'''

Initially, the genital systems of both sexes are morphologically similar and sexual development hence begins as an indifferent stage with an indifferent (‘bipotential’) gonad later forming either the testis or ovary. Both gonads have contributions from; mesothelium of the posterior abdominal wall cavity, mesenchyme beneath this and primordial germ cells (PGCs) that later differentiate to form sex cells.

In Week 5 of development, a thickening of mesothelium forms on the medial portion of the primitive kidney (the mesonephros). The formation of the gonadal ridge results from the proliferation of the mesothelium and mesenchymal tissue beneath it, as a bulge on the medial mesonephros. Projection of finger-like gonadal (epithelial) cords into the mesenchyme follows, segmenting the indifferent gonad into an internal medulla (covered by germinal epithelium) and external cortex. For embryos with a sex chromosome complex of XX, the medulla regresses while the cortex of the indifferent gonad differentiates to form the ovary.

PGCs reside among dorsal endodermal cells of the umbilical vesicle whose dorsal part is incorporated into the embryo during folding. They are the first cell type migrating through the primitive streak in gastrulation (3rd week) and then reside at the junctional region of the hindgut yolk sac. Following this, there is migration of the PGCs to the gonadal ridge along the hindgut’s dorsal mesentery, regulated by BMP-4, fragilis and stella genes. In week 6, these germ cells are incorporated into the gonadal cords and are called oogonia, having entered underlying mesenchyme.

In female embryos, ovary development is a slow process, with the ovary not histologically identifiable until week 10. Ovary development relies on the genes of the XX chromosome along with an autosomal gene. Gonadal cords form a basic rete ovarii (network of canals) by extension into the internal medulla, although the cords are not notable in the embryonic ovary. The rete ovarii and gonadal cords usually degrade and cease to exist.

[[File:Bailey329.jpg|500px]]

'''Transverse section of the ovary of a fox embryo'''

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466385578-2 Moore: The Developing Human, 9th ed. Chapter 12]

===Lab 9===

====Group 1- Respiratory====

Overall, the project at this stage consists of a good integration of text, images and references throughout. The introduction is well-written and gives an overview of the two parts of the respiratory system (conducting and respiratory zones). I think it is a good idea that your group has split this up and explained both parts separately as it helps to orient an unknowing reader, especially as the gross anatomical structures are also described (e.g. trachea, larynx, bronchi). However, in-text referencing is needed in this introductory segment to provide the reader with the source of all information, exactly where it appears. You could refer to Dr Hill’s instructions on how to do this if needed, or see another group’s page on Edit mode. Also, the images used in the introduction should have a small caption beneath them, otherwise it is hard to tell what the images show exactly and how this may be relevant to the complementary text.

In terms of heading and subheading organisation, I like how you have split the content up into 5 main areas of introduction, lung development stages, current research models/findings, historic findings and abnormalities. This makes the page easy to navigate and the subheadings under each section are relevant. The use of a table in the ‘lung development stages’ section is very well done and appropriate, as it segments the information into a clean, readable format that a student could simply refer to if they were learning from scratch. The information in the table is succinct and provides all the main points. The only improvement here I would suggest, is aligning the content to the left, as it may seem more pleasing to the eye to have even spacing rather than centre alignment. Also, the ‘references’ have been placed as subheading 2.1, whereas the other ‘reference’ sections have not been given a separate subheading, so I would consider making this consistent throughout the project page.

The section on current research models and findings is concise and informative, with good use of numbering to make the information easier to read rather than having long and chunky paragraphs. Although a minor detail, there is one part that says “a study conducted last year”. Since these Wiki pages will be left online, it is important to specify the exact year here, and provide an in-text reference to the study mentioned so a reader can easily locate it. I like the use of dot points in this section, making it look appealing, however the image used should also include a caption, as should the others on the page. Be careful of copyright infringement regarding image use, as there appears to be a file with a ‘Permission Error’ in this section, which may need to be manually removed.

The ‘historic findings’ section was also well-done, especially because it used dot points to segment the information and show the exact years of each discovery. Once again though, the image requires a caption and the references for this section seem to be split into 2 parts; one list from 1-14 then another from 1-4. I think the list from 1-4 needs a subheading to show how those sources are different to the ones above it, otherwise both lists need to be integrated into one.There are also some parts that have coding showing </ol> and </li> which just need to be removed with editing.

Lastly, the section on abnormalities is also of a high standard as each abnormality begins with a brief description then goes into details by using dot points. There is good use of in-text referencing followed by a reference list which is correctly formatted too. The image included has a caption which is good, as other sections lack this, however I would consider adding more images to make this part more visually appealing and engaging to the reader. It is evident that a lot of work has been done on this page as each section is detailed and referenced well, with relevant information.

====Group 2- Renal====

The introduction provided by this project is very good and includes in-text citations. Not only does it introduce the renal system’s components but also discusses its development briefly into the embryonic and fetal stages, focusing more on fetal. Also, by having the references as one long list at the very end of the page, this gives the project a clean and tidy look, which some of the others lack. I thought this was a great idea and very orderly.

While some sections are full of information, others are scarce or empty, such as the ‘Historical findings’ section. Some information on the development of knowledge on the renal system throughout history should be included here, maybe making use of dot points detailing specific year dates. The ‘Developmental Timeline’ provides a good overview of the system’s development, although weeks 3-5 may not be necessary as these are during the embryonic period and the focus here is on fetal development. However, it does provide an overall context which is good. This information may also be effectively translated into a table format for easier readability.

The section on ‘current research models’ was nicely written, with solid analysis of 2 research articles. Using any more articles to that level of depth may be too much information, so this is a good balance. It was very good to see the text actually explaining the accompanying image, which was labelled with a caption too. The introduction to the use of animal models and why these are important was effective also.

I particularly thought the sub-sectioning of the page into the main organs of the renal system was a smart idea rather than having the entire system as a clump of information as this way, it is easier to navigate through the information. The ‘kidney’ section was of a very high standard as the information was relevant and nicely split into different processes of fetal development such as nephrogenesis and renin production. It is very helpful as a reader to have explanations of the images used, making the page more interactive and useful. However, this is a file with a ‘Permission error’ present which would need removal due to copyright infringement; this should be sorted out before the project is due.

The following three sections on the urethra, ureter and bladder were also well-written, referenced correctly with in-text citations and the images used were relevant to the text. However, captioning the image in the urethra section would be good to give the reader knowledge of exactly what it shows. The ‘abnormalities’ section was again, well -researched and full of information, however it seems a little cluttered as lengthy references are placed under the text. Integrating these into the overall reference list at the end of the page would look clearer.

Overall, this project has been well done and there is evidence of consistency throughout the section formatting, suggesting the group members have been communicating between each other, which is good to see. Some improvements I would suggest are the use of hand-drawn images to make it easier for a student to learn off the project, and using tables to summarise some information e.g. timeline.

====Group 3- Gastrointestinal====

The introduction part of this project provided a good overview of the gastrointestinal tract and its components, also mentioning briefly the changes that occur in the fetal period. However, care must be taken to not capitalise words that are not needed e.g. Foregut, Midgut, Appendix etc. Although the information in the ‘timeline’ section is relevant, its formatting needs a bit of review as there are inconsistencies between the foregut, midgut and hindgut parts. It also seems that the in-text citations have just been arbitrarily placed in chronological order, with each line having a new reference. Also, this information may be better presented in table format to improve readability. Some simple editing may be needed to fix this.

The section on ‘Recent findings’ has some good information, however the reference needs to be properly cited and maybe a couple more articles would help give this part some substance. I thought it was effective to have the GIT split into the foregut, midgut and hindgut and then detail the fetal development under those titles. This gave the page a good structure. However, adding some images, both from online and student-drawn to the foregut and hindgut sections would help improve the aesthetics of the page. The hand-drawn images on the midgut section are effective learning tools to a student, but maybe could be drawn a little neater with darker colours as the blue labelling is difficult to read. They should also be captioned. The use of a table to show midgut herniation of fetuses was a good tool as it makes the information easier to read also.

Lastly, the section on abnormalities was well-detailed and I liked that the deformities were split into a definition and cause. An image of gastrochisis may be helpful for a reader to visualise the condition though. The in-text citations in this part were properly done and a long list of references being at the end of the page made the project look neat overall. Areas of improvement may be some simple formatting changes and evening out the information across sections, however a solid project so far.

====Group 4- Genital====

Overall, it is evident that a lot of work has been completed on this project as each section has a decent amount of information and there are images throughout the page. However, the addition of an ‘introduction’ section would help to orient the reader and help students gain an overall understanding of the topic.

The section on ‘system development’ seems to be well-researched, however the formatting of the content in short, one-sentence dot points makes it difficult to read and incongruent, so writing this out in small paragraphs would improve the readability. The capitalization of some words is unnecessary in both the dot points and the table, creating inconsistencies in the formatting. Also, some words are unnecessarily bolded which detracts from the aesthetic appeal of the page. However, the inclusion of a table to summarise the timeline information is an effective tool, although there is much more information provided for the male system than female system. It is really good to see the use of an image as it is relevant and clearly compares the male and female system development side-by side. I also think the video inclusion is fantastic as it would be an effective way to learn for a reader with no previous knowledge, making the page more interactive.

The section on ‘current research, models and findings’ contains lots of relevant information, however this is not referenced in-text and it is thus unclear where the information has been derived from. There also seems to be some unevenness between the depth of information between male and female systems, which some more research can easily remedy. In terms of current findings, the listing of the information in dot points makes it easier to read, however there are some parts italicised and capitalized that are not needed. It is great to see some hand-drawn images as these are simplistic, colourful and effective ways to accompany the text, adding to the page’s appeal. Take care to properly include images, as one of them appears as ‘alt text’ and the link does not show the image itself. Although some references appear under a ‘references’ title in this section others appear as a website links; formatting of these could improve neatness.

The following section on ‘historic findings’ contains evidence of extensive research as it is very detailed and well-written. However, I would consider breaking this part up into smaller sections using dot points as large paragraphs seem tedious to read. The hand-drawn image is a good inclusion, but labelling of it would be effective and adding a couple more would break up the long section visually. Also, there seem to only be in-text citations after long chunks of information; perhaps more sources should be used/consulted.

Lastly, the abnormalities section was comprehensive and detailed and enough information was given on some examples. This was just the right amount of content, as any more would seem excessive. Adding some more images with appropriate captioning is advised also. I liked that the references were listed altogether at the end of the page, making it neat and tidy. Overall, a solid project which just needs some formatting to improve further.

====Group 5- Integumentary====

The introduction of this page was good as it provided a great overview and insight into what the project would later go on to discuss. Perhaps a little information on defining the integumentary system itself would be valuable though, to let the reader know the constituents.

The sub-sectioning of the page’s content into ‘introduction, ‘development overview’, ‘recent findings’, ‘historic findings’ and ‘abnormalities’ was clever, as the development section then went on to describe each component such as skin, nails etc. This effectively segmented the information into smaller chunks that could easily be navigated to. I especially liked the use of the table in the ‘skin’ section, showing the week of development, description and image corresponding alongside it, as it provided a holistic approach to that section. However, there were no in-text citations in the ‘skin’, ‘hair’, ‘nail’ or ‘teeth’ sections, hence the source of the information is unclear. To do this correctly, Dr Hill’s Wiki help page should be consulted.

The use of various images with labelled captions was a strength of this project, as the pictures were effective in balancing the text components to make the page more visually appealing. Most of the sections under ‘development overview’ have a decent amount of content, however the ‘nails’ part is a bit lacking and also needs to be correctly cited. The use of the table of images alongside the description of developmental stage in the ‘teeth’ section was very good to include, however the image is captioned ‘The stages of embryonic teeth development’. This may be irrelevant as the project’s focus is on fetal development. Further research into this area may uncover more relevant information.

Although the section on ‘recent findings’ contains a lot of information, the use of chunky paragraphs detracts from the readability of the page and the purple boxes could be summarised into dot points to help the reader understand the content more quickly. The section on historic findings seems concise and relevant, however the image included says it has been removed/deleted, so this requires editing. Lastly, the ‘abnormalities’ section was very well-structured and written, as each example had a captioned image accompanying it to help the reader visualise. This section was also well-done in terms of in-text citations, with an extensive reference list provided at the end. Perhaps consider adding some student-drawn images and possibly a relevant video, but otherwise it is very good as it is. Overall, the project has a good layout and a decent amount of content; with some editing and formatting it can be improved further.

====Group 7- Neural====

Overall, the project contains a decent amount of content as it is, split up into appropriate subheadings, considering the large scope of the nervous system. The introduction provides a succinct description of the CNS, however including an outline of what topics the page intends to cover would be good to orient a reader that approaches the page for the first time. The descriptions of the brain and spinal cord are well-written, however require in-text citations and some words need not be capitalised e.g midbrain, hypothalamus. These can be easily fixed with proof-reading and further editing.

The use of an image to illustrate fetal development was a very good idea; although the diagram is itself seems complicated, it can be explained well with the accompanying text beneath. The segmentation of the timeline into 4 different parts made it easier to follow, although I would consider placing the images on the right hand side of the page to reduce the vertical length of the page and the scrolling required to navigate through it. The section on ‘brain development’ contained some relevant information, formatted in dot points which improves readability, however in-text citations are needed to allow the reader to source the information if required. The use of the table in this part was effective also; it was concise and straight to the point.

Although the brain development section was very well detailed, there was no information in the spinal cord and meninges sections; with further research, these need to be evened out, along with the current findings section which is just references at this stage, but still a good start to finding sources of information. The section on current research is well-detailed and contains a lot of information too, which is good to see. Fiinally, I thought the section on abnormalities was very well done, using subheadings to segment the content. The use of dot points allowed the information to be easily read off the page, and use of images to accompany them helped the reader to visualise the conditions. There is one image however that has been incorrectly uploaded; consulting Dr Hill’s Wiki help page can remedy this. Also, the placement of all references under one list at the end of the page was effective in neatening it up, that was very well done too.

Overall, the project’s content has been well-researched and there is evidence of good teamwork and communication. Perhaps the use of some student-drawn images and inclusion of a relevant video may be areas of improvement.

====Group 8- Musculoskeletal====

Overall, the project has some very detailed sections and some sections where content is scarce. It would be helpful to start off with an introduction of the musculoskeletal system so the reader is aware of its components and what the page intends to cover. The timeline of muscle development has good potential, I understand it is still being planned at this stage and with further research, it could definitely be effective. A table format would be useful to present this information. The following sections on background embryonic development and fetal myogenesis are well-researched and have a lot of content, however I would consider breaking it down into dot points to improve readability. The sections are cited correctly in-text though, which is good to see.

There is much more improvement in the tendon and second trimester development sections, as the chunks of text have been reduced to provide a succinct summary, however these need to have citations also. The use of some images here, either hand-drawn or from online would be beneficial, to have a balance between text and pictures and make the page more visually appealing. Other than the abnormalities section which provides a good, concise summary of Duchenne Muscular Dystrophy, the following sections seem to be only references at this stage. As long as these are used to compose some relevant paragraphs/dot points, this is fine considering there is still time to improve the page.

Overall, this page has good potential as the groundwork has been completed; it is now more a matter of writing up more information, adding images and possibly a relevant video. The part on ‘making gains’ would need to be removed for the final, but otherwise, it is definitely a decent amount of work so far, especially considering the few group members involved.

===Lab 10===

'''Research article- Stage-dependent requirement of neuroretinal Pax6 for lens and retina development'''

'''Methods summary'''

Embryonic mouse stem cells from timed pregnant females were recombined in a homologous fashion to form floxed Pax-6 alleles in the experimental mice. These embryos were then harvested, fixed, PBS-washed, cryopreserved and sectioned for immunohistochemistry staining in which embryos were permeabilized and washed with PBT and incubated. This was followed by RNA in-situ hybridisation, where RNA polymerase was used to create antisense mRNA probes, then X-gal staining occurred.

The study then measured the length of the cell cycle phases of the mice embryos to assess the role of Pax6. Using wild-type littermates as controls, they found the proportion of proliferating retinal progenitor cells (RPCs) by injecting timed pregnant females with BrDU, then fixing, cryopreserving and sectioning them. Following this was a process of antigen retrieval with several incubations to calculate cell proliferation rate.

Finally, the cell cycle rate at embryonic days 11.5 and 13 were found and the cell cycle and S phase lengths were determined, also calculating the total length of the G1, G2 and M phases. These results were then quantified by statistical analysis using a t-test, counting 3 fields for every individual eye.

'''Results summary'''

By combining the findings of the separate sections of the experiment, the study concluded that Pax6 has an essential role in both lens and retinal cell formation. It was found that Pax6 deletion strong hypocellularity in early RPCs. There was high expression of Pax6 in the surface ectoderm (SE) and optic vesicle (OV) control embryos while the levels of Pax6 stayed constant and unchanged even after Pax6 elimination in the OV, lens pit and SE. The hypocellularity of the retina was more pronounced with time, and retinae deficient in Pax6 became smaller progressively.

Another finding was that the population size of the RPCs was reduced by changed cell cycle length and imbalance between cells exiting the cell cycle and proliferation of eye progenitor cells. It was again observed that retinal cells deficient in Pax6 were very hypocellular and cycling cells were centrally localised in the retina. An increased rate of cell death was observed with increasing time and total cell cycle length of Pax6-deficient RPCs was significantly longer than the control embryos. Also, the down-regulation of cyclin D1 in Pax6-deficient mice suggested that absence of Pax6 drives RPCs to cell cycle exit. Together, these findings suggested that positive progression of RPCs through the cell cycle is regulated by Pax6.

Finally, another conclusive result reached by this study was that the absence of Pax6 in RPCs causes a hindrance in their proper differentiation program into retinal cells; indicating the essential role of Pax6 in proliferation of early progenitors. It was also found that deficiency of Pax6 in optic vesicles could lead to the arrest of lens development during the interaction of the OV and SE. As neither the lens nor retina was formed properly in Pax6 deficient embryos, this indicated the importance of Pax6 presence in the optic vesicle for correct eye morphogenesis in the developing embryo.

<pubmed>24523460</pubmed>

[https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Vision_Development#Lens Sensory-Vision development Wiki page]

===Lab 11===

This study by Masumoto et al sought to explore the potential of human induced pluripotent stem cells (hiPSCs) to regenerate damaged cardiac tissue, in particular vascular cells and cardiomyocytes (CMs).

CMs and vascular cells were simultaneously induced using a differentiation protocol wherein the levels of gene expression of cardiac mesoderm and progenitor genes peaked at day 5 of differentiation. They found that mesoderm-to-CM differentiation enhancement occurred during days 5-7 due to Dkk1 addition (an antagonist). When vascular cell induction with CMs using VEGF was attempted instead of Dkk1, this led to induction of ECs and CMs together. The study found that the cell populations had a composition of vascular endothelial cadherin, platelet-derived growth factor receptor beta and positive MCs. These findings collectively suggested that a change from ‘only CMs’ to ‘CMS and vascular cells’ could be induced by selectively controlling the direction of differentiation of cardiovascular cells.

The experiment also tried to develop sheets of cardiovascular cells from hiPSCs by continuous culture, re-plating and incubations. It was found that reducing temperature served to re-assemble self-pulsating sheets of cells after heating and that sheets were composed of 3-4 layers supported by collagen fibres in a stratified manner. These sheets were shown to have CMs evenly distributed throughout them via immunohistochemical techniques. Within the cell sheets were; CMs, MCs and undifferentiated cells and this composition was attributed to possible apoptotic cell death reducing numbers and reduced proliferation efficiency. Together, these results suggested that it was the hiPSCs only that had generated the CMs and vascular cells, forming a structure that resembled cardiac tissue very realistically.

Lastly, Masumoto et al also found that the transplantation of hiPSCs with CTSs could alleviate dysfunctions in the cardiovascular system even after infarction in rats, as all rats had survived the period of post-transplantation without signs of tumours arising. Using echocardiogram technology, it was observed that anterior wall contraction had been brought back to normal, left ventricle systolic function had improved and that there had been reduced thickening of the wall of myocardial infarcts. Furthermore, staining with Sirius red found that the rate and extent of fibrosis was significantly reduced after hiPSC-CTS transplantation.

In conclusion, Masumoto et al concluded that there remained ample scope for hiPSCs to regenerate cardiac tissue and thus restore cardiac function, if their capabilities were studied more widely by other researchers. The replacement ability and biomedical potential of these pluripotent stem cells hold great promise for the future of stem cell therapy.

<pubmed>25336194</pubmed>

User:Z3418702

2014-10-28T13:47:08Z

Z3418702: /* Lab 11 */

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:45, 6 August 2014 (EST)

==Lab attendance==

Lab 1----[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:57, 6 August 2014 (EST)

http://www.ncbi.nlm.nih.gov/pubmed

[http://www.ncbi.nlm.nih.gov/pubmed Pubmed]

[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]

<pubmed>25084016</pubmed>

Lab 2 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:20, 13 August 2014 (EST)

Lab 3 ----[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 13:08, 20 August 2014 (EST)

Lab 4- --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:34, 27 August 2014 (EST)

Lab 5 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:58, 3 September 2014 (EST)

Lab 6 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:45, 10 September 2014 (EST)

Lab 7 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 11:16, 17 September 2014 (EST)

Lab 9 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:20, 8 October 2014 (EST)

Lab 10 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:11, 15 October 2014 (EST)

Lab 11 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:33, 22 October 2014 (EST)

==Online Assessments==

===Lab 1===

'''Article 1:''' <pubmed>24592092</pubmed>

This study was conducted by the IVF Center at Kocaeli University, Turkey. It aimed to test the effect of biochemical markers in follicular fluid, such as nitrous oxide (NO), reduced glutathione (GSH) and malondialdehyde (MDA) on the outcome of in vitro fertilisation. The researchers selected 62 infertile women, all of whom were aged between 25 and 32, were non-smokers, had no systemic diseases, and were suffering from unexplained infertility with no signs of hormonal or ovulatory issues.

Ovulation was first induced in the women using long and short agonists along with a microdose flare-up, after which an oocyte was collected. This was followed by intracytoplasmic sperm injection (ICSI) as the preferred method of fertilisation, then the transfer of the embryo took place. To collect the FF samples, the dominant follicles were chosen and samples were centrifuged, supernatants were removed and stored.

To measure MDA levels, MDA was mixed with thiobarbaturic acid (TBA) which reacted to form a red compound. This mixture was incubated, cooled and assayed to read the absorbance of the butanol phase, and results were expressed in micromoles of MDA. Similarly, levels of GSH were measured in micromoles/L after being supplemented with metaphosphoric acid and assayed. However, NO levels were measured indirectly by measuring the nitrate and nitrite sample concentrations, deproteinising the sample, then measuring absorbance at 545nm using Griess reagent, expressing NO levels in nanomoles/L.

The embryos were then graded in terms of the size of the blastomere and degree of fragmentation, into Grades A-C, A being an even blastomere with <10% fragmentation. A single Grade A embryo was then transferred into each woman on Day 3 of the trial, after which they were categorised into 2 groups based on blood concentration of human chorionic gonadotropin; successful pregnancy (Group 1) and unsuccessful pregnancy (Group 2).

Finally, to analyse these results, the researchers used the women’s pregnancy status following IVF as the primary outcome measure. Statistic analysis was carried out according to non-parametric Mann-Whitney U test. The study found that the successful pregnancy group had significantly lower levels of fluid NO and significantly higher levels of fluid MDA than the unsuccessful pregnancy group. In analysing the correlation between IVF parameters and oxidative stress, the findings showed a positive weak correlation of MDA with fertilisation rate and the number of Grade A embryos. Also, ROC curve analysis implicated MDA as a highly sensitive predictor of pregnancy. Due to this significant difference in MDA levels between groups 1 and 2, the study concluded that MDA was the most suitable indicator of IVF success out of the 3 biochemical markers chosen for analysis.

'''Article 2:''' <pubmed>24914407</pubmed>

The objective of this study was to research the possible association between levels of plasma D-dimer, a haemostatic marker, and the success or failure of pregnancy in women undergoing IVF. The researchers selected 105 infertile women from the Ortona General Hospital’s Assisted Reproduction Unit who were undergoing IVF, indicated by factors such as tubal factor, endometriosis, male factor, anovulation and unexplained infertility.

The participants underwent ovarian stimulation by receiving daily subcutaneous injections of recombinant FSH (follicle stimulating hormone) with doses varying based on basal FSH level, the age of the woman and antral follicle count. This stimulation was begun upon complete pituitary suppression on the 3rd day of the menstrual cycle, and throughout the stimulation, hormonal fluctuations of luteinising hormone (LH) were controlled by injecting agonists and antagonists of GnRH.

Following the collection of oocytes, intracytoplasmic sperm injection (ICSI) was used to perform IVF and an embryo transfer was carried out, 14 days after which a pregnancy test was taken. The presence of a gestational sac with a fetal heartbeat after 7 weeks of gestation was the criterion for a clinical pregnancy.This ovarian stimulation protocol was followed by a venous blood sample to test D-dimer concentrations, where a latex quantitative assay was used with 200ng/mL being the threshold level for an abnormal D-dimer level. These assay levels were statistically analysed using a Mann-Whitney U-test and T-test.

The results of the study indicated significantly higher levels of circulating D-dimer in women with a failed pregnancy following IVF in comparison to those with a clinical or successful pregnancy. This difference was statistically valid even when taking age and vascular risk factors into account. It was found that women with concentrations of D-dimer above the threshold had a more dismal pregnancy outcome, and that D-dimer levels increased after the one-week administration of GnRH. Overall, only 38% of the participants had achieved a clinical pregnancy and the study concluded that high D-dimer concentrations are implicated in a higher risk of a failed pregnancy following IVF. This was consistent with previous postulations that a possible mechanism for failure is unsuccessful implantation and placentation, owing to a hypercoagulable vascular state, leading to increased risk of thrombolic events in maternal vessels to the placenta.

--[[User:Z8600021|Mark Hill]] - Both these papers are recent and present interesting findings. It would have helped you summary in the second paper if you had described what plasma D-dimer was. Your summaries are both correct and concise (5/5).

===Lab 2===

[[File:Fertilisation of medusa eggs by spermatozoids in vitro in sea water.png|300px]]

Fertilisation of medusa eggs by spermatozoids in vitro in sea water<ref><pubmed>23185235</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0046542]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:28, 21 August 2014 (EST) This is all correct, I have fixed the reference link below. Please in future use a shorter image title and do not use .jpg in the image description above (I have removed for you). (4/5)

<references/>

===Lab 3===

'''Adrenal gland'''

<pubmed>7011178</pubmed>
<pubmed>24116052</pubmed>

'''Gonad development'''

<pubmed>17237341</pubmed>
<pubmed>7623307</pubmed>

'''Placenta'''

<pubmed>10419690</pubmed>
<pubmed>7673080</pubmed>

--[[User:Z8600021|Mark Hill] These references are appropriate, you should have included some descriptions, even a single line, with the reference (4/5).

===Lab 4===

'''Summary of research article'''

This study by Chang et al. observed the effect of varying the intratracheal transplantation time of umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) on the attenuation of hyperoxic lung injury in neonatal rats. It was concluded that the optimal time window for stem cell transplantation was narrow; efficient only during the early but not late phases of inflammation. The findings were in line with previous research that the anti-inflammatory properties of UCB-derived MSCs play a crucial therapeutic role in the alleviation of bronchopulmonary dysplasia (BPD), through reducing hypoxia-induced injuries including increased apoptosis and impaired alveolarisation.

Tissue sampling and analysis of lung histopathology found that the Hypoxia Control (HC) group showed fewer, larger and more abnormally-sized alveoli compared to the Normoxia Control (NC) group. However, upon transplantation of UCB-derived MSCs, these alveolar impairments and changes in morphology were attenuated, especially when added on post-natal day 3 (HT3) than on post-natal day 10 (HT10).

The study’s comparison of the levels of pro-inflammatory cytokines such as IL-6α, IL-6β and TNF-α before and after the addition of the UCB-derived MSCs found that such molecular markers were significantly lower after HT3 transplantation than HT10 transplantation. These levels were much lower than the initial starting levels exhibited by the NC group, indicating the therapeutic effect of the cord cells. Furthermore, the hypoxia-induced reduction in VEGF and HGF levels and increase in lung collagen levels were both attenuated by the addition of the MSCs.

These findings led to the conclusion that the therapeutic efficacy of UCB-derived MSCs on treating BPD is indeed time-dependent; having potent effects in the early inflammatory process, which is then reduced in later stages. The study also tested any potential synergistic effects of combined early and late MSCs intratracheal transplantation, but none were found.

<pubmed>23349686</pubmed>

'''Vascular shunts'''

The 3 developmental vascular shunts in the fetal circulation that close postnatally are:

''a) Ductus arteriosus (Ductus Botalli):'' Connects the pulmonary artery to the proximal descending part of the aortic arch and prevents the output of the right ventricle from entering the unexpanded fetal lung, which is fluid-filled and non-functioning. This shunt transfers medium oxygen saturated blood and becomes the ligamentum arteriosum after closing at birth.

''b) Ductus venosus:'' Shunts blood from the left umbilical vein to the inferior vena cava. This carries well-oxygenated blood and allows placental blood to bypass the liver ultimately to the fetal brain.

''c) Foramen ovale (Foramen Botalli):'' Shunts blood that is highly saturated with oxygen from the right atrium to the left atrium and becomes the fossa ovalis after closing at birth.

===Lab 5===

'''Bronchogenic Cysts'''

Bronchogenic cysts (BCs) are an unusual and rare congenital abnormality of the bronchial tree; a generally benign type of malformation of the bronchopulmonary foregut. The classification of these cysts is into; those occurring in the mediastinum (65-90%), which have equal prevalence between the sexes, or those of intrapulmonary origin (lung or pleura) which display a slight male predominance <ref name="PMID23762726"><pubmed>23762726</pubmed></ref> Other sites such as intradiaphragmatic and retroperitoneal are rare, and consequently require close attention.

These lesions are characteristically unilocular, mucus field cysts which arise from the posterior walls of airway membranes during embryonic development. They currently account for 20-30% of congenital cystic bronchopulmonary foregut abnormalities and for only 5-10% of paediatric mediastinal masses. <ref name="PMID23762726"><pubmed>23762726</pubmed></ref> Although the exact cause of bronchogenic cysts is yet to be established, current research postulates that that their developmental cause is the abnormal budding of the tracheal diverticulum and proximal bronchial structures during embryogenesis in weeks 4-6. Bronchogenic cysts stem from abnormal buds from the tracheobronchial tree or primitive esophagus which fail to extend to the site of alveolar differentiation. Generally, early separation causes the system to move into the mediastinum, however it is when this separation occurs late that a BC forms <ref name="PMID23762726"><pubmed>23762726</pubmed></ref>. Histologically, these abnormal bronchogenic cysts are lined by pseudostratified, ciliated, columnar or cuboidal secretory respiratory epithelium and their walls comprise typical structural components of the airways such as smooth muscle, cartilage and mucinous glands. Cysts are typically not filled with air as they lack communication with the bronchial tree, but contain fluid comprising blood, proteinaceous fluid and calcium oxalate, resulting in a solid lesion manifesting on radiographic imaging such as MRI and CT scans <ref name="PMID18292738"><pubmed>18292738</pubmed></ref>

BCs are considered to be the most common form of foregut duplication cysts and are a congenital anomaly as they are asymptomatic and rarely arise in infants with diagnosis usually occurring post-natally. The clinical presentation of cysts is usually either asymptomatic or through airway obstruction causing respiratory distress or cystic infection causing compression of central lung parenchyma <ref name="PMID18760579><pubmed>18760579</pubmed></ref>

<references/>

===Lab 7===

'''Research article- Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary gland development'''

This study by Kioussi et al. investigated the role of the transcription factor ''Pax6'' in creating a dorsal-ventral boundary between cell types of the developing pituitary gland. The researchers considered the physical location of the six cell types in the pituitary that originate from a common primordium- corticotropes, thyrotropes, menalotropes, gonadotropes, somatotropes and lactotropes. They specifically focused on the regulation of cell differentiation by ''Pax6'' and the effects of its absence.

Following analysis of mutant mice embryos with a ''Small eye'' (''Sey'') mutation and ''Pax6'' gene deletion, the study found that ''Pax6'' plays a significant role as an early dorsal marker of the pituitary gland’s development. They found that ''Pax6'' transcripts were expressed and present in the nascent Rathke’s pouch, however excluded from the ventral section of the Sonic hedgehog (''Shh'') pouch, leading to the formation of a ventral zone between cells expressing ''Pax6'' and those expressing ''Shh''. A dorsal-ventral gradient for cell differentiation was evident and ''Pax6'' was seen to be excluded from the rostral zone of the pituitary. These two particular findings suggested that ''Pax6'' may be an essential element of the ‘transcriptional apparatus’ responsible for determining the position of the six pituitary cell lineages.

Furthermore, the research concluded that the absence of ''Pax6'' leads to a decrease in dorsal cell types from the ''Pit-1'' lineage (somatotropes and lactotropes) and an increase in cell types with ventral phenotypes such as thyrotropes. This was confirmed by discovering that the expression patterns of four molecular ventral markers such as GATA2 were uniformly dorsalised, leading to further increase in the population of thyrotropes.

Hence, these results implicated that ''Pax6'' functions as a transcriptional regulator in opposition to ventral signalling molecules, thus clearly delineating the developing dorsal cells from ventral cells in the differentiation stage of pituitary gland development. It has a key regulatory role in the formation of a sharp dorsal-ventral cell type margin through the inhibition of ''Shh'' ventral signals.

<pubmed>10588713</pubmed>

'''Tooth development'''

The cells and their layers that contribute to tooth development through odontogenesis (from week 6 of development) include:

*''Odontoblasts'': Mesenchymal cells of neural crest origin that produce predentin, which calcifies forming dentin in the process of dentinogenesis. Enamel epithelium causes odontoblast differentiation and these cells contribute to the outer dental pulp
*''Ameloblasts'': Derived from ectodermal cells of oral epithelium tissue. They differentiate from preameloblasts, activated by ectomesenchymal cells and produce enamel proteins such as amelogenin and enamelin to form enamel, the outer covering of the tooth’s crown.
*''Peridontal ligament'': Composed of connective tissue (bundles of collagen fibres), which secures the root of the tooth in the alveolar socket so it is not displaced. It surrounds the cementum of the tooth root.

===Lab 8===

'''Ovary development'''

Initially, the genital systems of both sexes are morphologically similar and sexual development hence begins as an indifferent stage with an indifferent (‘bipotential’) gonad later forming either the testis or ovary. Both gonads have contributions from; mesothelium of the posterior abdominal wall cavity, mesenchyme beneath this and primordial germ cells (PGCs) that later differentiate to form sex cells.

In Week 5 of development, a thickening of mesothelium forms on the medial portion of the primitive kidney (the mesonephros). The formation of the gonadal ridge results from the proliferation of the mesothelium and mesenchymal tissue beneath it, as a bulge on the medial mesonephros. Projection of finger-like gonadal (epithelial) cords into the mesenchyme follows, segmenting the indifferent gonad into an internal medulla (covered by germinal epithelium) and external cortex. For embryos with a sex chromosome complex of XX, the medulla regresses while the cortex of the indifferent gonad differentiates to form the ovary.

PGCs reside among dorsal endodermal cells of the umbilical vesicle whose dorsal part is incorporated into the embryo during folding. They are the first cell type migrating through the primitive streak in gastrulation (3rd week) and then reside at the junctional region of the hindgut yolk sac. Following this, there is migration of the PGCs to the gonadal ridge along the hindgut’s dorsal mesentery, regulated by BMP-4, fragilis and stella genes. In week 6, these germ cells are incorporated into the gonadal cords and are called oogonia, having entered underlying mesenchyme.

In female embryos, ovary development is a slow process, with the ovary not histologically identifiable until week 10. Ovary development relies on the genes of the XX chromosome along with an autosomal gene. Gonadal cords form a basic rete ovarii (network of canals) by extension into the internal medulla, although the cords are not notable in the embryonic ovary. The rete ovarii and gonadal cords usually degrade and cease to exist.

[[File:Bailey329.jpg|500px]]

'''Transverse section of the ovary of a fox embryo'''

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466385578-2 Moore: The Developing Human, 9th ed. Chapter 12]

===Lab 9===

====Group 1- Respiratory====

Overall, the project at this stage consists of a good integration of text, images and references throughout. The introduction is well-written and gives an overview of the two parts of the respiratory system (conducting and respiratory zones). I think it is a good idea that your group has split this up and explained both parts separately as it helps to orient an unknowing reader, especially as the gross anatomical structures are also described (e.g. trachea, larynx, bronchi). However, in-text referencing is needed in this introductory segment to provide the reader with the source of all information, exactly where it appears. You could refer to Dr Hill’s instructions on how to do this if needed, or see another group’s page on Edit mode. Also, the images used in the introduction should have a small caption beneath them, otherwise it is hard to tell what the images show exactly and how this may be relevant to the complementary text.

In terms of heading and subheading organisation, I like how you have split the content up into 5 main areas of introduction, lung development stages, current research models/findings, historic findings and abnormalities. This makes the page easy to navigate and the subheadings under each section are relevant. The use of a table in the ‘lung development stages’ section is very well done and appropriate, as it segments the information into a clean, readable format that a student could simply refer to if they were learning from scratch. The information in the table is succinct and provides all the main points. The only improvement here I would suggest, is aligning the content to the left, as it may seem more pleasing to the eye to have even spacing rather than centre alignment. Also, the ‘references’ have been placed as subheading 2.1, whereas the other ‘reference’ sections have not been given a separate subheading, so I would consider making this consistent throughout the project page.

The section on current research models and findings is concise and informative, with good use of numbering to make the information easier to read rather than having long and chunky paragraphs. Although a minor detail, there is one part that says “a study conducted last year”. Since these Wiki pages will be left online, it is important to specify the exact year here, and provide an in-text reference to the study mentioned so a reader can easily locate it. I like the use of dot points in this section, making it look appealing, however the image used should also include a caption, as should the others on the page. Be careful of copyright infringement regarding image use, as there appears to be a file with a ‘Permission Error’ in this section, which may need to be manually removed.

The ‘historic findings’ section was also well-done, especially because it used dot points to segment the information and show the exact years of each discovery. Once again though, the image requires a caption and the references for this section seem to be split into 2 parts; one list from 1-14 then another from 1-4. I think the list from 1-4 needs a subheading to show how those sources are different to the ones above it, otherwise both lists need to be integrated into one.There are also some parts that have coding showing </ol> and </li> which just need to be removed with editing.

Lastly, the section on abnormalities is also of a high standard as each abnormality begins with a brief description then goes into details by using dot points. There is good use of in-text referencing followed by a reference list which is correctly formatted too. The image included has a caption which is good, as other sections lack this, however I would consider adding more images to make this part more visually appealing and engaging to the reader. It is evident that a lot of work has been done on this page as each section is detailed and referenced well, with relevant information.

====Group 2- Renal====

The introduction provided by this project is very good and includes in-text citations. Not only does it introduce the renal system’s components but also discusses its development briefly into the embryonic and fetal stages, focusing more on fetal. Also, by having the references as one long list at the very end of the page, this gives the project a clean and tidy look, which some of the others lack. I thought this was a great idea and very orderly.

While some sections are full of information, others are scarce or empty, such as the ‘Historical findings’ section. Some information on the development of knowledge on the renal system throughout history should be included here, maybe making use of dot points detailing specific year dates. The ‘Developmental Timeline’ provides a good overview of the system’s development, although weeks 3-5 may not be necessary as these are during the embryonic period and the focus here is on fetal development. However, it does provide an overall context which is good. This information may also be effectively translated into a table format for easier readability.

The section on ‘current research models’ was nicely written, with solid analysis of 2 research articles. Using any more articles to that level of depth may be too much information, so this is a good balance. It was very good to see the text actually explaining the accompanying image, which was labelled with a caption too. The introduction to the use of animal models and why these are important was effective also.

I particularly thought the sub-sectioning of the page into the main organs of the renal system was a smart idea rather than having the entire system as a clump of information as this way, it is easier to navigate through the information. The ‘kidney’ section was of a very high standard as the information was relevant and nicely split into different processes of fetal development such as nephrogenesis and renin production. It is very helpful as a reader to have explanations of the images used, making the page more interactive and useful. However, this is a file with a ‘Permission error’ present which would need removal due to copyright infringement; this should be sorted out before the project is due.

The following three sections on the urethra, ureter and bladder were also well-written, referenced correctly with in-text citations and the images used were relevant to the text. However, captioning the image in the urethra section would be good to give the reader knowledge of exactly what it shows. The ‘abnormalities’ section was again, well -researched and full of information, however it seems a little cluttered as lengthy references are placed under the text. Integrating these into the overall reference list at the end of the page would look clearer.

Overall, this project has been well done and there is evidence of consistency throughout the section formatting, suggesting the group members have been communicating between each other, which is good to see. Some improvements I would suggest are the use of hand-drawn images to make it easier for a student to learn off the project, and using tables to summarise some information e.g. timeline.

====Group 3- Gastrointestinal====

The introduction part of this project provided a good overview of the gastrointestinal tract and its components, also mentioning briefly the changes that occur in the fetal period. However, care must be taken to not capitalise words that are not needed e.g. Foregut, Midgut, Appendix etc. Although the information in the ‘timeline’ section is relevant, its formatting needs a bit of review as there are inconsistencies between the foregut, midgut and hindgut parts. It also seems that the in-text citations have just been arbitrarily placed in chronological order, with each line having a new reference. Also, this information may be better presented in table format to improve readability. Some simple editing may be needed to fix this.

The section on ‘Recent findings’ has some good information, however the reference needs to be properly cited and maybe a couple more articles would help give this part some substance. I thought it was effective to have the GIT split into the foregut, midgut and hindgut and then detail the fetal development under those titles. This gave the page a good structure. However, adding some images, both from online and student-drawn to the foregut and hindgut sections would help improve the aesthetics of the page. The hand-drawn images on the midgut section are effective learning tools to a student, but maybe could be drawn a little neater with darker colours as the blue labelling is difficult to read. They should also be captioned. The use of a table to show midgut herniation of fetuses was a good tool as it makes the information easier to read also.

Lastly, the section on abnormalities was well-detailed and I liked that the deformities were split into a definition and cause. An image of gastrochisis may be helpful for a reader to visualise the condition though. The in-text citations in this part were properly done and a long list of references being at the end of the page made the project look neat overall. Areas of improvement may be some simple formatting changes and evening out the information across sections, however a solid project so far.

====Group 4- Genital====

Overall, it is evident that a lot of work has been completed on this project as each section has a decent amount of information and there are images throughout the page. However, the addition of an ‘introduction’ section would help to orient the reader and help students gain an overall understanding of the topic.

The section on ‘system development’ seems to be well-researched, however the formatting of the content in short, one-sentence dot points makes it difficult to read and incongruent, so writing this out in small paragraphs would improve the readability. The capitalization of some words is unnecessary in both the dot points and the table, creating inconsistencies in the formatting. Also, some words are unnecessarily bolded which detracts from the aesthetic appeal of the page. However, the inclusion of a table to summarise the timeline information is an effective tool, although there is much more information provided for the male system than female system. It is really good to see the use of an image as it is relevant and clearly compares the male and female system development side-by side. I also think the video inclusion is fantastic as it would be an effective way to learn for a reader with no previous knowledge, making the page more interactive.

The section on ‘current research, models and findings’ contains lots of relevant information, however this is not referenced in-text and it is thus unclear where the information has been derived from. There also seems to be some unevenness between the depth of information between male and female systems, which some more research can easily remedy. In terms of current findings, the listing of the information in dot points makes it easier to read, however there are some parts italicised and capitalized that are not needed. It is great to see some hand-drawn images as these are simplistic, colourful and effective ways to accompany the text, adding to the page’s appeal. Take care to properly include images, as one of them appears as ‘alt text’ and the link does not show the image itself. Although some references appear under a ‘references’ title in this section others appear as a website links; formatting of these could improve neatness.

The following section on ‘historic findings’ contains evidence of extensive research as it is very detailed and well-written. However, I would consider breaking this part up into smaller sections using dot points as large paragraphs seem tedious to read. The hand-drawn image is a good inclusion, but labelling of it would be effective and adding a couple more would break up the long section visually. Also, there seem to only be in-text citations after long chunks of information; perhaps more sources should be used/consulted.

Lastly, the abnormalities section was comprehensive and detailed and enough information was given on some examples. This was just the right amount of content, as any more would seem excessive. Adding some more images with appropriate captioning is advised also. I liked that the references were listed altogether at the end of the page, making it neat and tidy. Overall, a solid project which just needs some formatting to improve further.

====Group 5- Integumentary====

The introduction of this page was good as it provided a great overview and insight into what the project would later go on to discuss. Perhaps a little information on defining the integumentary system itself would be valuable though, to let the reader know the constituents.

The sub-sectioning of the page’s content into ‘introduction, ‘development overview’, ‘recent findings’, ‘historic findings’ and ‘abnormalities’ was clever, as the development section then went on to describe each component such as skin, nails etc. This effectively segmented the information into smaller chunks that could easily be navigated to. I especially liked the use of the table in the ‘skin’ section, showing the week of development, description and image corresponding alongside it, as it provided a holistic approach to that section. However, there were no in-text citations in the ‘skin’, ‘hair’, ‘nail’ or ‘teeth’ sections, hence the source of the information is unclear. To do this correctly, Dr Hill’s Wiki help page should be consulted.

The use of various images with labelled captions was a strength of this project, as the pictures were effective in balancing the text components to make the page more visually appealing. Most of the sections under ‘development overview’ have a decent amount of content, however the ‘nails’ part is a bit lacking and also needs to be correctly cited. The use of the table of images alongside the description of developmental stage in the ‘teeth’ section was very good to include, however the image is captioned ‘The stages of embryonic teeth development’. This may be irrelevant as the project’s focus is on fetal development. Further research into this area may uncover more relevant information.

Although the section on ‘recent findings’ contains a lot of information, the use of chunky paragraphs detracts from the readability of the page and the purple boxes could be summarised into dot points to help the reader understand the content more quickly. The section on historic findings seems concise and relevant, however the image included says it has been removed/deleted, so this requires editing. Lastly, the ‘abnormalities’ section was very well-structured and written, as each example had a captioned image accompanying it to help the reader visualise. This section was also well-done in terms of in-text citations, with an extensive reference list provided at the end. Perhaps consider adding some student-drawn images and possibly a relevant video, but otherwise it is very good as it is. Overall, the project has a good layout and a decent amount of content; with some editing and formatting it can be improved further.

====Group 7- Neural====

Overall, the project contains a decent amount of content as it is, split up into appropriate subheadings, considering the large scope of the nervous system. The introduction provides a succinct description of the CNS, however including an outline of what topics the page intends to cover would be good to orient a reader that approaches the page for the first time. The descriptions of the brain and spinal cord are well-written, however require in-text citations and some words need not be capitalised e.g midbrain, hypothalamus. These can be easily fixed with proof-reading and further editing.

The use of an image to illustrate fetal development was a very good idea; although the diagram is itself seems complicated, it can be explained well with the accompanying text beneath. The segmentation of the timeline into 4 different parts made it easier to follow, although I would consider placing the images on the right hand side of the page to reduce the vertical length of the page and the scrolling required to navigate through it. The section on ‘brain development’ contained some relevant information, formatted in dot points which improves readability, however in-text citations are needed to allow the reader to source the information if required. The use of the table in this part was effective also; it was concise and straight to the point.

Although the brain development section was very well detailed, there was no information in the spinal cord and meninges sections; with further research, these need to be evened out, along with the current findings section which is just references at this stage, but still a good start to finding sources of information. The section on current research is well-detailed and contains a lot of information too, which is good to see. Fiinally, I thought the section on abnormalities was very well done, using subheadings to segment the content. The use of dot points allowed the information to be easily read off the page, and use of images to accompany them helped the reader to visualise the conditions. There is one image however that has been incorrectly uploaded; consulting Dr Hill’s Wiki help page can remedy this. Also, the placement of all references under one list at the end of the page was effective in neatening it up, that was very well done too.

Overall, the project’s content has been well-researched and there is evidence of good teamwork and communication. Perhaps the use of some student-drawn images and inclusion of a relevant video may be areas of improvement.

====Group 8- Musculoskeletal====

Overall, the project has some very detailed sections and some sections where content is scarce. It would be helpful to start off with an introduction of the musculoskeletal system so the reader is aware of its components and what the page intends to cover. The timeline of muscle development has good potential, I understand it is still being planned at this stage and with further research, it could definitely be effective. A table format would be useful to present this information. The following sections on background embryonic development and fetal myogenesis are well-researched and have a lot of content, however I would consider breaking it down into dot points to improve readability. The sections are cited correctly in-text though, which is good to see.

There is much more improvement in the tendon and second trimester development sections, as the chunks of text have been reduced to provide a succinct summary, however these need to have citations also. The use of some images here, either hand-drawn or from online would be beneficial, to have a balance between text and pictures and make the page more visually appealing. Other than the abnormalities section which provides a good, concise summary of Duchenne Muscular Dystrophy, the following sections seem to be only references at this stage. As long as these are used to compose some relevant paragraphs/dot points, this is fine considering there is still time to improve the page.

Overall, this page has good potential as the groundwork has been completed; it is now more a matter of writing up more information, adding images and possibly a relevant video. The part on ‘making gains’ would need to be removed for the final, but otherwise, it is definitely a decent amount of work so far, especially considering the few group members involved.

===Lab 10===

'''Research article- Stage-dependent requirement of neuroretinal Pax6 for lens and retina development'''

'''Methods summary'''

Embryonic mouse stem cells from timed pregnant females were recombined in a homologous fashion to form floxed Pax-6 alleles in the experimental mice. These embryos were then harvested, fixed, PBS-washed, cryopreserved and sectioned for immunohistochemistry staining in which embryos were permeabilized and washed with PBT and incubated. This was followed by RNA in-situ hybridisation, where RNA polymerase was used to create antisense mRNA probes, then X-gal staining occurred.

The study then measured the length of the cell cycle phases of the mice embryos to assess the role of Pax6. Using wild-type littermates as controls, they found the proportion of proliferating retinal progenitor cells (RPCs) by injecting timed pregnant females with BrDU, then fixing, cryopreserving and sectioning them. Following this was a process of antigen retrieval with several incubations to calculate cell proliferation rate.

Finally, the cell cycle rate at embryonic days 11.5 and 13 were found and the cell cycle and S phase lengths were determined, also calculating the total length of the G1, G2 and M phases. These results were then quantified by statistical analysis using a t-test, counting 3 fields for every individual eye.

'''Results summary'''

By combining the findings of the separate sections of the experiment, the study concluded that Pax6 has an essential role in both lens and retinal cell formation. It was found that Pax6 deletion strong hypocellularity in early RPCs. There was high expression of Pax6 in the surface ectoderm (SE) and optic vesicle (OV) control embryos while the levels of Pax6 stayed constant and unchanged even after Pax6 elimination in the OV, lens pit and SE. The hypocellularity of the retina was more pronounced with time, and retinae deficient in Pax6 became smaller progressively.

Another finding was that the population size of the RPCs was reduced by changed cell cycle length and imbalance between cells exiting the cell cycle and proliferation of eye progenitor cells. It was again observed that retinal cells deficient in Pax6 were very hypocellular and cycling cells were centrally localised in the retina. An increased rate of cell death was observed with increasing time and total cell cycle length of Pax6-deficient RPCs was significantly longer than the control embryos. Also, the down-regulation of cyclin D1 in Pax6-deficient mice suggested that absence of Pax6 drives RPCs to cell cycle exit. Together, these findings suggested that positive progression of RPCs through the cell cycle is regulated by Pax6.

Finally, another conclusive result reached by this study was that the absence of Pax6 in RPCs causes a hindrance in their proper differentiation program into retinal cells; indicating the essential role of Pax6 in proliferation of early progenitors. It was also found that deficiency of Pax6 in optic vesicles could lead to the arrest of lens development during the interaction of the OV and SE. As neither the lens nor retina was formed properly in Pax6 deficient embryos, this indicated the importance of Pax6 presence in the optic vesicle for correct eye morphogenesis in the developing embryo.

<pubmed>24523460</pubmed>

[https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Vision_Development#Lens Sensory-Vision development Wiki page]

===Lab 11===

This study by Hidetoshi et al sought to explore the potential of human induced pluripotent stem cells (hiPSCs) to regenerate damaged cardiac tissue, in particular vascular cells and cardiomyocytes (CMs).

CMs and vascular cells were simultaneously induced using a differentiation protocol wherein the levels of gene expression of cardiac mesoderm and progenitor genes peaked at day 5 of differentiation. They found that mesoderm-to-CM differentiation enhancement occurred during days 5-7 due to Dkk1 addition (an antagonist). When vascular cell induction with CMs using VEGF was attempted instead of Dkk1, this led to induction of ECs and CMs together. The study found that the cell populations had a composition of vascular endothelial cadherin, platelet-derived growth factor receptor beta and positive MCs. These findings collectively suggested that a change from ‘only CMs’ to ‘CMS and vascular cells’ could be induced by selectively controlling the direction of differentiation of cardiovascular cells.

The experiment also tried to develop sheets of cardiovascular cells from hiPSCs by continuous culture, re-plating and incubations. It was found that reducing temperature served to re-assemble self-pulsating sheets of cells after heating and that sheets were composed of 3-4 layers supported by collagen fibres in a stratified manner. These sheets were shown to have CMs evenly distributed throughout them via immunohistochemical techniques. Within the cell sheets were; CMs, MCs and undifferentiated cells and this composition was attributed to possible apoptotic cell death reducing numbers and reduced proliferation efficiency. Together, these results suggested that it was the hiPSCs only that had generated the CMs and vascular cells, forming a structure that resembled cardiac tissue very realistically.

Lastly, Hidetoshi et al also found that the transplantation of hiPSCs with CTSs could alleviate dysfunctions in the cardiovascular system even after infarction in rats, as all rats had survived the period of post-transplantation without signs of tumours arising. Using echocardiogram technoogy, it was observed that anterior wall contraction had been brought back to normal, left ventricle systolic function had improved and that there had been reduced thickening of the wall of myocardial infarcts. Furthermore, staining with Sirius red found that the rate and extent of fibrosis was significantly reduced after hiPSC-CTS transplantation.

In conclusion, Hidetoshi et al concluded that there remained ample scope for hiPSCs to regenerate cardiac tissue and thus restore cardiac function, if their capabilities were studied more widely by other researchers. The replacement ability and biomedical potential of these pluripotent stem cells hold great promise for the future of stem cell therapy.

<pubmed>25336194</pubmed>

User:Z3418702

2014-10-28T13:45:43Z

Z3418702: /* Lab 11 */

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:45, 6 August 2014 (EST)

==Lab attendance==

Lab 1----[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:57, 6 August 2014 (EST)

http://www.ncbi.nlm.nih.gov/pubmed

[http://www.ncbi.nlm.nih.gov/pubmed Pubmed]

[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]

<pubmed>25084016</pubmed>

Lab 2 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:20, 13 August 2014 (EST)

Lab 3 ----[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 13:08, 20 August 2014 (EST)

Lab 4- --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:34, 27 August 2014 (EST)

Lab 5 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:58, 3 September 2014 (EST)

Lab 6 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:45, 10 September 2014 (EST)

Lab 7 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 11:16, 17 September 2014 (EST)

Lab 9 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:20, 8 October 2014 (EST)

Lab 10 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:11, 15 October 2014 (EST)

Lab 11 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:33, 22 October 2014 (EST)

==Online Assessments==

===Lab 1===

'''Article 1:''' <pubmed>24592092</pubmed>

This study was conducted by the IVF Center at Kocaeli University, Turkey. It aimed to test the effect of biochemical markers in follicular fluid, such as nitrous oxide (NO), reduced glutathione (GSH) and malondialdehyde (MDA) on the outcome of in vitro fertilisation. The researchers selected 62 infertile women, all of whom were aged between 25 and 32, were non-smokers, had no systemic diseases, and were suffering from unexplained infertility with no signs of hormonal or ovulatory issues.

Ovulation was first induced in the women using long and short agonists along with a microdose flare-up, after which an oocyte was collected. This was followed by intracytoplasmic sperm injection (ICSI) as the preferred method of fertilisation, then the transfer of the embryo took place. To collect the FF samples, the dominant follicles were chosen and samples were centrifuged, supernatants were removed and stored.

To measure MDA levels, MDA was mixed with thiobarbaturic acid (TBA) which reacted to form a red compound. This mixture was incubated, cooled and assayed to read the absorbance of the butanol phase, and results were expressed in micromoles of MDA. Similarly, levels of GSH were measured in micromoles/L after being supplemented with metaphosphoric acid and assayed. However, NO levels were measured indirectly by measuring the nitrate and nitrite sample concentrations, deproteinising the sample, then measuring absorbance at 545nm using Griess reagent, expressing NO levels in nanomoles/L.

The embryos were then graded in terms of the size of the blastomere and degree of fragmentation, into Grades A-C, A being an even blastomere with <10% fragmentation. A single Grade A embryo was then transferred into each woman on Day 3 of the trial, after which they were categorised into 2 groups based on blood concentration of human chorionic gonadotropin; successful pregnancy (Group 1) and unsuccessful pregnancy (Group 2).

Finally, to analyse these results, the researchers used the women’s pregnancy status following IVF as the primary outcome measure. Statistic analysis was carried out according to non-parametric Mann-Whitney U test. The study found that the successful pregnancy group had significantly lower levels of fluid NO and significantly higher levels of fluid MDA than the unsuccessful pregnancy group. In analysing the correlation between IVF parameters and oxidative stress, the findings showed a positive weak correlation of MDA with fertilisation rate and the number of Grade A embryos. Also, ROC curve analysis implicated MDA as a highly sensitive predictor of pregnancy. Due to this significant difference in MDA levels between groups 1 and 2, the study concluded that MDA was the most suitable indicator of IVF success out of the 3 biochemical markers chosen for analysis.

'''Article 2:''' <pubmed>24914407</pubmed>

The objective of this study was to research the possible association between levels of plasma D-dimer, a haemostatic marker, and the success or failure of pregnancy in women undergoing IVF. The researchers selected 105 infertile women from the Ortona General Hospital’s Assisted Reproduction Unit who were undergoing IVF, indicated by factors such as tubal factor, endometriosis, male factor, anovulation and unexplained infertility.

The participants underwent ovarian stimulation by receiving daily subcutaneous injections of recombinant FSH (follicle stimulating hormone) with doses varying based on basal FSH level, the age of the woman and antral follicle count. This stimulation was begun upon complete pituitary suppression on the 3rd day of the menstrual cycle, and throughout the stimulation, hormonal fluctuations of luteinising hormone (LH) were controlled by injecting agonists and antagonists of GnRH.

Following the collection of oocytes, intracytoplasmic sperm injection (ICSI) was used to perform IVF and an embryo transfer was carried out, 14 days after which a pregnancy test was taken. The presence of a gestational sac with a fetal heartbeat after 7 weeks of gestation was the criterion for a clinical pregnancy.This ovarian stimulation protocol was followed by a venous blood sample to test D-dimer concentrations, where a latex quantitative assay was used with 200ng/mL being the threshold level for an abnormal D-dimer level. These assay levels were statistically analysed using a Mann-Whitney U-test and T-test.

The results of the study indicated significantly higher levels of circulating D-dimer in women with a failed pregnancy following IVF in comparison to those with a clinical or successful pregnancy. This difference was statistically valid even when taking age and vascular risk factors into account. It was found that women with concentrations of D-dimer above the threshold had a more dismal pregnancy outcome, and that D-dimer levels increased after the one-week administration of GnRH. Overall, only 38% of the participants had achieved a clinical pregnancy and the study concluded that high D-dimer concentrations are implicated in a higher risk of a failed pregnancy following IVF. This was consistent with previous postulations that a possible mechanism for failure is unsuccessful implantation and placentation, owing to a hypercoagulable vascular state, leading to increased risk of thrombolic events in maternal vessels to the placenta.

--[[User:Z8600021|Mark Hill]] - Both these papers are recent and present interesting findings. It would have helped you summary in the second paper if you had described what plasma D-dimer was. Your summaries are both correct and concise (5/5).

===Lab 2===

[[File:Fertilisation of medusa eggs by spermatozoids in vitro in sea water.png|300px]]

Fertilisation of medusa eggs by spermatozoids in vitro in sea water<ref><pubmed>23185235</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0046542]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:28, 21 August 2014 (EST) This is all correct, I have fixed the reference link below. Please in future use a shorter image title and do not use .jpg in the image description above (I have removed for you). (4/5)

<references/>

===Lab 3===

'''Adrenal gland'''

<pubmed>7011178</pubmed>
<pubmed>24116052</pubmed>

'''Gonad development'''

<pubmed>17237341</pubmed>
<pubmed>7623307</pubmed>

'''Placenta'''

<pubmed>10419690</pubmed>
<pubmed>7673080</pubmed>

--[[User:Z8600021|Mark Hill] These references are appropriate, you should have included some descriptions, even a single line, with the reference (4/5).

===Lab 4===

'''Summary of research article'''

This study by Chang et al. observed the effect of varying the intratracheal transplantation time of umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) on the attenuation of hyperoxic lung injury in neonatal rats. It was concluded that the optimal time window for stem cell transplantation was narrow; efficient only during the early but not late phases of inflammation. The findings were in line with previous research that the anti-inflammatory properties of UCB-derived MSCs play a crucial therapeutic role in the alleviation of bronchopulmonary dysplasia (BPD), through reducing hypoxia-induced injuries including increased apoptosis and impaired alveolarisation.

Tissue sampling and analysis of lung histopathology found that the Hypoxia Control (HC) group showed fewer, larger and more abnormally-sized alveoli compared to the Normoxia Control (NC) group. However, upon transplantation of UCB-derived MSCs, these alveolar impairments and changes in morphology were attenuated, especially when added on post-natal day 3 (HT3) than on post-natal day 10 (HT10).

The study’s comparison of the levels of pro-inflammatory cytokines such as IL-6α, IL-6β and TNF-α before and after the addition of the UCB-derived MSCs found that such molecular markers were significantly lower after HT3 transplantation than HT10 transplantation. These levels were much lower than the initial starting levels exhibited by the NC group, indicating the therapeutic effect of the cord cells. Furthermore, the hypoxia-induced reduction in VEGF and HGF levels and increase in lung collagen levels were both attenuated by the addition of the MSCs.

These findings led to the conclusion that the therapeutic efficacy of UCB-derived MSCs on treating BPD is indeed time-dependent; having potent effects in the early inflammatory process, which is then reduced in later stages. The study also tested any potential synergistic effects of combined early and late MSCs intratracheal transplantation, but none were found.

<pubmed>23349686</pubmed>

'''Vascular shunts'''

The 3 developmental vascular shunts in the fetal circulation that close postnatally are:

''a) Ductus arteriosus (Ductus Botalli):'' Connects the pulmonary artery to the proximal descending part of the aortic arch and prevents the output of the right ventricle from entering the unexpanded fetal lung, which is fluid-filled and non-functioning. This shunt transfers medium oxygen saturated blood and becomes the ligamentum arteriosum after closing at birth.

''b) Ductus venosus:'' Shunts blood from the left umbilical vein to the inferior vena cava. This carries well-oxygenated blood and allows placental blood to bypass the liver ultimately to the fetal brain.

''c) Foramen ovale (Foramen Botalli):'' Shunts blood that is highly saturated with oxygen from the right atrium to the left atrium and becomes the fossa ovalis after closing at birth.

===Lab 5===

'''Bronchogenic Cysts'''

Bronchogenic cysts (BCs) are an unusual and rare congenital abnormality of the bronchial tree; a generally benign type of malformation of the bronchopulmonary foregut. The classification of these cysts is into; those occurring in the mediastinum (65-90%), which have equal prevalence between the sexes, or those of intrapulmonary origin (lung or pleura) which display a slight male predominance <ref name="PMID23762726"><pubmed>23762726</pubmed></ref> Other sites such as intradiaphragmatic and retroperitoneal are rare, and consequently require close attention.

These lesions are characteristically unilocular, mucus field cysts which arise from the posterior walls of airway membranes during embryonic development. They currently account for 20-30% of congenital cystic bronchopulmonary foregut abnormalities and for only 5-10% of paediatric mediastinal masses. <ref name="PMID23762726"><pubmed>23762726</pubmed></ref> Although the exact cause of bronchogenic cysts is yet to be established, current research postulates that that their developmental cause is the abnormal budding of the tracheal diverticulum and proximal bronchial structures during embryogenesis in weeks 4-6. Bronchogenic cysts stem from abnormal buds from the tracheobronchial tree or primitive esophagus which fail to extend to the site of alveolar differentiation. Generally, early separation causes the system to move into the mediastinum, however it is when this separation occurs late that a BC forms <ref name="PMID23762726"><pubmed>23762726</pubmed></ref>. Histologically, these abnormal bronchogenic cysts are lined by pseudostratified, ciliated, columnar or cuboidal secretory respiratory epithelium and their walls comprise typical structural components of the airways such as smooth muscle, cartilage and mucinous glands. Cysts are typically not filled with air as they lack communication with the bronchial tree, but contain fluid comprising blood, proteinaceous fluid and calcium oxalate, resulting in a solid lesion manifesting on radiographic imaging such as MRI and CT scans <ref name="PMID18292738"><pubmed>18292738</pubmed></ref>

BCs are considered to be the most common form of foregut duplication cysts and are a congenital anomaly as they are asymptomatic and rarely arise in infants with diagnosis usually occurring post-natally. The clinical presentation of cysts is usually either asymptomatic or through airway obstruction causing respiratory distress or cystic infection causing compression of central lung parenchyma <ref name="PMID18760579><pubmed>18760579</pubmed></ref>

<references/>

===Lab 7===

'''Research article- Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary gland development'''

This study by Kioussi et al. investigated the role of the transcription factor ''Pax6'' in creating a dorsal-ventral boundary between cell types of the developing pituitary gland. The researchers considered the physical location of the six cell types in the pituitary that originate from a common primordium- corticotropes, thyrotropes, menalotropes, gonadotropes, somatotropes and lactotropes. They specifically focused on the regulation of cell differentiation by ''Pax6'' and the effects of its absence.

Following analysis of mutant mice embryos with a ''Small eye'' (''Sey'') mutation and ''Pax6'' gene deletion, the study found that ''Pax6'' plays a significant role as an early dorsal marker of the pituitary gland’s development. They found that ''Pax6'' transcripts were expressed and present in the nascent Rathke’s pouch, however excluded from the ventral section of the Sonic hedgehog (''Shh'') pouch, leading to the formation of a ventral zone between cells expressing ''Pax6'' and those expressing ''Shh''. A dorsal-ventral gradient for cell differentiation was evident and ''Pax6'' was seen to be excluded from the rostral zone of the pituitary. These two particular findings suggested that ''Pax6'' may be an essential element of the ‘transcriptional apparatus’ responsible for determining the position of the six pituitary cell lineages.

Furthermore, the research concluded that the absence of ''Pax6'' leads to a decrease in dorsal cell types from the ''Pit-1'' lineage (somatotropes and lactotropes) and an increase in cell types with ventral phenotypes such as thyrotropes. This was confirmed by discovering that the expression patterns of four molecular ventral markers such as GATA2 were uniformly dorsalised, leading to further increase in the population of thyrotropes.

Hence, these results implicated that ''Pax6'' functions as a transcriptional regulator in opposition to ventral signalling molecules, thus clearly delineating the developing dorsal cells from ventral cells in the differentiation stage of pituitary gland development. It has a key regulatory role in the formation of a sharp dorsal-ventral cell type margin through the inhibition of ''Shh'' ventral signals.

<pubmed>10588713</pubmed>

'''Tooth development'''

The cells and their layers that contribute to tooth development through odontogenesis (from week 6 of development) include:

*''Odontoblasts'': Mesenchymal cells of neural crest origin that produce predentin, which calcifies forming dentin in the process of dentinogenesis. Enamel epithelium causes odontoblast differentiation and these cells contribute to the outer dental pulp
*''Ameloblasts'': Derived from ectodermal cells of oral epithelium tissue. They differentiate from preameloblasts, activated by ectomesenchymal cells and produce enamel proteins such as amelogenin and enamelin to form enamel, the outer covering of the tooth’s crown.
*''Peridontal ligament'': Composed of connective tissue (bundles of collagen fibres), which secures the root of the tooth in the alveolar socket so it is not displaced. It surrounds the cementum of the tooth root.

===Lab 8===

'''Ovary development'''

Initially, the genital systems of both sexes are morphologically similar and sexual development hence begins as an indifferent stage with an indifferent (‘bipotential’) gonad later forming either the testis or ovary. Both gonads have contributions from; mesothelium of the posterior abdominal wall cavity, mesenchyme beneath this and primordial germ cells (PGCs) that later differentiate to form sex cells.

In Week 5 of development, a thickening of mesothelium forms on the medial portion of the primitive kidney (the mesonephros). The formation of the gonadal ridge results from the proliferation of the mesothelium and mesenchymal tissue beneath it, as a bulge on the medial mesonephros. Projection of finger-like gonadal (epithelial) cords into the mesenchyme follows, segmenting the indifferent gonad into an internal medulla (covered by germinal epithelium) and external cortex. For embryos with a sex chromosome complex of XX, the medulla regresses while the cortex of the indifferent gonad differentiates to form the ovary.

PGCs reside among dorsal endodermal cells of the umbilical vesicle whose dorsal part is incorporated into the embryo during folding. They are the first cell type migrating through the primitive streak in gastrulation (3rd week) and then reside at the junctional region of the hindgut yolk sac. Following this, there is migration of the PGCs to the gonadal ridge along the hindgut’s dorsal mesentery, regulated by BMP-4, fragilis and stella genes. In week 6, these germ cells are incorporated into the gonadal cords and are called oogonia, having entered underlying mesenchyme.

In female embryos, ovary development is a slow process, with the ovary not histologically identifiable until week 10. Ovary development relies on the genes of the XX chromosome along with an autosomal gene. Gonadal cords form a basic rete ovarii (network of canals) by extension into the internal medulla, although the cords are not notable in the embryonic ovary. The rete ovarii and gonadal cords usually degrade and cease to exist.

[[File:Bailey329.jpg|500px]]

'''Transverse section of the ovary of a fox embryo'''

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466385578-2 Moore: The Developing Human, 9th ed. Chapter 12]

===Lab 9===

====Group 1- Respiratory====

Overall, the project at this stage consists of a good integration of text, images and references throughout. The introduction is well-written and gives an overview of the two parts of the respiratory system (conducting and respiratory zones). I think it is a good idea that your group has split this up and explained both parts separately as it helps to orient an unknowing reader, especially as the gross anatomical structures are also described (e.g. trachea, larynx, bronchi). However, in-text referencing is needed in this introductory segment to provide the reader with the source of all information, exactly where it appears. You could refer to Dr Hill’s instructions on how to do this if needed, or see another group’s page on Edit mode. Also, the images used in the introduction should have a small caption beneath them, otherwise it is hard to tell what the images show exactly and how this may be relevant to the complementary text.

In terms of heading and subheading organisation, I like how you have split the content up into 5 main areas of introduction, lung development stages, current research models/findings, historic findings and abnormalities. This makes the page easy to navigate and the subheadings under each section are relevant. The use of a table in the ‘lung development stages’ section is very well done and appropriate, as it segments the information into a clean, readable format that a student could simply refer to if they were learning from scratch. The information in the table is succinct and provides all the main points. The only improvement here I would suggest, is aligning the content to the left, as it may seem more pleasing to the eye to have even spacing rather than centre alignment. Also, the ‘references’ have been placed as subheading 2.1, whereas the other ‘reference’ sections have not been given a separate subheading, so I would consider making this consistent throughout the project page.

The section on current research models and findings is concise and informative, with good use of numbering to make the information easier to read rather than having long and chunky paragraphs. Although a minor detail, there is one part that says “a study conducted last year”. Since these Wiki pages will be left online, it is important to specify the exact year here, and provide an in-text reference to the study mentioned so a reader can easily locate it. I like the use of dot points in this section, making it look appealing, however the image used should also include a caption, as should the others on the page. Be careful of copyright infringement regarding image use, as there appears to be a file with a ‘Permission Error’ in this section, which may need to be manually removed.

The ‘historic findings’ section was also well-done, especially because it used dot points to segment the information and show the exact years of each discovery. Once again though, the image requires a caption and the references for this section seem to be split into 2 parts; one list from 1-14 then another from 1-4. I think the list from 1-4 needs a subheading to show how those sources are different to the ones above it, otherwise both lists need to be integrated into one.There are also some parts that have coding showing </ol> and </li> which just need to be removed with editing.

Lastly, the section on abnormalities is also of a high standard as each abnormality begins with a brief description then goes into details by using dot points. There is good use of in-text referencing followed by a reference list which is correctly formatted too. The image included has a caption which is good, as other sections lack this, however I would consider adding more images to make this part more visually appealing and engaging to the reader. It is evident that a lot of work has been done on this page as each section is detailed and referenced well, with relevant information.

====Group 2- Renal====

The introduction provided by this project is very good and includes in-text citations. Not only does it introduce the renal system’s components but also discusses its development briefly into the embryonic and fetal stages, focusing more on fetal. Also, by having the references as one long list at the very end of the page, this gives the project a clean and tidy look, which some of the others lack. I thought this was a great idea and very orderly.

While some sections are full of information, others are scarce or empty, such as the ‘Historical findings’ section. Some information on the development of knowledge on the renal system throughout history should be included here, maybe making use of dot points detailing specific year dates. The ‘Developmental Timeline’ provides a good overview of the system’s development, although weeks 3-5 may not be necessary as these are during the embryonic period and the focus here is on fetal development. However, it does provide an overall context which is good. This information may also be effectively translated into a table format for easier readability.

The section on ‘current research models’ was nicely written, with solid analysis of 2 research articles. Using any more articles to that level of depth may be too much information, so this is a good balance. It was very good to see the text actually explaining the accompanying image, which was labelled with a caption too. The introduction to the use of animal models and why these are important was effective also.

I particularly thought the sub-sectioning of the page into the main organs of the renal system was a smart idea rather than having the entire system as a clump of information as this way, it is easier to navigate through the information. The ‘kidney’ section was of a very high standard as the information was relevant and nicely split into different processes of fetal development such as nephrogenesis and renin production. It is very helpful as a reader to have explanations of the images used, making the page more interactive and useful. However, this is a file with a ‘Permission error’ present which would need removal due to copyright infringement; this should be sorted out before the project is due.

The following three sections on the urethra, ureter and bladder were also well-written, referenced correctly with in-text citations and the images used were relevant to the text. However, captioning the image in the urethra section would be good to give the reader knowledge of exactly what it shows. The ‘abnormalities’ section was again, well -researched and full of information, however it seems a little cluttered as lengthy references are placed under the text. Integrating these into the overall reference list at the end of the page would look clearer.

Overall, this project has been well done and there is evidence of consistency throughout the section formatting, suggesting the group members have been communicating between each other, which is good to see. Some improvements I would suggest are the use of hand-drawn images to make it easier for a student to learn off the project, and using tables to summarise some information e.g. timeline.

====Group 3- Gastrointestinal====

The introduction part of this project provided a good overview of the gastrointestinal tract and its components, also mentioning briefly the changes that occur in the fetal period. However, care must be taken to not capitalise words that are not needed e.g. Foregut, Midgut, Appendix etc. Although the information in the ‘timeline’ section is relevant, its formatting needs a bit of review as there are inconsistencies between the foregut, midgut and hindgut parts. It also seems that the in-text citations have just been arbitrarily placed in chronological order, with each line having a new reference. Also, this information may be better presented in table format to improve readability. Some simple editing may be needed to fix this.

The section on ‘Recent findings’ has some good information, however the reference needs to be properly cited and maybe a couple more articles would help give this part some substance. I thought it was effective to have the GIT split into the foregut, midgut and hindgut and then detail the fetal development under those titles. This gave the page a good structure. However, adding some images, both from online and student-drawn to the foregut and hindgut sections would help improve the aesthetics of the page. The hand-drawn images on the midgut section are effective learning tools to a student, but maybe could be drawn a little neater with darker colours as the blue labelling is difficult to read. They should also be captioned. The use of a table to show midgut herniation of fetuses was a good tool as it makes the information easier to read also.

Lastly, the section on abnormalities was well-detailed and I liked that the deformities were split into a definition and cause. An image of gastrochisis may be helpful for a reader to visualise the condition though. The in-text citations in this part were properly done and a long list of references being at the end of the page made the project look neat overall. Areas of improvement may be some simple formatting changes and evening out the information across sections, however a solid project so far.

====Group 4- Genital====

Overall, it is evident that a lot of work has been completed on this project as each section has a decent amount of information and there are images throughout the page. However, the addition of an ‘introduction’ section would help to orient the reader and help students gain an overall understanding of the topic.

The section on ‘system development’ seems to be well-researched, however the formatting of the content in short, one-sentence dot points makes it difficult to read and incongruent, so writing this out in small paragraphs would improve the readability. The capitalization of some words is unnecessary in both the dot points and the table, creating inconsistencies in the formatting. Also, some words are unnecessarily bolded which detracts from the aesthetic appeal of the page. However, the inclusion of a table to summarise the timeline information is an effective tool, although there is much more information provided for the male system than female system. It is really good to see the use of an image as it is relevant and clearly compares the male and female system development side-by side. I also think the video inclusion is fantastic as it would be an effective way to learn for a reader with no previous knowledge, making the page more interactive.

The section on ‘current research, models and findings’ contains lots of relevant information, however this is not referenced in-text and it is thus unclear where the information has been derived from. There also seems to be some unevenness between the depth of information between male and female systems, which some more research can easily remedy. In terms of current findings, the listing of the information in dot points makes it easier to read, however there are some parts italicised and capitalized that are not needed. It is great to see some hand-drawn images as these are simplistic, colourful and effective ways to accompany the text, adding to the page’s appeal. Take care to properly include images, as one of them appears as ‘alt text’ and the link does not show the image itself. Although some references appear under a ‘references’ title in this section others appear as a website links; formatting of these could improve neatness.

The following section on ‘historic findings’ contains evidence of extensive research as it is very detailed and well-written. However, I would consider breaking this part up into smaller sections using dot points as large paragraphs seem tedious to read. The hand-drawn image is a good inclusion, but labelling of it would be effective and adding a couple more would break up the long section visually. Also, there seem to only be in-text citations after long chunks of information; perhaps more sources should be used/consulted.

Lastly, the abnormalities section was comprehensive and detailed and enough information was given on some examples. This was just the right amount of content, as any more would seem excessive. Adding some more images with appropriate captioning is advised also. I liked that the references were listed altogether at the end of the page, making it neat and tidy. Overall, a solid project which just needs some formatting to improve further.

====Group 5- Integumentary====

The introduction of this page was good as it provided a great overview and insight into what the project would later go on to discuss. Perhaps a little information on defining the integumentary system itself would be valuable though, to let the reader know the constituents.

The sub-sectioning of the page’s content into ‘introduction, ‘development overview’, ‘recent findings’, ‘historic findings’ and ‘abnormalities’ was clever, as the development section then went on to describe each component such as skin, nails etc. This effectively segmented the information into smaller chunks that could easily be navigated to. I especially liked the use of the table in the ‘skin’ section, showing the week of development, description and image corresponding alongside it, as it provided a holistic approach to that section. However, there were no in-text citations in the ‘skin’, ‘hair’, ‘nail’ or ‘teeth’ sections, hence the source of the information is unclear. To do this correctly, Dr Hill’s Wiki help page should be consulted.

The use of various images with labelled captions was a strength of this project, as the pictures were effective in balancing the text components to make the page more visually appealing. Most of the sections under ‘development overview’ have a decent amount of content, however the ‘nails’ part is a bit lacking and also needs to be correctly cited. The use of the table of images alongside the description of developmental stage in the ‘teeth’ section was very good to include, however the image is captioned ‘The stages of embryonic teeth development’. This may be irrelevant as the project’s focus is on fetal development. Further research into this area may uncover more relevant information.

Although the section on ‘recent findings’ contains a lot of information, the use of chunky paragraphs detracts from the readability of the page and the purple boxes could be summarised into dot points to help the reader understand the content more quickly. The section on historic findings seems concise and relevant, however the image included says it has been removed/deleted, so this requires editing. Lastly, the ‘abnormalities’ section was very well-structured and written, as each example had a captioned image accompanying it to help the reader visualise. This section was also well-done in terms of in-text citations, with an extensive reference list provided at the end. Perhaps consider adding some student-drawn images and possibly a relevant video, but otherwise it is very good as it is. Overall, the project has a good layout and a decent amount of content; with some editing and formatting it can be improved further.

====Group 7- Neural====

Overall, the project contains a decent amount of content as it is, split up into appropriate subheadings, considering the large scope of the nervous system. The introduction provides a succinct description of the CNS, however including an outline of what topics the page intends to cover would be good to orient a reader that approaches the page for the first time. The descriptions of the brain and spinal cord are well-written, however require in-text citations and some words need not be capitalised e.g midbrain, hypothalamus. These can be easily fixed with proof-reading and further editing.

The use of an image to illustrate fetal development was a very good idea; although the diagram is itself seems complicated, it can be explained well with the accompanying text beneath. The segmentation of the timeline into 4 different parts made it easier to follow, although I would consider placing the images on the right hand side of the page to reduce the vertical length of the page and the scrolling required to navigate through it. The section on ‘brain development’ contained some relevant information, formatted in dot points which improves readability, however in-text citations are needed to allow the reader to source the information if required. The use of the table in this part was effective also; it was concise and straight to the point.

Although the brain development section was very well detailed, there was no information in the spinal cord and meninges sections; with further research, these need to be evened out, along with the current findings section which is just references at this stage, but still a good start to finding sources of information. The section on current research is well-detailed and contains a lot of information too, which is good to see. Fiinally, I thought the section on abnormalities was very well done, using subheadings to segment the content. The use of dot points allowed the information to be easily read off the page, and use of images to accompany them helped the reader to visualise the conditions. There is one image however that has been incorrectly uploaded; consulting Dr Hill’s Wiki help page can remedy this. Also, the placement of all references under one list at the end of the page was effective in neatening it up, that was very well done too.

Overall, the project’s content has been well-researched and there is evidence of good teamwork and communication. Perhaps the use of some student-drawn images and inclusion of a relevant video may be areas of improvement.

====Group 8- Musculoskeletal====

Overall, the project has some very detailed sections and some sections where content is scarce. It would be helpful to start off with an introduction of the musculoskeletal system so the reader is aware of its components and what the page intends to cover. The timeline of muscle development has good potential, I understand it is still being planned at this stage and with further research, it could definitely be effective. A table format would be useful to present this information. The following sections on background embryonic development and fetal myogenesis are well-researched and have a lot of content, however I would consider breaking it down into dot points to improve readability. The sections are cited correctly in-text though, which is good to see.

There is much more improvement in the tendon and second trimester development sections, as the chunks of text have been reduced to provide a succinct summary, however these need to have citations also. The use of some images here, either hand-drawn or from online would be beneficial, to have a balance between text and pictures and make the page more visually appealing. Other than the abnormalities section which provides a good, concise summary of Duchenne Muscular Dystrophy, the following sections seem to be only references at this stage. As long as these are used to compose some relevant paragraphs/dot points, this is fine considering there is still time to improve the page.

Overall, this page has good potential as the groundwork has been completed; it is now more a matter of writing up more information, adding images and possibly a relevant video. The part on ‘making gains’ would need to be removed for the final, but otherwise, it is definitely a decent amount of work so far, especially considering the few group members involved.

===Lab 10===

'''Research article- Stage-dependent requirement of neuroretinal Pax6 for lens and retina development'''

'''Methods summary'''

Embryonic mouse stem cells from timed pregnant females were recombined in a homologous fashion to form floxed Pax-6 alleles in the experimental mice. These embryos were then harvested, fixed, PBS-washed, cryopreserved and sectioned for immunohistochemistry staining in which embryos were permeabilized and washed with PBT and incubated. This was followed by RNA in-situ hybridisation, where RNA polymerase was used to create antisense mRNA probes, then X-gal staining occurred.

The study then measured the length of the cell cycle phases of the mice embryos to assess the role of Pax6. Using wild-type littermates as controls, they found the proportion of proliferating retinal progenitor cells (RPCs) by injecting timed pregnant females with BrDU, then fixing, cryopreserving and sectioning them. Following this was a process of antigen retrieval with several incubations to calculate cell proliferation rate.

Finally, the cell cycle rate at embryonic days 11.5 and 13 were found and the cell cycle and S phase lengths were determined, also calculating the total length of the G1, G2 and M phases. These results were then quantified by statistical analysis using a t-test, counting 3 fields for every individual eye.

'''Results summary'''

By combining the findings of the separate sections of the experiment, the study concluded that Pax6 has an essential role in both lens and retinal cell formation. It was found that Pax6 deletion strong hypocellularity in early RPCs. There was high expression of Pax6 in the surface ectoderm (SE) and optic vesicle (OV) control embryos while the levels of Pax6 stayed constant and unchanged even after Pax6 elimination in the OV, lens pit and SE. The hypocellularity of the retina was more pronounced with time, and retinae deficient in Pax6 became smaller progressively.

Another finding was that the population size of the RPCs was reduced by changed cell cycle length and imbalance between cells exiting the cell cycle and proliferation of eye progenitor cells. It was again observed that retinal cells deficient in Pax6 were very hypocellular and cycling cells were centrally localised in the retina. An increased rate of cell death was observed with increasing time and total cell cycle length of Pax6-deficient RPCs was significantly longer than the control embryos. Also, the down-regulation of cyclin D1 in Pax6-deficient mice suggested that absence of Pax6 drives RPCs to cell cycle exit. Together, these findings suggested that positive progression of RPCs through the cell cycle is regulated by Pax6.

Finally, another conclusive result reached by this study was that the absence of Pax6 in RPCs causes a hindrance in their proper differentiation program into retinal cells; indicating the essential role of Pax6 in proliferation of early progenitors. It was also found that deficiency of Pax6 in optic vesicles could lead to the arrest of lens development during the interaction of the OV and SE. As neither the lens nor retina was formed properly in Pax6 deficient embryos, this indicated the importance of Pax6 presence in the optic vesicle for correct eye morphogenesis in the developing embryo.

<pubmed>24523460</pubmed>

[https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Vision_Development#Lens Sensory-Vision development Wiki page]

===Lab 11===

This study by Hidetoshi et al sought to explore the potential of human induced pluripotent stem cells (hiPSCs) to regenerate damaged cardiac tissue, in particular vascular cells and cardiomyocytes (CMs).

CMs and vascular cells were simultaneously induced using a differentiation protocol wherein the levels of gene expression of cardiac mesoderm and progenitor genes peaked at day 5 of differentiation. They found that mesoderm-to-CM differentiation enhancement occurred during days 5-7 due to Dkk1 addition (an antagonist). When vascular cell induction with CMs using VEGF was attempted instead of Dkk1, this led to induction of ECs and CMs together. The study found that the cell populations had a composition of vascular endothelial cadherin, platelet-derived growth factor receptor beta and positive MCs. These findings collectively suggested that a change from ‘only CMs’ to ‘CMS and vascular cells’ could be induced by selectively controlling the direction of differentiation of cardiovascular cells.

The experiment also tried to develop sheets of cardiovascular cells from hiPSCs by continuous culture, re-plating and incubations. It was found that reducing temperature served to re-assemble self-pulsating sheets of cells after heating and that sheets were composed of 3-4 layers supported by collagen fibres in a stratified manner. These sheets were shown to have CMs evenly distributed throughout them via immunohistochemical techniques. Within the cell sheets were; CMs, MCs and undifferentiated cells and this composition was attributed to possible apoptotic cell death reducing numbers and reduced proliferation efficiency. Together, these results suggested that it was the hiPSCs only that had generated the CMs and vascular cells, forming a structure that resembled cardiac tissue very realistically.

Lastly, Hidetoshi et al also found that the transplantation of hiPSCs with CTSs could alleviate dysfunctions in the cardiovascular system even after infarction in rats, as all rats had survived the period of post-transplantation without signs of tumours arising. Using echocardiogram technoogy, it was observed that anterior wall contraction had been brought back to normal, left ventricle systolic function had improved and that there had been reduced thickening of the wall of myocardial infarcts. Furthermore, staining with Sirius red found that the rate and extent of fibrosis was significantly reduced after hiPSC-CTS transplantation.

In conclusion, Hidetoshi et al concluded that there remained ample scope for hiPSCs to regenerate cardiac tissue and thus restore cardiac function, if their capabilities were studied more widely by other researchers. The replacement ability and biomedical potential of these pluripotent stem cells hold great promise for the future of stem cell therapy.

<pubmed>25336194</pubmed>

User:Z3418702

2014-10-28T13:41:09Z

Z3418702:

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:45, 6 August 2014 (EST)

==Lab attendance==

Lab 1----[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:57, 6 August 2014 (EST)

http://www.ncbi.nlm.nih.gov/pubmed

[http://www.ncbi.nlm.nih.gov/pubmed Pubmed]

[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]

<pubmed>25084016</pubmed>

Lab 2 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:20, 13 August 2014 (EST)

Lab 3 ----[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 13:08, 20 August 2014 (EST)

Lab 4- --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:34, 27 August 2014 (EST)

Lab 5 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:58, 3 September 2014 (EST)

Lab 6 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:45, 10 September 2014 (EST)

Lab 7 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 11:16, 17 September 2014 (EST)

Lab 9 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:20, 8 October 2014 (EST)

Lab 10 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:11, 15 October 2014 (EST)

Lab 11 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:33, 22 October 2014 (EST)

==Online Assessments==

===Lab 1===

'''Article 1:''' <pubmed>24592092</pubmed>

This study was conducted by the IVF Center at Kocaeli University, Turkey. It aimed to test the effect of biochemical markers in follicular fluid, such as nitrous oxide (NO), reduced glutathione (GSH) and malondialdehyde (MDA) on the outcome of in vitro fertilisation. The researchers selected 62 infertile women, all of whom were aged between 25 and 32, were non-smokers, had no systemic diseases, and were suffering from unexplained infertility with no signs of hormonal or ovulatory issues.

Ovulation was first induced in the women using long and short agonists along with a microdose flare-up, after which an oocyte was collected. This was followed by intracytoplasmic sperm injection (ICSI) as the preferred method of fertilisation, then the transfer of the embryo took place. To collect the FF samples, the dominant follicles were chosen and samples were centrifuged, supernatants were removed and stored.

To measure MDA levels, MDA was mixed with thiobarbaturic acid (TBA) which reacted to form a red compound. This mixture was incubated, cooled and assayed to read the absorbance of the butanol phase, and results were expressed in micromoles of MDA. Similarly, levels of GSH were measured in micromoles/L after being supplemented with metaphosphoric acid and assayed. However, NO levels were measured indirectly by measuring the nitrate and nitrite sample concentrations, deproteinising the sample, then measuring absorbance at 545nm using Griess reagent, expressing NO levels in nanomoles/L.

The embryos were then graded in terms of the size of the blastomere and degree of fragmentation, into Grades A-C, A being an even blastomere with <10% fragmentation. A single Grade A embryo was then transferred into each woman on Day 3 of the trial, after which they were categorised into 2 groups based on blood concentration of human chorionic gonadotropin; successful pregnancy (Group 1) and unsuccessful pregnancy (Group 2).

Finally, to analyse these results, the researchers used the women’s pregnancy status following IVF as the primary outcome measure. Statistic analysis was carried out according to non-parametric Mann-Whitney U test. The study found that the successful pregnancy group had significantly lower levels of fluid NO and significantly higher levels of fluid MDA than the unsuccessful pregnancy group. In analysing the correlation between IVF parameters and oxidative stress, the findings showed a positive weak correlation of MDA with fertilisation rate and the number of Grade A embryos. Also, ROC curve analysis implicated MDA as a highly sensitive predictor of pregnancy. Due to this significant difference in MDA levels between groups 1 and 2, the study concluded that MDA was the most suitable indicator of IVF success out of the 3 biochemical markers chosen for analysis.

'''Article 2:''' <pubmed>24914407</pubmed>

The objective of this study was to research the possible association between levels of plasma D-dimer, a haemostatic marker, and the success or failure of pregnancy in women undergoing IVF. The researchers selected 105 infertile women from the Ortona General Hospital’s Assisted Reproduction Unit who were undergoing IVF, indicated by factors such as tubal factor, endometriosis, male factor, anovulation and unexplained infertility.

The participants underwent ovarian stimulation by receiving daily subcutaneous injections of recombinant FSH (follicle stimulating hormone) with doses varying based on basal FSH level, the age of the woman and antral follicle count. This stimulation was begun upon complete pituitary suppression on the 3rd day of the menstrual cycle, and throughout the stimulation, hormonal fluctuations of luteinising hormone (LH) were controlled by injecting agonists and antagonists of GnRH.

Following the collection of oocytes, intracytoplasmic sperm injection (ICSI) was used to perform IVF and an embryo transfer was carried out, 14 days after which a pregnancy test was taken. The presence of a gestational sac with a fetal heartbeat after 7 weeks of gestation was the criterion for a clinical pregnancy.This ovarian stimulation protocol was followed by a venous blood sample to test D-dimer concentrations, where a latex quantitative assay was used with 200ng/mL being the threshold level for an abnormal D-dimer level. These assay levels were statistically analysed using a Mann-Whitney U-test and T-test.

The results of the study indicated significantly higher levels of circulating D-dimer in women with a failed pregnancy following IVF in comparison to those with a clinical or successful pregnancy. This difference was statistically valid even when taking age and vascular risk factors into account. It was found that women with concentrations of D-dimer above the threshold had a more dismal pregnancy outcome, and that D-dimer levels increased after the one-week administration of GnRH. Overall, only 38% of the participants had achieved a clinical pregnancy and the study concluded that high D-dimer concentrations are implicated in a higher risk of a failed pregnancy following IVF. This was consistent with previous postulations that a possible mechanism for failure is unsuccessful implantation and placentation, owing to a hypercoagulable vascular state, leading to increased risk of thrombolic events in maternal vessels to the placenta.

--[[User:Z8600021|Mark Hill]] - Both these papers are recent and present interesting findings. It would have helped you summary in the second paper if you had described what plasma D-dimer was. Your summaries are both correct and concise (5/5).

===Lab 2===

[[File:Fertilisation of medusa eggs by spermatozoids in vitro in sea water.png|300px]]

Fertilisation of medusa eggs by spermatozoids in vitro in sea water<ref><pubmed>23185235</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0046542]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:28, 21 August 2014 (EST) This is all correct, I have fixed the reference link below. Please in future use a shorter image title and do not use .jpg in the image description above (I have removed for you). (4/5)

<references/>

===Lab 3===

'''Adrenal gland'''

<pubmed>7011178</pubmed>
<pubmed>24116052</pubmed>

'''Gonad development'''

<pubmed>17237341</pubmed>
<pubmed>7623307</pubmed>

'''Placenta'''

<pubmed>10419690</pubmed>
<pubmed>7673080</pubmed>

--[[User:Z8600021|Mark Hill] These references are appropriate, you should have included some descriptions, even a single line, with the reference (4/5).

===Lab 4===

'''Summary of research article'''

This study by Chang et al. observed the effect of varying the intratracheal transplantation time of umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) on the attenuation of hyperoxic lung injury in neonatal rats. It was concluded that the optimal time window for stem cell transplantation was narrow; efficient only during the early but not late phases of inflammation. The findings were in line with previous research that the anti-inflammatory properties of UCB-derived MSCs play a crucial therapeutic role in the alleviation of bronchopulmonary dysplasia (BPD), through reducing hypoxia-induced injuries including increased apoptosis and impaired alveolarisation.

Tissue sampling and analysis of lung histopathology found that the Hypoxia Control (HC) group showed fewer, larger and more abnormally-sized alveoli compared to the Normoxia Control (NC) group. However, upon transplantation of UCB-derived MSCs, these alveolar impairments and changes in morphology were attenuated, especially when added on post-natal day 3 (HT3) than on post-natal day 10 (HT10).

The study’s comparison of the levels of pro-inflammatory cytokines such as IL-6α, IL-6β and TNF-α before and after the addition of the UCB-derived MSCs found that such molecular markers were significantly lower after HT3 transplantation than HT10 transplantation. These levels were much lower than the initial starting levels exhibited by the NC group, indicating the therapeutic effect of the cord cells. Furthermore, the hypoxia-induced reduction in VEGF and HGF levels and increase in lung collagen levels were both attenuated by the addition of the MSCs.

These findings led to the conclusion that the therapeutic efficacy of UCB-derived MSCs on treating BPD is indeed time-dependent; having potent effects in the early inflammatory process, which is then reduced in later stages. The study also tested any potential synergistic effects of combined early and late MSCs intratracheal transplantation, but none were found.

<pubmed>23349686</pubmed>

'''Vascular shunts'''

The 3 developmental vascular shunts in the fetal circulation that close postnatally are:

''a) Ductus arteriosus (Ductus Botalli):'' Connects the pulmonary artery to the proximal descending part of the aortic arch and prevents the output of the right ventricle from entering the unexpanded fetal lung, which is fluid-filled and non-functioning. This shunt transfers medium oxygen saturated blood and becomes the ligamentum arteriosum after closing at birth.

''b) Ductus venosus:'' Shunts blood from the left umbilical vein to the inferior vena cava. This carries well-oxygenated blood and allows placental blood to bypass the liver ultimately to the fetal brain.

''c) Foramen ovale (Foramen Botalli):'' Shunts blood that is highly saturated with oxygen from the right atrium to the left atrium and becomes the fossa ovalis after closing at birth.

===Lab 5===

'''Bronchogenic Cysts'''

Bronchogenic cysts (BCs) are an unusual and rare congenital abnormality of the bronchial tree; a generally benign type of malformation of the bronchopulmonary foregut. The classification of these cysts is into; those occurring in the mediastinum (65-90%), which have equal prevalence between the sexes, or those of intrapulmonary origin (lung or pleura) which display a slight male predominance <ref name="PMID23762726"><pubmed>23762726</pubmed></ref> Other sites such as intradiaphragmatic and retroperitoneal are rare, and consequently require close attention.

These lesions are characteristically unilocular, mucus field cysts which arise from the posterior walls of airway membranes during embryonic development. They currently account for 20-30% of congenital cystic bronchopulmonary foregut abnormalities and for only 5-10% of paediatric mediastinal masses. <ref name="PMID23762726"><pubmed>23762726</pubmed></ref> Although the exact cause of bronchogenic cysts is yet to be established, current research postulates that that their developmental cause is the abnormal budding of the tracheal diverticulum and proximal bronchial structures during embryogenesis in weeks 4-6. Bronchogenic cysts stem from abnormal buds from the tracheobronchial tree or primitive esophagus which fail to extend to the site of alveolar differentiation. Generally, early separation causes the system to move into the mediastinum, however it is when this separation occurs late that a BC forms <ref name="PMID23762726"><pubmed>23762726</pubmed></ref>. Histologically, these abnormal bronchogenic cysts are lined by pseudostratified, ciliated, columnar or cuboidal secretory respiratory epithelium and their walls comprise typical structural components of the airways such as smooth muscle, cartilage and mucinous glands. Cysts are typically not filled with air as they lack communication with the bronchial tree, but contain fluid comprising blood, proteinaceous fluid and calcium oxalate, resulting in a solid lesion manifesting on radiographic imaging such as MRI and CT scans <ref name="PMID18292738"><pubmed>18292738</pubmed></ref>

BCs are considered to be the most common form of foregut duplication cysts and are a congenital anomaly as they are asymptomatic and rarely arise in infants with diagnosis usually occurring post-natally. The clinical presentation of cysts is usually either asymptomatic or through airway obstruction causing respiratory distress or cystic infection causing compression of central lung parenchyma <ref name="PMID18760579><pubmed>18760579</pubmed></ref>

<references/>

===Lab 7===

'''Research article- Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary gland development'''

This study by Kioussi et al. investigated the role of the transcription factor ''Pax6'' in creating a dorsal-ventral boundary between cell types of the developing pituitary gland. The researchers considered the physical location of the six cell types in the pituitary that originate from a common primordium- corticotropes, thyrotropes, menalotropes, gonadotropes, somatotropes and lactotropes. They specifically focused on the regulation of cell differentiation by ''Pax6'' and the effects of its absence.

Following analysis of mutant mice embryos with a ''Small eye'' (''Sey'') mutation and ''Pax6'' gene deletion, the study found that ''Pax6'' plays a significant role as an early dorsal marker of the pituitary gland’s development. They found that ''Pax6'' transcripts were expressed and present in the nascent Rathke’s pouch, however excluded from the ventral section of the Sonic hedgehog (''Shh'') pouch, leading to the formation of a ventral zone between cells expressing ''Pax6'' and those expressing ''Shh''. A dorsal-ventral gradient for cell differentiation was evident and ''Pax6'' was seen to be excluded from the rostral zone of the pituitary. These two particular findings suggested that ''Pax6'' may be an essential element of the ‘transcriptional apparatus’ responsible for determining the position of the six pituitary cell lineages.

Furthermore, the research concluded that the absence of ''Pax6'' leads to a decrease in dorsal cell types from the ''Pit-1'' lineage (somatotropes and lactotropes) and an increase in cell types with ventral phenotypes such as thyrotropes. This was confirmed by discovering that the expression patterns of four molecular ventral markers such as GATA2 were uniformly dorsalised, leading to further increase in the population of thyrotropes.

Hence, these results implicated that ''Pax6'' functions as a transcriptional regulator in opposition to ventral signalling molecules, thus clearly delineating the developing dorsal cells from ventral cells in the differentiation stage of pituitary gland development. It has a key regulatory role in the formation of a sharp dorsal-ventral cell type margin through the inhibition of ''Shh'' ventral signals.

<pubmed>10588713</pubmed>

'''Tooth development'''

The cells and their layers that contribute to tooth development through odontogenesis (from week 6 of development) include:

*''Odontoblasts'': Mesenchymal cells of neural crest origin that produce predentin, which calcifies forming dentin in the process of dentinogenesis. Enamel epithelium causes odontoblast differentiation and these cells contribute to the outer dental pulp
*''Ameloblasts'': Derived from ectodermal cells of oral epithelium tissue. They differentiate from preameloblasts, activated by ectomesenchymal cells and produce enamel proteins such as amelogenin and enamelin to form enamel, the outer covering of the tooth’s crown.
*''Peridontal ligament'': Composed of connective tissue (bundles of collagen fibres), which secures the root of the tooth in the alveolar socket so it is not displaced. It surrounds the cementum of the tooth root.

===Lab 8===

'''Ovary development'''

Initially, the genital systems of both sexes are morphologically similar and sexual development hence begins as an indifferent stage with an indifferent (‘bipotential’) gonad later forming either the testis or ovary. Both gonads have contributions from; mesothelium of the posterior abdominal wall cavity, mesenchyme beneath this and primordial germ cells (PGCs) that later differentiate to form sex cells.

In Week 5 of development, a thickening of mesothelium forms on the medial portion of the primitive kidney (the mesonephros). The formation of the gonadal ridge results from the proliferation of the mesothelium and mesenchymal tissue beneath it, as a bulge on the medial mesonephros. Projection of finger-like gonadal (epithelial) cords into the mesenchyme follows, segmenting the indifferent gonad into an internal medulla (covered by germinal epithelium) and external cortex. For embryos with a sex chromosome complex of XX, the medulla regresses while the cortex of the indifferent gonad differentiates to form the ovary.

PGCs reside among dorsal endodermal cells of the umbilical vesicle whose dorsal part is incorporated into the embryo during folding. They are the first cell type migrating through the primitive streak in gastrulation (3rd week) and then reside at the junctional region of the hindgut yolk sac. Following this, there is migration of the PGCs to the gonadal ridge along the hindgut’s dorsal mesentery, regulated by BMP-4, fragilis and stella genes. In week 6, these germ cells are incorporated into the gonadal cords and are called oogonia, having entered underlying mesenchyme.

In female embryos, ovary development is a slow process, with the ovary not histologically identifiable until week 10. Ovary development relies on the genes of the XX chromosome along with an autosomal gene. Gonadal cords form a basic rete ovarii (network of canals) by extension into the internal medulla, although the cords are not notable in the embryonic ovary. The rete ovarii and gonadal cords usually degrade and cease to exist.

[[File:Bailey329.jpg|500px]]

'''Transverse section of the ovary of a fox embryo'''

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466385578-2 Moore: The Developing Human, 9th ed. Chapter 12]

===Lab 9===

====Group 1- Respiratory====

Overall, the project at this stage consists of a good integration of text, images and references throughout. The introduction is well-written and gives an overview of the two parts of the respiratory system (conducting and respiratory zones). I think it is a good idea that your group has split this up and explained both parts separately as it helps to orient an unknowing reader, especially as the gross anatomical structures are also described (e.g. trachea, larynx, bronchi). However, in-text referencing is needed in this introductory segment to provide the reader with the source of all information, exactly where it appears. You could refer to Dr Hill’s instructions on how to do this if needed, or see another group’s page on Edit mode. Also, the images used in the introduction should have a small caption beneath them, otherwise it is hard to tell what the images show exactly and how this may be relevant to the complementary text.

In terms of heading and subheading organisation, I like how you have split the content up into 5 main areas of introduction, lung development stages, current research models/findings, historic findings and abnormalities. This makes the page easy to navigate and the subheadings under each section are relevant. The use of a table in the ‘lung development stages’ section is very well done and appropriate, as it segments the information into a clean, readable format that a student could simply refer to if they were learning from scratch. The information in the table is succinct and provides all the main points. The only improvement here I would suggest, is aligning the content to the left, as it may seem more pleasing to the eye to have even spacing rather than centre alignment. Also, the ‘references’ have been placed as subheading 2.1, whereas the other ‘reference’ sections have not been given a separate subheading, so I would consider making this consistent throughout the project page.

The section on current research models and findings is concise and informative, with good use of numbering to make the information easier to read rather than having long and chunky paragraphs. Although a minor detail, there is one part that says “a study conducted last year”. Since these Wiki pages will be left online, it is important to specify the exact year here, and provide an in-text reference to the study mentioned so a reader can easily locate it. I like the use of dot points in this section, making it look appealing, however the image used should also include a caption, as should the others on the page. Be careful of copyright infringement regarding image use, as there appears to be a file with a ‘Permission Error’ in this section, which may need to be manually removed.

The ‘historic findings’ section was also well-done, especially because it used dot points to segment the information and show the exact years of each discovery. Once again though, the image requires a caption and the references for this section seem to be split into 2 parts; one list from 1-14 then another from 1-4. I think the list from 1-4 needs a subheading to show how those sources are different to the ones above it, otherwise both lists need to be integrated into one.There are also some parts that have coding showing </ol> and </li> which just need to be removed with editing.

Lastly, the section on abnormalities is also of a high standard as each abnormality begins with a brief description then goes into details by using dot points. There is good use of in-text referencing followed by a reference list which is correctly formatted too. The image included has a caption which is good, as other sections lack this, however I would consider adding more images to make this part more visually appealing and engaging to the reader. It is evident that a lot of work has been done on this page as each section is detailed and referenced well, with relevant information.

====Group 2- Renal====

The introduction provided by this project is very good and includes in-text citations. Not only does it introduce the renal system’s components but also discusses its development briefly into the embryonic and fetal stages, focusing more on fetal. Also, by having the references as one long list at the very end of the page, this gives the project a clean and tidy look, which some of the others lack. I thought this was a great idea and very orderly.

While some sections are full of information, others are scarce or empty, such as the ‘Historical findings’ section. Some information on the development of knowledge on the renal system throughout history should be included here, maybe making use of dot points detailing specific year dates. The ‘Developmental Timeline’ provides a good overview of the system’s development, although weeks 3-5 may not be necessary as these are during the embryonic period and the focus here is on fetal development. However, it does provide an overall context which is good. This information may also be effectively translated into a table format for easier readability.

The section on ‘current research models’ was nicely written, with solid analysis of 2 research articles. Using any more articles to that level of depth may be too much information, so this is a good balance. It was very good to see the text actually explaining the accompanying image, which was labelled with a caption too. The introduction to the use of animal models and why these are important was effective also.

I particularly thought the sub-sectioning of the page into the main organs of the renal system was a smart idea rather than having the entire system as a clump of information as this way, it is easier to navigate through the information. The ‘kidney’ section was of a very high standard as the information was relevant and nicely split into different processes of fetal development such as nephrogenesis and renin production. It is very helpful as a reader to have explanations of the images used, making the page more interactive and useful. However, this is a file with a ‘Permission error’ present which would need removal due to copyright infringement; this should be sorted out before the project is due.

The following three sections on the urethra, ureter and bladder were also well-written, referenced correctly with in-text citations and the images used were relevant to the text. However, captioning the image in the urethra section would be good to give the reader knowledge of exactly what it shows. The ‘abnormalities’ section was again, well -researched and full of information, however it seems a little cluttered as lengthy references are placed under the text. Integrating these into the overall reference list at the end of the page would look clearer.

Overall, this project has been well done and there is evidence of consistency throughout the section formatting, suggesting the group members have been communicating between each other, which is good to see. Some improvements I would suggest are the use of hand-drawn images to make it easier for a student to learn off the project, and using tables to summarise some information e.g. timeline.

====Group 3- Gastrointestinal====

The introduction part of this project provided a good overview of the gastrointestinal tract and its components, also mentioning briefly the changes that occur in the fetal period. However, care must be taken to not capitalise words that are not needed e.g. Foregut, Midgut, Appendix etc. Although the information in the ‘timeline’ section is relevant, its formatting needs a bit of review as there are inconsistencies between the foregut, midgut and hindgut parts. It also seems that the in-text citations have just been arbitrarily placed in chronological order, with each line having a new reference. Also, this information may be better presented in table format to improve readability. Some simple editing may be needed to fix this.

The section on ‘Recent findings’ has some good information, however the reference needs to be properly cited and maybe a couple more articles would help give this part some substance. I thought it was effective to have the GIT split into the foregut, midgut and hindgut and then detail the fetal development under those titles. This gave the page a good structure. However, adding some images, both from online and student-drawn to the foregut and hindgut sections would help improve the aesthetics of the page. The hand-drawn images on the midgut section are effective learning tools to a student, but maybe could be drawn a little neater with darker colours as the blue labelling is difficult to read. They should also be captioned. The use of a table to show midgut herniation of fetuses was a good tool as it makes the information easier to read also.

Lastly, the section on abnormalities was well-detailed and I liked that the deformities were split into a definition and cause. An image of gastrochisis may be helpful for a reader to visualise the condition though. The in-text citations in this part were properly done and a long list of references being at the end of the page made the project look neat overall. Areas of improvement may be some simple formatting changes and evening out the information across sections, however a solid project so far.

====Group 4- Genital====

Overall, it is evident that a lot of work has been completed on this project as each section has a decent amount of information and there are images throughout the page. However, the addition of an ‘introduction’ section would help to orient the reader and help students gain an overall understanding of the topic.

The section on ‘system development’ seems to be well-researched, however the formatting of the content in short, one-sentence dot points makes it difficult to read and incongruent, so writing this out in small paragraphs would improve the readability. The capitalization of some words is unnecessary in both the dot points and the table, creating inconsistencies in the formatting. Also, some words are unnecessarily bolded which detracts from the aesthetic appeal of the page. However, the inclusion of a table to summarise the timeline information is an effective tool, although there is much more information provided for the male system than female system. It is really good to see the use of an image as it is relevant and clearly compares the male and female system development side-by side. I also think the video inclusion is fantastic as it would be an effective way to learn for a reader with no previous knowledge, making the page more interactive.

The section on ‘current research, models and findings’ contains lots of relevant information, however this is not referenced in-text and it is thus unclear where the information has been derived from. There also seems to be some unevenness between the depth of information between male and female systems, which some more research can easily remedy. In terms of current findings, the listing of the information in dot points makes it easier to read, however there are some parts italicised and capitalized that are not needed. It is great to see some hand-drawn images as these are simplistic, colourful and effective ways to accompany the text, adding to the page’s appeal. Take care to properly include images, as one of them appears as ‘alt text’ and the link does not show the image itself. Although some references appear under a ‘references’ title in this section others appear as a website links; formatting of these could improve neatness.

The following section on ‘historic findings’ contains evidence of extensive research as it is very detailed and well-written. However, I would consider breaking this part up into smaller sections using dot points as large paragraphs seem tedious to read. The hand-drawn image is a good inclusion, but labelling of it would be effective and adding a couple more would break up the long section visually. Also, there seem to only be in-text citations after long chunks of information; perhaps more sources should be used/consulted.

Lastly, the abnormalities section was comprehensive and detailed and enough information was given on some examples. This was just the right amount of content, as any more would seem excessive. Adding some more images with appropriate captioning is advised also. I liked that the references were listed altogether at the end of the page, making it neat and tidy. Overall, a solid project which just needs some formatting to improve further.

====Group 5- Integumentary====

The introduction of this page was good as it provided a great overview and insight into what the project would later go on to discuss. Perhaps a little information on defining the integumentary system itself would be valuable though, to let the reader know the constituents.

The sub-sectioning of the page’s content into ‘introduction, ‘development overview’, ‘recent findings’, ‘historic findings’ and ‘abnormalities’ was clever, as the development section then went on to describe each component such as skin, nails etc. This effectively segmented the information into smaller chunks that could easily be navigated to. I especially liked the use of the table in the ‘skin’ section, showing the week of development, description and image corresponding alongside it, as it provided a holistic approach to that section. However, there were no in-text citations in the ‘skin’, ‘hair’, ‘nail’ or ‘teeth’ sections, hence the source of the information is unclear. To do this correctly, Dr Hill’s Wiki help page should be consulted.

The use of various images with labelled captions was a strength of this project, as the pictures were effective in balancing the text components to make the page more visually appealing. Most of the sections under ‘development overview’ have a decent amount of content, however the ‘nails’ part is a bit lacking and also needs to be correctly cited. The use of the table of images alongside the description of developmental stage in the ‘teeth’ section was very good to include, however the image is captioned ‘The stages of embryonic teeth development’. This may be irrelevant as the project’s focus is on fetal development. Further research into this area may uncover more relevant information.

Although the section on ‘recent findings’ contains a lot of information, the use of chunky paragraphs detracts from the readability of the page and the purple boxes could be summarised into dot points to help the reader understand the content more quickly. The section on historic findings seems concise and relevant, however the image included says it has been removed/deleted, so this requires editing. Lastly, the ‘abnormalities’ section was very well-structured and written, as each example had a captioned image accompanying it to help the reader visualise. This section was also well-done in terms of in-text citations, with an extensive reference list provided at the end. Perhaps consider adding some student-drawn images and possibly a relevant video, but otherwise it is very good as it is. Overall, the project has a good layout and a decent amount of content; with some editing and formatting it can be improved further.

====Group 7- Neural====

Overall, the project contains a decent amount of content as it is, split up into appropriate subheadings, considering the large scope of the nervous system. The introduction provides a succinct description of the CNS, however including an outline of what topics the page intends to cover would be good to orient a reader that approaches the page for the first time. The descriptions of the brain and spinal cord are well-written, however require in-text citations and some words need not be capitalised e.g midbrain, hypothalamus. These can be easily fixed with proof-reading and further editing.

The use of an image to illustrate fetal development was a very good idea; although the diagram is itself seems complicated, it can be explained well with the accompanying text beneath. The segmentation of the timeline into 4 different parts made it easier to follow, although I would consider placing the images on the right hand side of the page to reduce the vertical length of the page and the scrolling required to navigate through it. The section on ‘brain development’ contained some relevant information, formatted in dot points which improves readability, however in-text citations are needed to allow the reader to source the information if required. The use of the table in this part was effective also; it was concise and straight to the point.

Although the brain development section was very well detailed, there was no information in the spinal cord and meninges sections; with further research, these need to be evened out, along with the current findings section which is just references at this stage, but still a good start to finding sources of information. The section on current research is well-detailed and contains a lot of information too, which is good to see. Fiinally, I thought the section on abnormalities was very well done, using subheadings to segment the content. The use of dot points allowed the information to be easily read off the page, and use of images to accompany them helped the reader to visualise the conditions. There is one image however that has been incorrectly uploaded; consulting Dr Hill’s Wiki help page can remedy this. Also, the placement of all references under one list at the end of the page was effective in neatening it up, that was very well done too.

Overall, the project’s content has been well-researched and there is evidence of good teamwork and communication. Perhaps the use of some student-drawn images and inclusion of a relevant video may be areas of improvement.

====Group 8- Musculoskeletal====

Overall, the project has some very detailed sections and some sections where content is scarce. It would be helpful to start off with an introduction of the musculoskeletal system so the reader is aware of its components and what the page intends to cover. The timeline of muscle development has good potential, I understand it is still being planned at this stage and with further research, it could definitely be effective. A table format would be useful to present this information. The following sections on background embryonic development and fetal myogenesis are well-researched and have a lot of content, however I would consider breaking it down into dot points to improve readability. The sections are cited correctly in-text though, which is good to see.

There is much more improvement in the tendon and second trimester development sections, as the chunks of text have been reduced to provide a succinct summary, however these need to have citations also. The use of some images here, either hand-drawn or from online would be beneficial, to have a balance between text and pictures and make the page more visually appealing. Other than the abnormalities section which provides a good, concise summary of Duchenne Muscular Dystrophy, the following sections seem to be only references at this stage. As long as these are used to compose some relevant paragraphs/dot points, this is fine considering there is still time to improve the page.

Overall, this page has good potential as the groundwork has been completed; it is now more a matter of writing up more information, adding images and possibly a relevant video. The part on ‘making gains’ would need to be removed for the final, but otherwise, it is definitely a decent amount of work so far, especially considering the few group members involved.

===Lab 10===

'''Research article- Stage-dependent requirement of neuroretinal Pax6 for lens and retina development'''

'''Methods summary'''

Embryonic mouse stem cells from timed pregnant females were recombined in a homologous fashion to form floxed Pax-6 alleles in the experimental mice. These embryos were then harvested, fixed, PBS-washed, cryopreserved and sectioned for immunohistochemistry staining in which embryos were permeabilized and washed with PBT and incubated. This was followed by RNA in-situ hybridisation, where RNA polymerase was used to create antisense mRNA probes, then X-gal staining occurred.

The study then measured the length of the cell cycle phases of the mice embryos to assess the role of Pax6. Using wild-type littermates as controls, they found the proportion of proliferating retinal progenitor cells (RPCs) by injecting timed pregnant females with BrDU, then fixing, cryopreserving and sectioning them. Following this was a process of antigen retrieval with several incubations to calculate cell proliferation rate.

Finally, the cell cycle rate at embryonic days 11.5 and 13 were found and the cell cycle and S phase lengths were determined, also calculating the total length of the G1, G2 and M phases. These results were then quantified by statistical analysis using a t-test, counting 3 fields for every individual eye.

'''Results summary'''

By combining the findings of the separate sections of the experiment, the study concluded that Pax6 has an essential role in both lens and retinal cell formation. It was found that Pax6 deletion strong hypocellularity in early RPCs. There was high expression of Pax6 in the surface ectoderm (SE) and optic vesicle (OV) control embryos while the levels of Pax6 stayed constant and unchanged even after Pax6 elimination in the OV, lens pit and SE. The hypocellularity of the retina was more pronounced with time, and retinae deficient in Pax6 became smaller progressively.

Another finding was that the population size of the RPCs was reduced by changed cell cycle length and imbalance between cells exiting the cell cycle and proliferation of eye progenitor cells. It was again observed that retinal cells deficient in Pax6 were very hypocellular and cycling cells were centrally localised in the retina. An increased rate of cell death was observed with increasing time and total cell cycle length of Pax6-deficient RPCs was significantly longer than the control embryos. Also, the down-regulation of cyclin D1 in Pax6-deficient mice suggested that absence of Pax6 drives RPCs to cell cycle exit. Together, these findings suggested that positive progression of RPCs through the cell cycle is regulated by Pax6.

Finally, another conclusive result reached by this study was that the absence of Pax6 in RPCs causes a hindrance in their proper differentiation program into retinal cells; indicating the essential role of Pax6 in proliferation of early progenitors. It was also found that deficiency of Pax6 in optic vesicles could lead to the arrest of lens development during the interaction of the OV and SE. As neither the lens nor retina was formed properly in Pax6 deficient embryos, this indicated the importance of Pax6 presence in the optic vesicle for correct eye morphogenesis in the developing embryo.

<pubmed>24523460</pubmed>

[https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Vision_Development#Lens Sensory-Vision development Wiki page]

===Lab 11===

This study by Hidetoshi et al sought to explore the potential of human induced pluripotent stem cells (hiPSCs) to regenerate damaged cardiac tissue, in particular vascular cells and cardiomyocytes (CMs).

CMs and vascular cells were simultaneously induced using a differentiation protocol wherein the levels of gene expression of cardiac mesoderm and progenitor genes peaked at day 5 of differentiation. They found that mesoderm-to-CM differentiation enhancement occurred during days 5-7 due to Dkk1 addition (an antagonist). When vascular cell induction with CMs using VEGF was attempted instead of Dkk1, this led to induction of ECs and CMs together. The study found that the cell populations had a composition of vascular endothelial cadherin, platelet-derived growth factor receptor beta and positive MCs. These findings collectively suggested that a change from ‘only CMs’ to ‘CMS and vascular cells’ could be induced by selectively controlling the direction of differentiation of cardiovascular cells.

The experiment also tried to develop sheets of cardiovascular cells from hiPSCs by continuous culture, re-plating and incubations. It was found that reducing temperature served to re-assemble self-pulsating sheets of cells after heating and that sheets were composed of 3-4 layers supported by collagen fibres in a stratified manner. These sheets were shown to have CMs evenly distributed throughout them via immunohistochemical techniques. Within the cell sheets were; CMs, MCs and undifferentiated cells and this composition was attributed to possible apoptotic cell death reducing numbers and reduced proliferation efficiency. Together, these results suggested that it was the hiPSCs only that had generated the CMs and vascular cells, forming a structure that resembled cardiac tissue very realistically.

Lastly, Hidetoshi et al also found that the transplantation of hiPSCs with CTSs could alleviate dysfunctions in the cardiovascular system even after infarction in rats, as all rats had survived the period of post-transplantation without signs of tumours arising. Using echocardiogram technoogy, it was observed that anterior wall contraction had been brought back to normal, left ventricle systolic function had improved and that there had been reduced thickening of the wall of myocardial infarcts. Furthermore, staining with Sirius red found that the rate and extent of fibrosis was significantly reduced after hiPSC-CTS transplantation.

In conclusion, Hidetoshi et al concluded that there remained ample scope for hiPSCs to regenerate cardiac tissue and thus restore cardiac function, if their capabilities were studied more widely by other researchers. The replacement ability and biomedical potential of these pluripotent stem cells hold great promise for the future of stem cell therapy.

User:Z3418702

2014-10-28T13:38:34Z

Z3418702:

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:45, 6 August 2014 (EST)

==Lab attendance==

Lab 1----[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:57, 6 August 2014 (EST)

http://www.ncbi.nlm.nih.gov/pubmed

[http://www.ncbi.nlm.nih.gov/pubmed Pubmed]

[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]

<pubmed>25084016</pubmed>

Lab 2 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:20, 13 August 2014 (EST)

Lab 3 ----[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 13:08, 20 August 2014 (EST)

Lab 4- --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:34, 27 August 2014 (EST)

Lab 5 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:58, 3 September 2014 (EST)

Lab 6 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:45, 10 September 2014 (EST)

Lab 7 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 11:16, 17 September 2014 (EST)

Lab 9 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:20, 8 October 2014 (EST)

Lab 10 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:11, 15 October 2014 (EST)

Lab 11 --[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 12:33, 22 October 2014 (EST)

==Online Assessments==

===Lab 1===

'''Article 1:''' <pubmed>24592092</pubmed>

This study was conducted by the IVF Center at Kocaeli University, Turkey. It aimed to test the effect of biochemical markers in follicular fluid, such as nitrous oxide (NO), reduced glutathione (GSH) and malondialdehyde (MDA) on the outcome of in vitro fertilisation. The researchers selected 62 infertile women, all of whom were aged between 25 and 32, were non-smokers, had no systemic diseases, and were suffering from unexplained infertility with no signs of hormonal or ovulatory issues.

Ovulation was first induced in the women using long and short agonists along with a microdose flare-up, after which an oocyte was collected. This was followed by intracytoplasmic sperm injection (ICSI) as the preferred method of fertilisation, then the transfer of the embryo took place. To collect the FF samples, the dominant follicles were chosen and samples were centrifuged, supernatants were removed and stored.

To measure MDA levels, MDA was mixed with thiobarbaturic acid (TBA) which reacted to form a red compound. This mixture was incubated, cooled and assayed to read the absorbance of the butanol phase, and results were expressed in micromoles of MDA. Similarly, levels of GSH were measured in micromoles/L after being supplemented with metaphosphoric acid and assayed. However, NO levels were measured indirectly by measuring the nitrate and nitrite sample concentrations, deproteinising the sample, then measuring absorbance at 545nm using Griess reagent, expressing NO levels in nanomoles/L.

The embryos were then graded in terms of the size of the blastomere and degree of fragmentation, into Grades A-C, A being an even blastomere with <10% fragmentation. A single Grade A embryo was then transferred into each woman on Day 3 of the trial, after which they were categorised into 2 groups based on blood concentration of human chorionic gonadotropin; successful pregnancy (Group 1) and unsuccessful pregnancy (Group 2).

Finally, to analyse these results, the researchers used the women’s pregnancy status following IVF as the primary outcome measure. Statistic analysis was carried out according to non-parametric Mann-Whitney U test. The study found that the successful pregnancy group had significantly lower levels of fluid NO and significantly higher levels of fluid MDA than the unsuccessful pregnancy group. In analysing the correlation between IVF parameters and oxidative stress, the findings showed a positive weak correlation of MDA with fertilisation rate and the number of Grade A embryos. Also, ROC curve analysis implicated MDA as a highly sensitive predictor of pregnancy. Due to this significant difference in MDA levels between groups 1 and 2, the study concluded that MDA was the most suitable indicator of IVF success out of the 3 biochemical markers chosen for analysis.

'''Article 2:''' <pubmed>24914407</pubmed>

The objective of this study was to research the possible association between levels of plasma D-dimer, a haemostatic marker, and the success or failure of pregnancy in women undergoing IVF. The researchers selected 105 infertile women from the Ortona General Hospital’s Assisted Reproduction Unit who were undergoing IVF, indicated by factors such as tubal factor, endometriosis, male factor, anovulation and unexplained infertility.

The participants underwent ovarian stimulation by receiving daily subcutaneous injections of recombinant FSH (follicle stimulating hormone) with doses varying based on basal FSH level, the age of the woman and antral follicle count. This stimulation was begun upon complete pituitary suppression on the 3rd day of the menstrual cycle, and throughout the stimulation, hormonal fluctuations of luteinising hormone (LH) were controlled by injecting agonists and antagonists of GnRH.

Following the collection of oocytes, intracytoplasmic sperm injection (ICSI) was used to perform IVF and an embryo transfer was carried out, 14 days after which a pregnancy test was taken. The presence of a gestational sac with a fetal heartbeat after 7 weeks of gestation was the criterion for a clinical pregnancy.This ovarian stimulation protocol was followed by a venous blood sample to test D-dimer concentrations, where a latex quantitative assay was used with 200ng/mL being the threshold level for an abnormal D-dimer level. These assay levels were statistically analysed using a Mann-Whitney U-test and T-test.

The results of the study indicated significantly higher levels of circulating D-dimer in women with a failed pregnancy following IVF in comparison to those with a clinical or successful pregnancy. This difference was statistically valid even when taking age and vascular risk factors into account. It was found that women with concentrations of D-dimer above the threshold had a more dismal pregnancy outcome, and that D-dimer levels increased after the one-week administration of GnRH. Overall, only 38% of the participants had achieved a clinical pregnancy and the study concluded that high D-dimer concentrations are implicated in a higher risk of a failed pregnancy following IVF. This was consistent with previous postulations that a possible mechanism for failure is unsuccessful implantation and placentation, owing to a hypercoagulable vascular state, leading to increased risk of thrombolic events in maternal vessels to the placenta.

--[[User:Z8600021|Mark Hill]] - Both these papers are recent and present interesting findings. It would have helped you summary in the second paper if you had described what plasma D-dimer was. Your summaries are both correct and concise (5/5).

===Lab 2===

[[File:Fertilisation of medusa eggs by spermatozoids in vitro in sea water.png|300px]]

Fertilisation of medusa eggs by spermatozoids in vitro in sea water<ref><pubmed>23185235</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0046542]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:28, 21 August 2014 (EST) This is all correct, I have fixed the reference link below. Please in future use a shorter image title and do not use .jpg in the image description above (I have removed for you). (4/5)

<references/>

===Lab 3===

'''Adrenal gland'''

<pubmed>7011178</pubmed>
<pubmed>24116052</pubmed>

'''Gonad development'''

<pubmed>17237341</pubmed>
<pubmed>7623307</pubmed>

'''Placenta'''

<pubmed>10419690</pubmed>
<pubmed>7673080</pubmed>

--[[User:Z8600021|Mark Hill] These references are appropriate, you should have included some descriptions, even a single line, with the reference (4/5).

===Lab 4===

'''Summary of research article'''

This study by Chang et al. observed the effect of varying the intratracheal transplantation time of umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) on the attenuation of hyperoxic lung injury in neonatal rats. It was concluded that the optimal time window for stem cell transplantation was narrow; efficient only during the early but not late phases of inflammation. The findings were in line with previous research that the anti-inflammatory properties of UCB-derived MSCs play a crucial therapeutic role in the alleviation of bronchopulmonary dysplasia (BPD), through reducing hypoxia-induced injuries including increased apoptosis and impaired alveolarisation.

Tissue sampling and analysis of lung histopathology found that the Hypoxia Control (HC) group showed fewer, larger and more abnormally-sized alveoli compared to the Normoxia Control (NC) group. However, upon transplantation of UCB-derived MSCs, these alveolar impairments and changes in morphology were attenuated, especially when added on post-natal day 3 (HT3) than on post-natal day 10 (HT10).

The study’s comparison of the levels of pro-inflammatory cytokines such as IL-6α, IL-6β and TNF-α before and after the addition of the UCB-derived MSCs found that such molecular markers were significantly lower after HT3 transplantation than HT10 transplantation. These levels were much lower than the initial starting levels exhibited by the NC group, indicating the therapeutic effect of the cord cells. Furthermore, the hypoxia-induced reduction in VEGF and HGF levels and increase in lung collagen levels were both attenuated by the addition of the MSCs.

These findings led to the conclusion that the therapeutic efficacy of UCB-derived MSCs on treating BPD is indeed time-dependent; having potent effects in the early inflammatory process, which is then reduced in later stages. The study also tested any potential synergistic effects of combined early and late MSCs intratracheal transplantation, but none were found.

<pubmed>23349686</pubmed>

'''Vascular shunts'''

The 3 developmental vascular shunts in the fetal circulation that close postnatally are:

''a) Ductus arteriosus (Ductus Botalli):'' Connects the pulmonary artery to the proximal descending part of the aortic arch and prevents the output of the right ventricle from entering the unexpanded fetal lung, which is fluid-filled and non-functioning. This shunt transfers medium oxygen saturated blood and becomes the ligamentum arteriosum after closing at birth.

''b) Ductus venosus:'' Shunts blood from the left umbilical vein to the inferior vena cava. This carries well-oxygenated blood and allows placental blood to bypass the liver ultimately to the fetal brain.

''c) Foramen ovale (Foramen Botalli):'' Shunts blood that is highly saturated with oxygen from the right atrium to the left atrium and becomes the fossa ovalis after closing at birth.

===Lab 5===

'''Bronchogenic Cysts'''

Bronchogenic cysts (BCs) are an unusual and rare congenital abnormality of the bronchial tree; a generally benign type of malformation of the bronchopulmonary foregut. The classification of these cysts is into; those occurring in the mediastinum (65-90%), which have equal prevalence between the sexes, or those of intrapulmonary origin (lung or pleura) which display a slight male predominance <ref name="PMID23762726"><pubmed>23762726</pubmed></ref> Other sites such as intradiaphragmatic and retroperitoneal are rare, and consequently require close attention.

These lesions are characteristically unilocular, mucus field cysts which arise from the posterior walls of airway membranes during embryonic development. They currently account for 20-30% of congenital cystic bronchopulmonary foregut abnormalities and for only 5-10% of paediatric mediastinal masses. <ref name="PMID23762726"><pubmed>23762726</pubmed></ref> Although the exact cause of bronchogenic cysts is yet to be established, current research postulates that that their developmental cause is the abnormal budding of the tracheal diverticulum and proximal bronchial structures during embryogenesis in weeks 4-6. Bronchogenic cysts stem from abnormal buds from the tracheobronchial tree or primitive esophagus which fail to extend to the site of alveolar differentiation. Generally, early separation causes the system to move into the mediastinum, however it is when this separation occurs late that a BC forms <ref name="PMID23762726"><pubmed>23762726</pubmed></ref>. Histologically, these abnormal bronchogenic cysts are lined by pseudostratified, ciliated, columnar or cuboidal secretory respiratory epithelium and their walls comprise typical structural components of the airways such as smooth muscle, cartilage and mucinous glands. Cysts are typically not filled with air as they lack communication with the bronchial tree, but contain fluid comprising blood, proteinaceous fluid and calcium oxalate, resulting in a solid lesion manifesting on radiographic imaging such as MRI and CT scans <ref name="PMID18292738"><pubmed>18292738</pubmed></ref>

BCs are considered to be the most common form of foregut duplication cysts and are a congenital anomaly as they are asymptomatic and rarely arise in infants with diagnosis usually occurring post-natally. The clinical presentation of cysts is usually either asymptomatic or through airway obstruction causing respiratory distress or cystic infection causing compression of central lung parenchyma <ref name="PMID18760579><pubmed>18760579</pubmed></ref>

<references/>

===Lab 7===

'''Research article- Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary gland development'''

This study by Kioussi et al. investigated the role of the transcription factor ''Pax6'' in creating a dorsal-ventral boundary between cell types of the developing pituitary gland. The researchers considered the physical location of the six cell types in the pituitary that originate from a common primordium- corticotropes, thyrotropes, menalotropes, gonadotropes, somatotropes and lactotropes. They specifically focused on the regulation of cell differentiation by ''Pax6'' and the effects of its absence.

Following analysis of mutant mice embryos with a ''Small eye'' (''Sey'') mutation and ''Pax6'' gene deletion, the study found that ''Pax6'' plays a significant role as an early dorsal marker of the pituitary gland’s development. They found that ''Pax6'' transcripts were expressed and present in the nascent Rathke’s pouch, however excluded from the ventral section of the Sonic hedgehog (''Shh'') pouch, leading to the formation of a ventral zone between cells expressing ''Pax6'' and those expressing ''Shh''. A dorsal-ventral gradient for cell differentiation was evident and ''Pax6'' was seen to be excluded from the rostral zone of the pituitary. These two particular findings suggested that ''Pax6'' may be an essential element of the ‘transcriptional apparatus’ responsible for determining the position of the six pituitary cell lineages.

Furthermore, the research concluded that the absence of ''Pax6'' leads to a decrease in dorsal cell types from the ''Pit-1'' lineage (somatotropes and lactotropes) and an increase in cell types with ventral phenotypes such as thyrotropes. This was confirmed by discovering that the expression patterns of four molecular ventral markers such as GATA2 were uniformly dorsalised, leading to further increase in the population of thyrotropes.

Hence, these results implicated that ''Pax6'' functions as a transcriptional regulator in opposition to ventral signalling molecules, thus clearly delineating the developing dorsal cells from ventral cells in the differentiation stage of pituitary gland development. It has a key regulatory role in the formation of a sharp dorsal-ventral cell type margin through the inhibition of ''Shh'' ventral signals.

<pubmed>10588713</pubmed>

'''Tooth development'''

The cells and their layers that contribute to tooth development through odontogenesis (from week 6 of development) include:

*''Odontoblasts'': Mesenchymal cells of neural crest origin that produce predentin, which calcifies forming dentin in the process of dentinogenesis. Enamel epithelium causes odontoblast differentiation and these cells contribute to the outer dental pulp
*''Ameloblasts'': Derived from ectodermal cells of oral epithelium tissue. They differentiate from preameloblasts, activated by ectomesenchymal cells and produce enamel proteins such as amelogenin and enamelin to form enamel, the outer covering of the tooth’s crown.
*''Peridontal ligament'': Composed of connective tissue (bundles of collagen fibres), which secures the root of the tooth in the alveolar socket so it is not displaced. It surrounds the cementum of the tooth root.

===Lab 8===

'''Ovary development'''

Initially, the genital systems of both sexes are morphologically similar and sexual development hence begins as an indifferent stage with an indifferent (‘bipotential’) gonad later forming either the testis or ovary. Both gonads have contributions from; mesothelium of the posterior abdominal wall cavity, mesenchyme beneath this and primordial germ cells (PGCs) that later differentiate to form sex cells.

In Week 5 of development, a thickening of mesothelium forms on the medial portion of the primitive kidney (the mesonephros). The formation of the gonadal ridge results from the proliferation of the mesothelium and mesenchymal tissue beneath it, as a bulge on the medial mesonephros. Projection of finger-like gonadal (epithelial) cords into the mesenchyme follows, segmenting the indifferent gonad into an internal medulla (covered by germinal epithelium) and external cortex. For embryos with a sex chromosome complex of XX, the medulla regresses while the cortex of the indifferent gonad differentiates to form the ovary.

PGCs reside among dorsal endodermal cells of the umbilical vesicle whose dorsal part is incorporated into the embryo during folding. They are the first cell type migrating through the primitive streak in gastrulation (3rd week) and then reside at the junctional region of the hindgut yolk sac. Following this, there is migration of the PGCs to the gonadal ridge along the hindgut’s dorsal mesentery, regulated by BMP-4, fragilis and stella genes. In week 6, these germ cells are incorporated into the gonadal cords and are called oogonia, having entered underlying mesenchyme.

In female embryos, ovary development is a slow process, with the ovary not histologically identifiable until week 10. Ovary development relies on the genes of the XX chromosome along with an autosomal gene. Gonadal cords form a basic rete ovarii (network of canals) by extension into the internal medulla, although the cords are not notable in the embryonic ovary. The rete ovarii and gonadal cords usually degrade and cease to exist.

[[File:Bailey329.jpg|500px]]

'''Transverse section of the ovary of a fox embryo'''

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466385578-2 Moore: The Developing Human, 9th ed. Chapter 12]

===Lab 9===

====Group 1- Respiratory====

Overall, the project at this stage consists of a good integration of text, images and references throughout. The introduction is well-written and gives an overview of the two parts of the respiratory system (conducting and respiratory zones). I think it is a good idea that your group has split this up and explained both parts separately as it helps to orient an unknowing reader, especially as the gross anatomical structures are also described (e.g. trachea, larynx, bronchi). However, in-text referencing is needed in this introductory segment to provide the reader with the source of all information, exactly where it appears. You could refer to Dr Hill’s instructions on how to do this if needed, or see another group’s page on Edit mode. Also, the images used in the introduction should have a small caption beneath them, otherwise it is hard to tell what the images show exactly and how this may be relevant to the complementary text.

In terms of heading and subheading organisation, I like how you have split the content up into 5 main areas of introduction, lung development stages, current research models/findings, historic findings and abnormalities. This makes the page easy to navigate and the subheadings under each section are relevant. The use of a table in the ‘lung development stages’ section is very well done and appropriate, as it segments the information into a clean, readable format that a student could simply refer to if they were learning from scratch. The information in the table is succinct and provides all the main points. The only improvement here I would suggest, is aligning the content to the left, as it may seem more pleasing to the eye to have even spacing rather than centre alignment. Also, the ‘references’ have been placed as subheading 2.1, whereas the other ‘reference’ sections have not been given a separate subheading, so I would consider making this consistent throughout the project page.

The section on current research models and findings is concise and informative, with good use of numbering to make the information easier to read rather than having long and chunky paragraphs. Although a minor detail, there is one part that says “a study conducted last year”. Since these Wiki pages will be left online, it is important to specify the exact year here, and provide an in-text reference to the study mentioned so a reader can easily locate it. I like the use of dot points in this section, making it look appealing, however the image used should also include a caption, as should the others on the page. Be careful of copyright infringement regarding image use, as there appears to be a file with a ‘Permission Error’ in this section, which may need to be manually removed.

The ‘historic findings’ section was also well-done, especially because it used dot points to segment the information and show the exact years of each discovery. Once again though, the image requires a caption and the references for this section seem to be split into 2 parts; one list from 1-14 then another from 1-4. I think the list from 1-4 needs a subheading to show how those sources are different to the ones above it, otherwise both lists need to be integrated into one.There are also some parts that have coding showing </ol> and </li> which just need to be removed with editing.

Lastly, the section on abnormalities is also of a high standard as each abnormality begins with a brief description then goes into details by using dot points. There is good use of in-text referencing followed by a reference list which is correctly formatted too. The image included has a caption which is good, as other sections lack this, however I would consider adding more images to make this part more visually appealing and engaging to the reader. It is evident that a lot of work has been done on this page as each section is detailed and referenced well, with relevant information.

====Group 2- Renal====

The introduction provided by this project is very good and includes in-text citations. Not only does it introduce the renal system’s components but also discusses its development briefly into the embryonic and fetal stages, focusing more on fetal. Also, by having the references as one long list at the very end of the page, this gives the project a clean and tidy look, which some of the others lack. I thought this was a great idea and very orderly.

While some sections are full of information, others are scarce or empty, such as the ‘Historical findings’ section. Some information on the development of knowledge on the renal system throughout history should be included here, maybe making use of dot points detailing specific year dates. The ‘Developmental Timeline’ provides a good overview of the system’s development, although weeks 3-5 may not be necessary as these are during the embryonic period and the focus here is on fetal development. However, it does provide an overall context which is good. This information may also be effectively translated into a table format for easier readability.

The section on ‘current research models’ was nicely written, with solid analysis of 2 research articles. Using any more articles to that level of depth may be too much information, so this is a good balance. It was very good to see the text actually explaining the accompanying image, which was labelled with a caption too. The introduction to the use of animal models and why these are important was effective also.

I particularly thought the sub-sectioning of the page into the main organs of the renal system was a smart idea rather than having the entire system as a clump of information as this way, it is easier to navigate through the information. The ‘kidney’ section was of a very high standard as the information was relevant and nicely split into different processes of fetal development such as nephrogenesis and renin production. It is very helpful as a reader to have explanations of the images used, making the page more interactive and useful. However, this is a file with a ‘Permission error’ present which would need removal due to copyright infringement; this should be sorted out before the project is due.

The following three sections on the urethra, ureter and bladder were also well-written, referenced correctly with in-text citations and the images used were relevant to the text. However, captioning the image in the urethra section would be good to give the reader knowledge of exactly what it shows. The ‘abnormalities’ section was again, well -researched and full of information, however it seems a little cluttered as lengthy references are placed under the text. Integrating these into the overall reference list at the end of the page would look clearer.

Overall, this project has been well done and there is evidence of consistency throughout the section formatting, suggesting the group members have been communicating between each other, which is good to see. Some improvements I would suggest are the use of hand-drawn images to make it easier for a student to learn off the project, and using tables to summarise some information e.g. timeline.

====Group 3- Gastrointestinal====

The introduction part of this project provided a good overview of the gastrointestinal tract and its components, also mentioning briefly the changes that occur in the fetal period. However, care must be taken to not capitalise words that are not needed e.g. Foregut, Midgut, Appendix etc. Although the information in the ‘timeline’ section is relevant, its formatting needs a bit of review as there are inconsistencies between the foregut, midgut and hindgut parts. It also seems that the in-text citations have just been arbitrarily placed in chronological order, with each line having a new reference. Also, this information may be better presented in table format to improve readability. Some simple editing may be needed to fix this.

The section on ‘Recent findings’ has some good information, however the reference needs to be properly cited and maybe a couple more articles would help give this part some substance. I thought it was effective to have the GIT split into the foregut, midgut and hindgut and then detail the fetal development under those titles. This gave the page a good structure. However, adding some images, both from online and student-drawn to the foregut and hindgut sections would help improve the aesthetics of the page. The hand-drawn images on the midgut section are effective learning tools to a student, but maybe could be drawn a little neater with darker colours as the blue labelling is difficult to read. They should also be captioned. The use of a table to show midgut herniation of fetuses was a good tool as it makes the information easier to read also.

Lastly, the section on abnormalities was well-detailed and I liked that the deformities were split into a definition and cause. An image of gastrochisis may be helpful for a reader to visualise the condition though. The in-text citations in this part were properly done and a long list of references being at the end of the page made the project look neat overall. Areas of improvement may be some simple formatting changes and evening out the information across sections, however a solid project so far.

====Group 4- Genital====

Overall, it is evident that a lot of work has been completed on this project as each section has a decent amount of information and there are images throughout the page. However, the addition of an ‘introduction’ section would help to orient the reader and help students gain an overall understanding of the topic.

The section on ‘system development’ seems to be well-researched, however the formatting of the content in short, one-sentence dot points makes it difficult to read and incongruent, so writing this out in small paragraphs would improve the readability. The capitalization of some words is unnecessary in both the dot points and the table, creating inconsistencies in the formatting. Also, some words are unnecessarily bolded which detracts from the aesthetic appeal of the page. However, the inclusion of a table to summarise the timeline information is an effective tool, although there is much more information provided for the male system than female system. It is really good to see the use of an image as it is relevant and clearly compares the male and female system development side-by side. I also think the video inclusion is fantastic as it would be an effective way to learn for a reader with no previous knowledge, making the page more interactive.

The section on ‘current research, models and findings’ contains lots of relevant information, however this is not referenced in-text and it is thus unclear where the information has been derived from. There also seems to be some unevenness between the depth of information between male and female systems, which some more research can easily remedy. In terms of current findings, the listing of the information in dot points makes it easier to read, however there are some parts italicised and capitalized that are not needed. It is great to see some hand-drawn images as these are simplistic, colourful and effective ways to accompany the text, adding to the page’s appeal. Take care to properly include images, as one of them appears as ‘alt text’ and the link does not show the image itself. Although some references appear under a ‘references’ title in this section others appear as a website links; formatting of these could improve neatness.

The following section on ‘historic findings’ contains evidence of extensive research as it is very detailed and well-written. However, I would consider breaking this part up into smaller sections using dot points as large paragraphs seem tedious to read. The hand-drawn image is a good inclusion, but labelling of it would be effective and adding a couple more would break up the long section visually. Also, there seem to only be in-text citations after long chunks of information; perhaps more sources should be used/consulted.

Lastly, the abnormalities section was comprehensive and detailed and enough information was given on some examples. This was just the right amount of content, as any more would seem excessive. Adding some more images with appropriate captioning is advised also. I liked that the references were listed altogether at the end of the page, making it neat and tidy. Overall, a solid project which just needs some formatting to improve further.

====Group 5- Integumentary====

The introduction of this page was good as it provided a great overview and insight into what the project would later go on to discuss. Perhaps a little information on defining the integumentary system itself would be valuable though, to let the reader know the constituents.

The sub-sectioning of the page’s content into ‘introduction, ‘development overview’, ‘recent findings’, ‘historic findings’ and ‘abnormalities’ was clever, as the development section then went on to describe each component such as skin, nails etc. This effectively segmented the information into smaller chunks that could easily be navigated to. I especially liked the use of the table in the ‘skin’ section, showing the week of development, description and image corresponding alongside it, as it provided a holistic approach to that section. However, there were no in-text citations in the ‘skin’, ‘hair’, ‘nail’ or ‘teeth’ sections, hence the source of the information is unclear. To do this correctly, Dr Hill’s Wiki help page should be consulted.

The use of various images with labelled captions was a strength of this project, as the pictures were effective in balancing the text components to make the page more visually appealing. Most of the sections under ‘development overview’ have a decent amount of content, however the ‘nails’ part is a bit lacking and also needs to be correctly cited. The use of the table of images alongside the description of developmental stage in the ‘teeth’ section was very good to include, however the image is captioned ‘The stages of embryonic teeth development’. This may be irrelevant as the project’s focus is on fetal development. Further research into this area may uncover more relevant information.

Although the section on ‘recent findings’ contains a lot of information, the use of chunky paragraphs detracts from the readability of the page and the purple boxes could be summarised into dot points to help the reader understand the content more quickly. The section on historic findings seems concise and relevant, however the image included says it has been removed/deleted, so this requires editing. Lastly, the ‘abnormalities’ section was very well-structured and written, as each example had a captioned image accompanying it to help the reader visualise. This section was also well-done in terms of in-text citations, with an extensive reference list provided at the end. Perhaps consider adding some student-drawn images and possibly a relevant video, but otherwise it is very good as it is. Overall, the project has a good layout and a decent amount of content; with some editing and formatting it can be improved further.

====Group 7- Neural====

Overall, the project contains a decent amount of content as it is, split up into appropriate subheadings, considering the large scope of the nervous system. The introduction provides a succinct description of the CNS, however including an outline of what topics the page intends to cover would be good to orient a reader that approaches the page for the first time. The descriptions of the brain and spinal cord are well-written, however require in-text citations and some words need not be capitalised e.g midbrain, hypothalamus. These can be easily fixed with proof-reading and further editing.

The use of an image to illustrate fetal development was a very good idea; although the diagram is itself seems complicated, it can be explained well with the accompanying text beneath. The segmentation of the timeline into 4 different parts made it easier to follow, although I would consider placing the images on the right hand side of the page to reduce the vertical length of the page and the scrolling required to navigate through it. The section on ‘brain development’ contained some relevant information, formatted in dot points which improves readability, however in-text citations are needed to allow the reader to source the information if required. The use of the table in this part was effective also; it was concise and straight to the point.

Although the brain development section was very well detailed, there was no information in the spinal cord and meninges sections; with further research, these need to be evened out, along with the current findings section which is just references at this stage, but still a good start to finding sources of information. The section on current research is well-detailed and contains a lot of information too, which is good to see. Fiinally, I thought the section on abnormalities was very well done, using subheadings to segment the content. The use of dot points allowed the information to be easily read off the page, and use of images to accompany them helped the reader to visualise the conditions. There is one image however that has been incorrectly uploaded; consulting Dr Hill’s Wiki help page can remedy this. Also, the placement of all references under one list at the end of the page was effective in neatening it up, that was very well done too.

Overall, the project’s content has been well-researched and there is evidence of good teamwork and communication. Perhaps the use of some student-drawn images and inclusion of a relevant video may be areas of improvement.

====Group 8- Musculoskeletal====

Overall, the project has some very detailed sections and some sections where content is scarce. It would be helpful to start off with an introduction of the musculoskeletal system so the reader is aware of its components and what the page intends to cover. The timeline of muscle development has good potential, I understand it is still being planned at this stage and with further research, it could definitely be effective. A table format would be useful to present this information. The following sections on background embryonic development and fetal myogenesis are well-researched and have a lot of content, however I would consider breaking it down into dot points to improve readability. The sections are cited correctly in-text though, which is good to see.

There is much more improvement in the tendon and second trimester development sections, as the chunks of text have been reduced to provide a succinct summary, however these need to have citations also. The use of some images here, either hand-drawn or from online would be beneficial, to have a balance between text and pictures and make the page more visually appealing. Other than the abnormalities section which provides a good, concise summary of Duchenne Muscular Dystrophy, the following sections seem to be only references at this stage. As long as these are used to compose some relevant paragraphs/dot points, this is fine considering there is still time to improve the page.

Overall, this page has good potential as the groundwork has been completed; it is now more a matter of writing up more information, adding images and possibly a relevant video. The part on ‘making gains’ would need to be removed for the final, but otherwise, it is definitely a decent amount of work so far, especially considering the few group members involved.

===Lab 10===

'''Research article- Stage-dependent requirement of neuroretinal Pax6 for lens and retina development'''

'''Methods summary'''

Embryonic mouse stem cells from timed pregnant females were recombined in a homologous fashion to form floxed Pax-6 alleles in the experimental mice. These embryos were then harvested, fixed, PBS-washed, cryopreserved and sectioned for immunohistochemistry staining in which embryos were permeabilized and washed with PBT and incubated. This was followed by RNA in-situ hybridisation, where RNA polymerase was used to create antisense mRNA probes, then X-gal staining occurred.

The study then measured the length of the cell cycle phases of the mice embryos to assess the role of Pax6. Using wild-type littermates as controls, they found the proportion of proliferating retinal progenitor cells (RPCs) by injecting timed pregnant females with BrDU, then fixing, cryopreserving and sectioning them. Following this was a process of antigen retrieval with several incubations to calculate cell proliferation rate.

Finally, the cell cycle rate at embryonic days 11.5 and 13 were found and the cell cycle and S phase lengths were determined, also calculating the total length of the G1, G2 and M phases. These results were then quantified by statistical analysis using a t-test, counting 3 fields for every individual eye.

'''Results summary'''

By combining the findings of the separate sections of the experiment, the study concluded that Pax6 has an essential role in both lens and retinal cell formation. It was found that Pax6 deletion strong hypocellularity in early RPCs. There was high expression of Pax6 in the surface ectoderm (SE) and optic vesicle (OV) control embryos while the levels of Pax6 stayed constant and unchanged even after Pax6 elimination in the OV, lens pit and SE. The hypocellularity of the retina was more pronounced with time, and retinae deficient in Pax6 became smaller progressively.

Another finding was that the population size of the RPCs was reduced by changed cell cycle length and imbalance between cells exiting the cell cycle and proliferation of eye progenitor cells. It was again observed that retinal cells deficient in Pax6 were very hypocellular and cycling cells were centrally localised in the retina. An increased rate of cell death was observed with increasing time and total cell cycle length of Pax6-deficient RPCs was significantly longer than the control embryos. Also, the down-regulation of cyclin D1 in Pax6-deficient mice suggested that absence of Pax6 drives RPCs to cell cycle exit. Together, these findings suggested that positive progression of RPCs through the cell cycle is regulated by Pax6.

Finally, another conclusive result reached by this study was that the absence of Pax6 in RPCs causes a hindrance in their proper differentiation program into retinal cells; indicating the essential role of Pax6 in proliferation of early progenitors. It was also found that deficiency of Pax6 in optic vesicles could lead to the arrest of lens development during the interaction of the OV and SE. As neither the lens nor retina was formed properly in Pax6 deficient embryos, this indicated the importance of Pax6 presence in the optic vesicle for correct eye morphogenesis in the developing embryo.

<pubmed>24523460</pubmed>

[https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Vision_Development#Lens Sensory-Vision development Wiki page]

===Lab 11===

This study by Hidetoshi et al sought to explore the potential of human induced pluripotent stem cells (hiPSCs) to regenerate damaged cardiac tissue, in particular vascular cells and cardiomyocytes (CMs).

CMs and vascular cells were simultaneously induced using a differentiation protocol wherein the levels of gene expression of cardiac mesoderm and progenitor genes peaked at day 5 of differentiation. They found that mesoderm-to-CM differentiation enhancement occurred during days 5-7 due to Dkk1 addition (an antagonist). When vascular cell induction with CMs using VEGF was attempted instead of Dkk1, this led to induction of ECs and CMs together. The study found that the cell populations had a composition of vascular endothelial cadherin, platelet-derived growth factor receptor beta and positive MCs. These findings collectively suggested that a change from ‘only CMs’ to ‘CMS and vascular cells’ could be induced by selectively controlling the direction of differentiation of cardiovascular cells.

The experiment also tried to develop sheets of cardiovascular cells from hiPSCs by continuous culture, re-plating and incubations. It was found that reducing temperature served to re-assemble self-pulsating sheets of cells after heating and that sheets were composed of 3-4 layers supported by collagen fibres in a stratified manner. These sheets were shown to have CMs evenly distributed throughout them via immunohistochemical techniques. Within the cell sheets were; CMs, MCs and undifferentiated cells and this composition was attributed to possible apoptotic cell death reducing numbers and reduced proliferation efficiency. Together, these results suggested that it was the hiPSCs only that had generated the CMs and vascular cells, forming a structure that resembled cardiac tissue very realistically.

Lastly, Hidetoshi et al also found that the transplantation of hiPSCs with CTSs could alleviate dysfunctions in the cardiovascular system even after infarction in rats, as all rats had survived the period of post-transplantation without signs of tumours arising. Using echocardiogram technoogy, it was observed that anterior wall contraction had been brought back to normal, left ventricle systolic function had improved and that there had been reduced thickening of the wall of myocardial infarcts. Furthermore, staining with Sirius red found that the rate and extent of fibrosis was significantly reduced after hiPSC-CTS transplantation.

In conclusion, Hidetoshi et al concluded that there remained ample scope for hiPSCs to regenerate cardiac tissue and thus restore cardiac function, if their capabilities were studied more widely by other researchers. The replacement ability and biomedical potential of these pluripotent stem cells hold great promise for the future of stem cell therapy.

<pubmed>25336194/pubmed>

2014 Group Project 6

2014-10-24T03:59:22Z

Z3418702:

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

The endocrine system is awesome!

==Pineal gland==
===Fetal development===

[[File:Keith1902 fig167.jpg|200px|thumb|right| Image 1: schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|Image 2: Shows the location of the pineal gland in the adult brain.]]

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon reproductive hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>.

Melatonin plays an important role during fetal development. Both pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammalian fetus, intrinsic circadian rhythms are already established prior to birth.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || Pinealocytes || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

[[File:Primary brain vesicles.jpg|150px|left|thumb|Image 3: Primary brain vesicles]]'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle (Image 3).<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
[[File:Week 6 embryonic development of CNS.jpg|150px|left|thumb|Image 4: Week 6 embryonic development of CNS]]
[[File:Week 11 fetal development of CNS.jpg|150px|right|thumb|Image 5: Week 11 fetal development of CNS]]

*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement and an evagination of the pineal gland is visible (shown in image 4).

[[File:Fetal pineal gland 01.jpg|150px|thumb|right|Image 6: shows a fetal pineal gland at the end of the first trimester of development.]]

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum

*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis (shown in Image 5)

*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

===Abnormalities===

* '''Pineal tumors'''

Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>
[[File:Congenital hydrocephalus MRI02.jpg|150px|thumb|right|Image 7: Infant with obstructive congenital hydrocephalus]]

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signalling pathways, the Hyothalamus-Pituitary-Adrenal (HPA) and the Hypothalamus-Pituitary-Gonad (HPG) and exerts most of it's influence on the body through these two axes.
[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || (also known as antidiuretic hormone) Controls the body's water balance electrolyte concentration and blood pressure by increasing water permeability in distal convoluted tubules and in the collecting duct of nephrons in the kidney. Results in higher reabsorption of water in kidneys and thus higher blood volume and pressure.
|-
| Oxytocin || || Magnocellular neurosecretory cells || Stimulates lactation, hormone release during labor causes the muscles of the uterus contract
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Releases thyroid-stimulating hormone (TSH) as well as limited prolactin from anterior pituitary
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Inhibits release of prolactin from anterior pituitary
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Stimulates release of growth hormone from anterior pituitary
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Releases adrenocorticotropic hormone (ACTH) from anterior pituitary
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Stimulates release of follicle-stimulating hormone (FSH) as well as luteinizing hormone (LH) from anterior pituitary.
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Stimulates release of growth hormone (GH) from anterior pituitary and also has inhibitory effect on release of thyroid-stimulating hormone (TSH) from the anterior pituitary
|}

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in fetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Fetal oxytocin may initiate or accelerate the course of labor whereas vasopressin plays a role in the adaptation to stress caused by the birth process by redistribution of fetal blood flow.

'''Timeline'''

[[File:Development of hypothalamus.jpg|900px|right|thumb|Image 3: Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).
[[File:Stage 22 image 057.jpg|200x|thumb|Image 1. Histological cross-section of stage 22 embryo]]
* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

===Abnormalities===

*'''Congenital Hypothalamic Hamartoma'''

A hypothalamic hamartoma arises from the region of the tuber cinereum and is commonly associated with isosexual precocious puberty, i.e. puberty that develops unusually early in infants. It involves the alteration of pathways that modulate gonadotropins and contain releasing hormones within the floor of the third ventricle. .<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref> Precocious puberty may either result from a physical manipulation of inhibitory pathways by the hamartoma or a direct neurosecretory process of the hamartoma itself. Seizures are also another common clinical presentation in children with a hypothalamic hamartoma. MR imaging is typically used to identify and monitor the growth of a hypothalamic hamartoma during embryonic and fetal development. Research has shown a trend of congenital hamartomas forming in the embryo within a period of 26 weeks. Because of the known association with other congenital anomalies of the central nervous system, hypothalamic hamartoma is thought to form as early as 4 weeks and may in fact be part of a developmental abnormality spectrum.<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref>. Treatment options are currently limited to post-natal deliver of leuprolide acetate to the infant and in general it is relatively effective in managing and treating the condition.

==Pituitary gland==
[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]
=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>
* Anterior pituitary

[[File:Anterior Pituitary Hormones.jpg|300px|right|thumb|Timeline of anterior pituitary hormone expression and synthesis]]

By week 8 of embryological development, the pituitary gland is fully formed and begins functioning as a control centre for release of hormones that are vital for subsequent organ development.

* Week 10 - Growth Hormone and ACTH detectable
* Week 21 - Vasopressin hormone synthesis established

'''Anterior Pituitary - Adenohypophysis'''

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || No function in fetal development. All postnatal action.
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|}

'''Posterior Pituitary - Neurohypophysis'''

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://www.sciencedirect.com/science/article/pii/S030100820900046X#></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Cardiomyogenesis
* Protective action of fetal neurons during brain development
* Neuronal development and plasticity <ref name =Yuzo Murata, Ming-Zi Li, Sadahiko Masuko>Yuzo Murata, Ming-Zi Li, Sadahiko Masuko, 2011, '''Developmental expression of oxytocin receptors in the neonatal medulla
oblongata and pons''', Neuroscience Letters; 502 (2011), pp157-161, http://www.sciencedirect.com/science/article/pii/S0304394011010949#></ref>
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Regulates fetal renal function
* Regulates amniotic fluid content and concentration
* Regulates blood pressure, heart rate, cardiac output and placental blood flow <ref name =M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher >M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher , 1993, '''Vasopressin receptors and effects during fetal development''', Regulatory Peptides; 45, pp203-208, http://www.sciencedirect.com/science/article/pii/016701159390207O#></ref>
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

'''How far has the thyroid gland developed by week 8 of gestation?'''
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

'''Fetal Stage of Thyroid Development - from week 8 of gestation onwards:'''
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis<ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>
* Week 16 - 18 is when fetal thyroid hormone synthesis occurs
** Prior to this, the fetus receives vital maternal thyroid hormones via the placenta

'''Thyroid Hormone Action'''
The following table explains the ontogenic action of thyroid hormone on the developing fetus. Thyroid hormones are essential in brain and central nervous system development in the fetus. A lot of neurological disorders are associated with insufficient thyroid hormone synthesis:

{| class="wikitable"
|-
! Hormone !! Types !! Ontogenic Action
|-
| Thyroid Hormone ||
* T3 - triiodothyronine
* T4 - thyroxine
|| Brain development:
* Central Nervous System development and maturation <ref name =J Patel, K Landers, H Li, R H Mortimer and K Richard>J Patel, K Landers, H Li, R H Mortimer and K Richard, 2011, '''Thyroid hormones and fetal neurological development''', Journal of Endocrinology:209;1-8, http://joe.endocrinology-journals.org.wwwproxy0.library.unsw.edu.au/content/209/1/1.full.pdf+html></ref>
*Glial cell proliferation
*Neural myelination
*Axon and dendrite sprouting
*Synapse formation
|}

===Abnormalities===

'''Hypothyroidism'''
[[File:Hypothyroidism.jpg|300px|right|thumb|This image compares a normal thyroid gland (a) anatomy with a hypothyroidism thyroid gland (b)]]

Hypothyroidism is an abnormality that can occur in fetal development were there is insufficient thyroid hormone action. This can be due to mutations in the thyroid-stimulating hormone receptor on the thyroid gland, hence the hypothalmic-pituitary-thyroid axis communication is lost. This then results in distinct decrease in T3 and T4 levels in the fetus. Follow on effects of this deficiency include abnormal brain and central nervous system development due to lack of neuron branching and myelination. Postnatally, this can cause learning difficulties, issues with olfactory and optic systems and impaired reflex actions. <ref name =Jung-Yu C. Hsu, Stuart A. Stein and Xiao-Ming Xu>Jung-Yu C. Hsu, Stuart A. Stein and Xiao-Ming Xu, 2008, '''Abnormal Growth of the Corticospinal Axons Into the Lumbar Spinal Cord of the hyt/hyt Mouse With Congenital Hypothyroidism''', Journal of Neuroscience Research: 86; 3126-3139, http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/store/10.1002/jnr.21750/asset/21750_ftp.pdfv=1&t=i1lzkkit&s=8b2bb85677790b58b7415f9376e06a5c4329578b></ref>

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|right|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone || Secreted by || Function || Image
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine. || [[File:Active parathyroid hormone assay cartoon.png|200px|thumb|This images shows an active parathyroid hormone and its chemical structure.]]
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

'''Fetal hyperparathyroidism'''

Fetal hyperparathyroidism is a condition that is caused when an excess of parathyroid hormone (PTH) is present the bloodstream.<ref><pubmed> 1745971</pubmed></ref> This may be due to an overstimulated maternal parathyroid gland out of all the four which transfers the over accumulated PTH to the fetus. Normal fetal development requires 25–30 gms of calcium for bone mineralization and around 80% of this calcium accretion is observed in the third trimester of pregnancy. However the calcium gradient of 1.0:1.4 is no longer maintained when there is hyperparathyroidism present.<ref><pubmed> 12140371</pubmed></ref>Instead the gradient is elevated causing fetal parathyroid gland suppression thereby leading to Hypocalcemia. Calcium mobilisation then becomes difficult and hence fetal tetany may occur followed by miscarriage.<ref><pubmed> 25327435</pubmed></ref> In the event that the fetus survives, postnatal problems such as the baby having weak bones will be likely and would require calcium treatment throughout most of their lives.

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

'''Thymic aplasia'''

Thymic aplasia is a condition that has a strong correlation to DiGeorge syndrome. This syndrome is a congenital birth defect which occurs when the fetus either inherits an abnormal chromosome 22 or has a mutation of the same chromosome. In particularly, the mutation is a deletion of the genomic information packaged in the chromosomes and normally occurs when there isn’t proper recombination of chromosomal material during fertilisation.<ref><pubmed>4166528</pubmed></ref> As a result of this deletion, the third and fourth pharyngeal pouches fail to develop in the twelfth gestational week, thereby leading to the absence or partial absence of the thymus and parathyroid glands. Other associated abnormalities with thymic aplasia as a result of the deletion of chromosome 22 genetic material are severe cardiac defects, low immunity, hypocalcaemia and facial abnormalities. <ref><pubmed>5057550</pubmed></ref> Statistics suggest that the thymic aplasia may occur in 1:4000 to 1:6395 of fetuses.<ref><pubmed> 10861201</pubmed></ref> Treatment is normally difficult for fetuses that exhibit thymic aplasia, however calcium levels can be monitored and regulated and heart problems can be resolved though surgery. Immunity defects can be managed from controlling phosphorus levels in the fetus and protecting them from sources of infection.<ref><pubmed>1454183</pubmed></ref>
[[File:Histopathology of the thymus with hyperplasia.jpg|250px|thumb|right|This image shows the histopathology of the thymus with hyperplasia and thymoma]]

'''Thymoma'''

Thymoma is the term given to the neoplasms of the thymus gland. These tumours emerge from the thymic epithelium cells of the thymus gland and do not normally show cytologic characteristics of malignancy, however are considered malignant as they are likely to undergo invasion. Thymomas are classified into different types based on the content and structure of the cells. If the tumour has spindle cell conformation, it is known as type A thymoma and constitutes to 4% to 7% of all thymomas. The tumor is made up of neoplastic thymic epithelial cells that exhibit a spindle oval shape conformation, lack nuclear atypia and have low levels of non-neoplastic lymphocytes. Mixed thymoma, also known as type AB thymoma are similar to a type A thymoma except that the foci is enriched with non-neoplastic lymphocytes. It makes up approximately 28% to 34% of all thymomas.<ref><pubmed>25143131</pubmed></ref>Type B1 thymoma also termed as lymphocytic thymoma is similar to a healthy functional thymus as it contains a large proportion of cells exhibiting features indistinguishable from a healthy thymic cortex with areas similar to thymic medulla. It makes up for approximately 9% to 20% of all thymomas.<ref><pubmed>24672784</pubmed></ref>Cortical thymoma, also known as type B2 thymoma contains neoplastic epithelial cells which appear scattered with vesicular nuclei and distinct nucleoli located in a dense population of non-neoplastic lymphocytes.<ref><pubmed>2698424</pubmed></ref>It is similar to type B1 thymoma but the foci of medullary differentiation are less visible. It makes up for approximately 20% to 36% of all thymomas. Epithelial thymoma, also known as type B3 thymoma is formed mainly from polygonal shaped epithelial cells that show no atypia. The mixture of non-neoplastic lymphocytes gives the tumour a sheet-like appearance. This makes up for approximately 10% to 14% of all thymomas. Since some of these are hard to differentiate from normal thymus tissues, there is poor prognosis.

Thymomas have been closely linked with another disease called myasthenia gravis. It is caused when nerve impulses are disrupted at the neuromuscular junction of skeletal muscles from the lack of binding of acetylcholine (neurotransmitter) to acetylcholine receptors needed to generate muscle contraction. Antibodies produced from the thymus gland destroy the acetylcholine receptors and hence have a strong correlation to myasthenia gravis. <ref><pubmed>21747138</pubmed></ref> Since thymomas contain more cells than normal and are malignant, it is more likely to generate antibodies which target acetylcholine receptors. The formation of these antibodies in B cells is T cell dependent. The T cells involved in this mechanism are generated in the thymus via nontolerogenic thymopoiesis through an abnormal function of thymic epithelial cells.<ref><pubmed> 20402580</pubmed></ref> Overall, incorrect signalling messages could be sent out and hence cause an autoimmune attack.

==Pancreas==
===Fetal development===
[[File:Development of the pancreas during fetal development.jpg|250px|thumb|right|This images shows normal pancreatic development of the fetus.]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
[[File:Ratio of alpha & beta cells at different phases of fetal development.png|350px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref> <ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

*'''Annular Pancreas'''
[[File:Annular pancreas.jpg|200px|thumb|right|This image shows annular pancreas where a ring of the pancreatic tissue encircles the growing duodenum.]]
Annular pancreas is a rare abnormality that can occur during fetal development in which a ring of the pancreatic tissue encircles the growing duodenum.<ref><pubmed>25124266</pubmed></ref> It occurs in 1 out of 7000 birth and is commonly associated with other abnormalities such as esophageal atresia and malrotation of the midgut. It is assumed that annular pancreas occurs when the tip of right ventral bud sticks to the duodenal wall which then forms a ring from the continuous stretching of the wall during rotation.<ref><pubmed> 25165593</pubmed></ref> This part of the pancreas can constrict the duodenum thereby restricting the flow of food to the intestines of the gastrointestinal tract.<ref><pubmed>24890427</pubmed></ref> Furthermore, annular pancreas is divided into two forms. Complete annular pancreas is when the pancreatic parenchyma wraps around the 2nd part of the duodenum completely whereas in incomplete annular pancreas, the tissue only surrounds the duodenum partially.<ref><pubmed> 24741860</pubmed></ref>Treatment for annular pancreas mainly involves surgery to bypass the constricted portion of the duodenum.

*'''Gestational diabetes mellitus'''

Gestational diabetes mellitus (GDM) is a disorder in which women without any history of diabetes show elevated blood glucose levels during pregnancy normally around the third trimester. It is caused when insulin receptors fail to respond correctly due to interference from signalling molecules related to pregnancy such as the interaction between human placental lactogen, prolactin and estradiol with the insulin receptors.<ref><pubmed>2141655</pubmed></ref> As a result, high blood glucose levels are observed. Patients with GDM have high levels of insulin resistance with increased β-cells production of the pancreas since the high levels of blood glucose are not interacting with the abnormal insulin receptors. Glucose is known to diffuse through the placenta via GLUT1 carrier situated in the syncytiotrophoblast of both the microvillus and basal membranes. With GDM, the number of GLUT1 molecules increase and hence placing high levels of glucose to the fetus since insulin itself cannot diffuse across the placenta and counteract this extremity.<ref><pubmed>25333246</pubmed></ref> This mechanism is known to lead to excessive growth at birth with a low glucose environment as it declines and high insulin production overall leading to hypoglycaemia.<ref><pubmed>25315294</pubmed></ref>It can also lead to jaundice and seizures in the new born with mothers having high susceptibility to type 2 diabetes mellitus. GDM can be controlled by monitoring blood sugar levels and controlling levels of glucose and insulin through pharmaceutical drugs.

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*'''Congenital Adrenal Hyperplasia (CAH)'''

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more.[[File:Cushing's syndrome.jpg|150px|right|thumb|This image shows a 3-month old child with classic signs of Cushing’s syndrome; central obesity, chubby cheeks and moon facies]] Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

*'''Cushing's Syndrome'''

Cushing’s Syndrome (CS) is a metabolic disorder characterised by abnormally high production of endogenous cortisol or exogenous levels of corticosteroids, which disrupts the metabolism of macromolecules such as lipids and carbohydrates. It is most common in obese adults aged 20-50 and the most common cause is the therapeutic administration of exogenous ACTH <ref><pubmed>24656295</pubmed></ref>. Cushing’s Syndrome’s two forms are either ACTH-dependent CS (80-85% of patients) or ACTH independent. The etiology of the dependent form is adrenal gland hyperplasia and excessive ACTH secretion by adenomas in the pituitary, however other causes include; small cell lung carcinoma ACTH production ectopically, or medullary thyroid carcinomas. <ref name= PMID24365350><pubmed>24365350</pubmed></ref> The independent form is however caused by neoplastic growths in the adrenal gland such as carcinomas, adenomas and macronodular hyperplasia. Clinical manifestations of this disorder include; moon facies, cataracts, hyperglycaemia, abnormal fat distribution, poor wounding of the skin, obesity in the central body and muscle wasting in 60% of patients. <ref name= PMID24365350><pubmed>24365350</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''
'''How far has the ovary developed by week 8 of gestation?'''
*Week 5- Thickening of mesothelium forms on the mesonephros. Formation of the gonadal ridge results from proliferation of the mesothelium and mesenchymal tissue beneath it <ref name= PMID>17237341<pubmed>17237341</pubmed></ref>
*Projection of finger-like gonadal (epithelial) cords into the mesenchyme. Indifferent gonad segmented medulla )regresses) and cortex (differentiates to form the ovary)
*PGCs migrate through the primitive streak in gastrulation and then reside at the junctional region of the hindgut yolk sac. Migration of the PGCs to the gonadal ridge along the hindgut’s dorsal mesentery <ref name= PMID>17237341<pubmed>17237341</pubmed></ref>
*Week 6- PGCs incorporated into the gonadal cords and are called oogonia, having entered underlying mesenchyme.

'''Fetal stage of ovarian development - from week 8 of gestation onwards:'''

'''Timeline'''
[[File:Fetal ovary morphogenesis (mouse).jpg|300px|right|thumb|Diagramatic representation of fetal mouse ovary morphogenesis]]
*Weeks 8 to 9- Gonad is identifiable as an ovary now due to change in internal structure. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates. Inner ovary; disintegrating blastema surrounded by a thick blastemal layer. Tissue has a cortical region (encloses PGCs) and a central medullary region (reticulum of somatic cells) <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>
*Weeks 10 to 12- Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue <ref name= PMID>22106406<pubmed>22106406</pubmed></ref>
*Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium. Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups. Medulla contains less densely-packed globules, mainly oogonia <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>
*Weeks 14 to 28- In mid-gestation; depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth <ref name= PMID>22106406<pubmed>22106406</pubmed></ref>
*Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium. Primordial follicle formation is the result of active mitosis of oogonia <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>

===Abnormalities===

*Congenital gonadal dysgenesis – Turner Syndrome

Female congenital gonadal dysgenesis syndrome refers to a condition where the fetus undergoes abnormal gonadal development with a presentation of streaks of connective tissue on the developing ovary, also referred to as "streak gonads". Streak ovaries extend from the lateral pelvic wall to the attachment of the utero-ovarian ligaments and are essentially sections of functionless tissue. They vary considerably in size but are usually approximately 4 cm in length and 2–3 mm in width. Dysgenetic ovaries are characterized by also absence of follicular structures and oocytes. In women, the most common cause of congenital gonadal dysgenesis is Turner syndrome, 45X which has a prevalence of approximately 1 in 2500 new born girls worldwide<ref name= PMID15475933><pubmed>15475933</pubmed></ref>. Turner syndrome is a genetic abnormality due to an incomplete or completely missing X chromosome in females. Growth hormones treatments such as estrogen replacement therapy may be used after the child has reached 12-13 years of age to help treat the symptoms<ref name= PMID0001417><pubmed>0001417</pubmed></ref>.

==Testis==
===Fetal development===

[[File:Testis and ovary.jpg|300px|right|thumb|This image shows the cell types that constitute the testis and ovary during gestation]]
'''How far has the testis developed by week 8 of gestation?'''
*By week 8, masculine differentiation is induced in the mesonephric duct and external genitalia. This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>
*Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>

'''Fetal stage of testicular development - from week 8 of gestation onwards'''

'''Timeline'''
*Week 9- Yellowish elongated tube with mesonephros laterally and urinary bladder inferomedially
*Week 13- Testes have acquired the ellipsoidal shape found in the adult and are located above the inguinal canal in the groin region. Convexly curved across all but posterior surface <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*Week 16- Located above deep inguinal ring, convexly curved anterior border and flat posterior border covered by epididymis
*Week 17- Migration of testes begins
*Week 24- Testes grow in size and still located about the deep inguinal ring or inside inguinal canal. The testicular poles seem more prominent. Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26 <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
*Week 30- Testes sinus is towards lower portion of testes and epididymis tail continuous with vas deferens. Testes are located in the scrotum having passed through the superficial inguinal ring
*Week 36- Testes located within scrotal sac, they enlarge in size and are maximally convex <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
===Abnormalities===

*'''Klinefelter’s syndrome'''

Klinefelter’s syndrome is the common form of congenital primary hypogonadism with a prevalence of an estimated 1 in 1000 men. Male hypogonadism is defined as a testicular dysfunction resulting in decreased sperm and testosterone production<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.. This genetic disorder occurs when a male is born with an additional X chromosome causing complications and a general underdevelopment of structures such as the seminiferous tubules and Leydig cells within the testis. As a consequence, the size of the testis is abnormally small and the patient has a low sperm count and testosterone levels. In addition to infertility caused by testosterone deficiency, men born with this disorder frequently have increased length of their long bones, including those in the arms, legs, and hands. Many other complications exist independent of the testosterone deficiency seen with these patients<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''
[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]
*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

*'''Placenta accreta'''

[[File:Placenta accreta.jpg|150px|right|thumb|This image shows an area of profuse bleeding in the human placenta, with a region of placenta accreta indicated by the arrow]]

Placenta accreta (PA )is a rare obstetric abnormality characterised by abnormal insertion of the placenta to the myometrium of the uterus. The 3 types of PA are classified based on the depth of invasion; placenta accreta (superficial- chorionic villi attach to myometrium rather than just decidua basalis), placenta increta (middle layer) or placenta perceta (deep) being the most dire with 1 in 7000 incidence. <ref name= PMID23127895><pubmed>23127895</pubmed></ref> PA has an incidence of 1 in 2500 deliveries and is associated with grand-scale haemorrhage and requires hysterectomy and blood transfusion. <ref name= PMID21280984><pubmed>21280984</pubmed></ref> The condition normally occurs in the lower segment of the uterus which is prone to bleeding being poorly contractile and a site of angiogenesis. Prenatal diagnosis of PA is based on second and third trimester ulstrasound findings indicating; retroplacental zone loss, many lucanue in the vasculature and a very thin (<1mm) retroplacental thickness of the myometrium.<ref name= PMID21280984><pubmed>21280984</pubmed></ref> PA has a 40% likelihood in women aged over 35 who have had Caesarian section with placenta previa in their uterine scars. <ref name= PMID23127895><pubmed>23127895</pubmed></ref>

==Recent Findings==

{|
|-bgcolor="F5FFFA"
|
'''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''<ref><pubmed>22912418</pubmed></ref>

''Jennifer R Gardiner, Abigail L Jackson, Julie Gordon, Heiko Lickert, Nancy R Manley, M Albert Basson '''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''. Development: 2012, 139(18);3456-66 PMID: 22912418''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.
|}

{|
|-bgcolor="F5FFFA"
|'''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''<ref><pubmed>23300903</pubmed></ref>

''Stéphanie Migrenne, Evelyne Moreau, Pirjo Pakarinen, Andrée Dierich, Jorge Merlet, René Habert, Chrystèle Racine '''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''. PLoS ONE: 2012, 7(12);e53257 PMID: 23300903''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.
|}

{|
|-bgcolor="F5FFFA"
|'''Neuropeptide Y in the Adult and Fetal Human Pineal Gland'''<ref><pubmed>24757681</pubmed></ref>

''Morten Møller, Pansiri Phansuwan-Pujito, Corin Badiu '''Neuropeptide Y in the adult and fetal human pineal gland'''. Biomed Res Int: 2014, 2014;868567 PMID: 24757681''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland. Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.
|}

{|
|-bgcolor="F5FFFA"

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, '''Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation.’'' Neuroscience Letters. 556; pp 124–128 http://www.sciencedirect.com/science/article/pii/S0304394013009300</ref>

This study investigates the expression of the voltage operated calcium channels subunits α1A and α1D in the male and female bovine hypothalamus during four embryonic stages of development. The expression of both these subunits have been identified in the brain of adult mammals, however, their distribution and expression during fetal neuronal differentiation has not yet been determined<ref name=Peruffoa>A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, ‘Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation.’ Neuroscience Letters. 556; pp 124–128 http://www.sciencedirect.com/science/article/pii/S0304394013009300</ref>.

The results suggest that expressions of α1A and α1D are correlated with the stage of development, with an increase only in males that peaks on the last period of gestation. Bovine male hypothalami showed significantly higher α1A and α1D expression values in comparison to female ones during the whole developmental period. Additionally immunohistological studies confirmed the presence of the α1A and α1D protein subunits in fetal hypothalamic neurons starting from the third fetal stage.

These calcium channels may have a role in modulating physiological responses of surrounding neural structures during the second trimester of gestation while the hypothalamus is defined and networks start to develop. Due to the long duration of the pregnancy like humans, fetal bovine tissues may represent an important model for translational studies on the human hypothalamic development. In contrast with rodent models, in long gestation species such as the bovine, the critical period for hypothalamic sexual differentiation occurs in earlier gestation phases and thus presents a more relevant model to correlate to human embryonic sexual development<ref name=Peruffoa>A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, ‘Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation.’ Neuroscience Letters. 556; pp 124–128 http://www.sciencedirect.com/science/article/pii/S0304394013009300</ref>.
|}

=References=

<references/>

File:Testis and ovary.jpg

2014-10-24T03:55:19Z

Z3418702: ==Ovary and testis cell types== Image indicating the different component cells of the mammalian testis and ovary in gestation. This ia a student drawn representation, adapted from <ref>Dagmar Wilhelm, Jennifer X Yang, Paul Thomas Chapter Three – Mamm...

==Ovary and testis cell types==
Image indicating the different component cells of the mammalian testis and ovary in gestation. This ia a student drawn representation, adapted from <ref>Dagmar Wilhelm, Jennifer X Yang, Paul Thomas Chapter Three – Mammalian Sex Determination and Gonad Development. Current topics in developmental biology: 2013, 106; 89-121, http://www.sciencedirect.com/science/article/pii/B9780124160217000031</ref>

===Reference===
<references/>

'''Copyright'''

Beginning six months after publication, I z3418702 grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode

{{Template:Student Image}}

2014 Group Project 6

2014-10-24T02:28:50Z

Z3418702: /* Abnormalities */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

The endocrine system is awesome!

==Pineal gland==
===Fetal development===

[[File:Keith1902 fig167.jpg|200px|thumb|right| Image 1: schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|Image 2: Shows the location of the pineal gland in the adult brain.]]

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon reproductive hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>.

Melatonin plays an important role during fetal development. Both pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammalian fetus, intrinsic circadian rhythms are already established prior to birth.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || Pinealocytes || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

[[File:Primary brain vesicles.jpg|150px|left|thumb|Image 3: Primary brain vesicles]]'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle (Image 3).<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
[[File:Week 6 embryonic development of CNS.jpg|150px|left|thumb|Image 4: Week 6 embryonic development of CNS]]
[[File:Week 11 fetal development of CNS.jpg|150px|right|thumb|Image 5: Week 11 fetal development of CNS]]

*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement and an evagination of the pineal gland is visible (shown in image 4).

[[File:Fetal pineal gland 01.jpg|150px|thumb|right|Image 6: shows a fetal pineal gland at the end of the first trimester of development.]]

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum

*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis (shown in Image 5)

*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

===Abnormalities===

* '''Pineal tumors'''

Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>
[[File:Congenital hydrocephalus MRI02.jpg|150px|thumb|right|Image 7: Infant with obstructive congenital hydrocephalus]]

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signalling pathways, the Hyothalamus-Pituitary-Adrenal (HPA) and the Hypothalamus-Pituitary-Gonad (HPG) and exerts most of it's influence on the body through these two axes.
[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]
[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || (also known as antidiuretic hormone) Controls the body's water balance electrolyte concentration and blood pressure by increasing water permeability in distal convoluted tubules and in the collecting duct of nephrons in the kidney. Results in higher reabsorption of water in kidneys and thus higher blood volume and pressure.
|-
| Oxytocin || || Magnocellular neurosecretory cells || Stimulates lactation, hormone release during labor causes the muscles of the uterus contract
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Releases thyroid-stimulating hormone (TSH) as well as limited prolactin from anterior pituitary
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Inhibits release of prolactin from anterior pituitary
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Stimulates release of growth hormone from anterior pituitary
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Releases adrenocorticotropic hormone (ACTH) from anterior pituitary
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Stimulates release of follicle-stimulating hormone (FSH) as well as luteinizing hormone (LH) from anterior pituitary.
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Stimulates release of growth hormone (GH) from anterior pituitary and also has inhibitory effect on release of thyroid-stimulating hormone (TSH) from the anterior pituitary
|}

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in fetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Fetal oxytocin may initiate or accelerate the course of labor whereas vasopressin plays a role in the adaptation to stress caused by the birth process by redistribution of fetal blood flow.

'''Timeline'''

[[File:Development of hypothalamus.jpg|900px|right|thumb|Image 3: Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).
[[File:Stage 22 image 057.jpg|200x|thumb|Image 1. Histological cross-section of stage 22 embryo]]
* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

===Abnormalities===

*'''Congenital Hypothalamic Hamartoma'''

A hypothalamic hamartoma arises from the region of the tuber cinereum and is commonly associated with isosexual precocious puberty, i.e. puberty that develops unusually early in infants. It involves the alteration of pathways that modulate gonadotropins and contain releasing hormones within the floor of the third ventricle. .<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref> Precocious puberty may either result from a physical manipulation of inhibitory pathways by the hamartoma or a direct neurosecretory process of the hamartoma itself. Seizures are also another common clinical presentation in children with a hypothalamic hamartoma. MR imaging is typically used to identify and monitor the growth of a hypothalamic hamartoma during embryonic and fetal development. Research has shown a trend of congenital hamartomas forming in the embryo within a period of 26 weeks. Because of the known association with other congenital anomalies of the central nervous system, hypothalamic hamartoma is thought to form as early as 4 weeks and may in fact be part of a developmental abnormality spectrum.<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref>. Treatment options are currently limited to post-natal deliver of leuprolide acetate to the infant and in general it is relatively effective in managing and treating the condition.

*

==Pituitary gland==
[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]
=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>
* Anterior pituitary

[[File:Anterior Pituitary Hormones.jpg|300px|right|thumb|Timeline of anterior pituitary hormone expression and synthesis]]

By week 8 of embryological development, the pituitary gland is fully formed and begins functioning as a control centre for release of hormones that are vital for subsequent organ development.

* Week 10 - Growth Hormone and ACTH detectable
* Week 21 - Vasopressin hormone synthesis established

'''Anterior Pituitary - Adenohypophysis'''

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || No function in fetal development. All postnatal action.
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|}

'''Posterior Pituitary - Neurohypophysis'''

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://www.sciencedirect.com/science/article/pii/S030100820900046X#></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Cardiomyogenesis
* Protective action of fetal neurons during brain development
* Neuronal development and plasticity <ref name =Yuzo Murata, Ming-Zi Li, Sadahiko Masuko>Yuzo Murata, Ming-Zi Li, Sadahiko Masuko, 2011, '''Developmental expression of oxytocin receptors in the neonatal medulla
oblongata and pons''', Neuroscience Letters; 502 (2011), pp157-161, http://www.sciencedirect.com/science/article/pii/S0304394011010949#></ref>
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Regulates fetal renal function
* Regulates amniotic fluid content and concentration
* Regulates blood pressure, heart rate, cardiac output and placental blood flow <ref name =M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher >M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher , 1993, '''Vasopressin receptors and effects during fetal development''', Regulatory Peptides; 45, pp203-208, http://www.sciencedirect.com/science/article/pii/016701159390207O#></ref>
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

'''How far has the thyroid gland developed by week 8 of gestation?'''
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

'''Fetal Stage of Thyroid Development - from week 8 of gestation onwards:'''
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis<ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>
* Week 16 - 18 is when fetal thyroid hormone synthesis occurs
** Prior to this, the fetus receives vital maternal thyroid hormones via the placenta

'''Thyroid Hormone Action'''
The following table explains the ontogenic action of thyroid hormone on the developing fetus. Thyroid hormones are essential in brain and central nervous system development in the fetus. A lot of neurological disorders are associated with insufficient thyroid hormone synthesis:

{| class="wikitable"
|-
! Hormone !! Types !! Ontogenic Action
|-
| Thyroid Hormone ||
* T3 - triiodothyronine
* T4 - thyroxine
|| Brain development:
* Central Nervous System development and maturation <ref name =J Patel, K Landers, H Li, R H Mortimer and K Richard>J Patel, K Landers, H Li, R H Mortimer and K Richard, 2011, '''Thyroid hormones and fetal neurological development''', Journal of Endocrinology:209;1-8, http://joe.endocrinology-journals.org.wwwproxy0.library.unsw.edu.au/content/209/1/1.full.pdf+html></ref>
*Glial cell proliferation
*Neural myelination
*Axon and dendrite sprouting
*Synapse formation
|}

===Abnormalities===

'''Hypothyroidism'''
[[File:Hypothyroidism.jpg|300px|right|thumb|This image compares a normal thyroid gland (a) anatomy with a hypothyroidism thyroid gland (b)]]

Hypothyroidism is an abnormality that can occur in fetal development were there is insufficient thyroid hormone action. This can be due to mutations in the thyroid-stimulating hormone receptor on the thyroid gland, hence the hypothalmic-pituitary-thyroid axis communication is lost. This then results in distinct decrease in T3 and T4 levels in the fetus. Follow on effects of this deficiency include abnormal brain and central nervous system development due to lack of neuron branching and myelination. Postnatally, this can cause learning difficulties, issues with olfactory and optic systems and impaired reflex actions. <ref name =Jung-Yu C. Hsu, Stuart A. Stein and Xiao-Ming Xu>Jung-Yu C. Hsu, Stuart A. Stein and Xiao-Ming Xu, 2008, '''Abnormal Growth of the Corticospinal Axons Into the Lumbar Spinal Cord of the hyt/hyt Mouse With Congenital Hypothyroidism''', Journal of Neuroscience Research: 86; 3126-3139, http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/store/10.1002/jnr.21750/asset/21750_ftp.pdfv=1&t=i1lzkkit&s=8b2bb85677790b58b7415f9376e06a5c4329578b></ref>

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|right|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone || Secreted by || Function || Image
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine. || [[File:Active parathyroid hormone assay cartoon.png|200px|thumb|This images shows an active parathyroid hormone and its chemical structure.]]
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

'''Fetal hyperparathyroidism'''

Fetal hyperparathyroidism is a condition that is caused when an excess of parathyroid hormone (PTH) is present the bloodstream.<ref><pubmed> 1745971</pubmed></ref> This may be due to an overstimulated maternal parathyroid gland out of all the four which transfers the over accumulated PTH to the fetus. Normal fetal development requires 25–30 gms of calcium for bone mineralization and around 80% of this calcium accretion is observed in the third trimester of pregnancy. However the calcium gradient of 1.0:1.4 is no longer maintained when there is hyperparathyroidism present.<ref><pubmed> 12140371</pubmed></ref>Instead the gradient is elevated causing fetal parathyroid gland suppression thereby leading to Hypocalcemia. Calcium mobilisation then becomes difficult and hence fetal tetany may occur followed by miscarriage.<ref><pubmed> 25327435</pubmed></ref> In the event that the fetus survives, postnatal problems such as the baby having weak bones will be likely and would require calcium treatment throughout most of their lives.

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

'''Thymic aplasia'''

Thymic aplasia is a condition that has a strong correlation to DiGeorge syndrome. This syndrome is a congenital birth defect which occurs when the fetus either inherits an abnormal chromosome 22 or has a mutation of the same chromosome. In particularly, the mutation is a deletion of the genomic information packaged in the chromosomes and normally occurs when there isn’t proper recombination of chromosomal material during fertilisation.<ref><pubmed>4166528</pubmed></ref> As a result of this deletion, the third and fourth pharyngeal pouches fail to develop in the twelfth gestational week, thereby leading to the absence or partial absence of the thymus and parathyroid glands. Other associated abnormalities with thymic aplasia as a result of the deletion of chromosome 22 genetic material are severe cardiac defects, low immunity, hypocalcaemia and facial abnormalities. <ref><pubmed>5057550</pubmed></ref> Statistics suggest that the thymic aplasia may occur in 1:4000 to 1:6395 of fetuses.<ref><pubmed> 10861201</pubmed></ref> Treatment is normally difficult for fetuses that exhibit thymic aplasia, however calcium levels can be monitored and regulated and heart problems can be resolved though surgery. Immunity defects can be managed from controlling phosphorus levels in the fetus and protecting them from sources of infection.<ref><pubmed>1454183</pubmed></ref>
[[File:Histopathology of the thymus with hyperplasia.jpg|250px|thumb|right|This image shows the histopathology of the thymus with hyperplasia and thymoma]]

'''Thymoma'''

Thymoma is the term given to the neoplasms of the thymus gland. These tumours emerge from the thymic epithelium cells of the thymus gland and do not normally show cytologic characteristics of malignancy, however are considered malignant as they are likely to undergo invasion. Thymomas are classified into different types based on the content and structure of the cells. If the tumour has spindle cell conformation, it is known as type A thymoma and constitutes to 4% to 7% of all thymomas. The tumor is made up of neoplastic thymic epithelial cells that exhibit a spindle oval shape conformation, lack nuclear atypia and have low levels of non-neoplastic lymphocytes. Mixed thymoma, also known as type AB thymoma are similar to a type A thymoma except that the foci is enriched with non-neoplastic lymphocytes. It makes up approximately 28% to 34% of all thymomas.<ref><pubmed>25143131</pubmed></ref>Type B1 thymoma also termed as lymphocytic thymoma is similar to a healthy functional thymus as it contains a large proportion of cells exhibiting features indistinguishable from a healthy thymic cortex with areas similar to thymic medulla. It makes up for approximately 9% to 20% of all thymomas.<ref><pubmed>24672784</pubmed></ref>Cortical thymoma, also known as type B2 thymoma contains neoplastic epithelial cells which appear scattered with vesicular nuclei and distinct nucleoli located in a dense population of non-neoplastic lymphocytes.<ref><pubmed>2698424</pubmed></ref>It is similar to type B1 thymoma but the foci of medullary differentiation are less visible. It makes up for approximately 20% to 36% of all thymomas. Epithelial thymoma, also known as type B3 thymoma is formed mainly from polygonal shaped epithelial cells that show no atypia. The mixture of non-neoplastic lymphocytes gives the tumour a sheet-like appearance. This makes up for approximately 10% to 14% of all thymomas. Since some of these are hard to differentiate from normal thymus tissues, there is poor prognosis.

Thymomas have been closely linked with another disease called myasthenia gravis. It is caused when nerve impulses are disrupted at the neuromuscular junction of skeletal muscles from the lack of binding of acetylcholine (neurotransmitter) to acetylcholine receptors needed to generate muscle contraction. Antibodies produced from the thymus gland destroy the acetylcholine receptors and hence have a strong correlation to myasthenia gravis. <ref><pubmed>21747138</pubmed></ref> Since thymomas contain more cells than normal and are malignant, it is more likely to generate antibodies which target acetylcholine receptors. The formation of these antibodies in B cells is T cell dependent. The T cells involved in this mechanism are generated in the thymus via nontolerogenic thymopoiesis through an abnormal function of thymic epithelial cells.<ref><pubmed> 20402580</pubmed></ref> Overall, incorrect signalling messages could be sent out and hence cause an autoimmune attack.

==Pancreas==
===Fetal development===
[[File:Development of the pancreas during fetal development.jpg|250px|thumb|right|This images shows normal pancreatic development of the fetus.]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
[[File:Ratio of alpha & beta cells at different phases of fetal development.png|350px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref> <ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

*'''Annular Pancreas'''
[[File:Annular pancreas.jpg|200px|thumb|right|This image shows annular pancreas where a ring of the pancreatic tissue encircles the growing duodenum.]]
Annular pancreas is a rare abnormality that can occur during fetal development in which a ring of the pancreatic tissue encircles the growing duodenum.<ref><pubmed>25124266</pubmed></ref> It occurs in 1 out of 7000 birth and is commonly associated with other abnormalities such as esophageal atresia and malrotation of the midgut. It is assumed that annular pancreas occurs when the tip of right ventral bud sticks to the duodenal wall which then forms a ring from the continuous stretching of the wall during rotation.<ref><pubmed> 25165593</pubmed></ref> This part of the pancreas can constrict the duodenum thereby restricting the flow of food to the intestines of the gastrointestinal tract.<ref><pubmed>24890427</pubmed></ref> Furthermore, annular pancreas is divided into two forms. Complete annular pancreas is when the pancreatic parenchyma wraps around the 2nd part of the duodenum completely whereas in incomplete annular pancreas, the tissue only surrounds the duodenum partially.<ref><pubmed> 24741860</pubmed></ref>Treatment for annular pancreas mainly involves surgery to bypass the constricted portion of the duodenum.

*'''Gestational diabetes mellitus'''

Gestational diabetes mellitus (GDM) is a disorder in which women without any history of diabetes show elevated blood glucose levels during pregnancy normally around the third trimester. It is caused when insulin receptors fail to respond correctly due to interference from signalling molecules related to pregnancy such as the interaction between human placental lactogen, prolactin and estradiol with the insulin receptors.<ref><pubmed>2141655</pubmed></ref> As a result, high blood glucose levels are observed. Patients with GDM have high levels of insulin resistance with increased β-cells production of the pancreas since the high levels of blood glucose are not interacting with the abnormal insulin receptors. Glucose is known to diffuse through the placenta via GLUT1 carrier situated in the syncytiotrophoblast of both the microvillus and basal membranes. With GDM, the number of GLUT1 molecules increase and hence placing high levels of glucose to the fetus since insulin itself cannot diffuse across the placenta and counteract this extremity.<ref><pubmed>25333246</pubmed></ref> This mechanism is known to lead to excessive growth at birth with a low glucose environment as it declines and high insulin production overall leading to hypoglycaemia.<ref><pubmed>25315294</pubmed></ref>It can also lead to jaundice and seizures in the new born with mothers having high susceptibility to type 2 diabetes mellitus. GDM can be controlled by monitoring blood sugar levels and controlling levels of glucose and insulin through pharmaceutical drugs.

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*'''Congenital Adrenal Hyperplasia (CAH)'''

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more.[[File:Cushing's syndrome.jpg|150px|right|thumb|This image shows a 3-month old child with classic signs of Cushing’s syndrome; central obesity, chubby cheeks and moon facies]] Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

*'''Cushing's Syndrome'''

Cushing’s Syndrome (CS) is a metabolic disorder characterised by abnormally high production of endogenous cortisol or exogenous levels of corticosteroids, which disrupts the metabolism of macromolecules such as lipids and carbohydrates. It is most common in obese adults aged 20-50 and the most common cause is the therapeutic administration of exogenous ACTH <ref><pubmed>24656295</pubmed></ref>. Cushing’s Syndrome’s two forms are either ACTH-dependent CS (80-85% of patients) or ACTH independent. The etiology of the dependent form is adrenal gland hyperplasia and excessive ACTH secretion by adenomas in the pituitary, however other causes include; small cell lung carcinoma ACTH production ectopically, or medullary thyroid carcinomas. <ref name= PMID24365350><pubmed>24365350</pubmed></ref> The independent form is however caused by neoplastic growths in the adrenal gland such as carcinomas, adenomas and macronodular hyperplasia. Clinical manifestations of this disorder include; moon facies, cataracts, hyperglycaemia, abnormal fat distribution, poor wounding of the skin, obesity in the central body and muscle wasting in 60% of patients. <ref name= PMID24365350><pubmed>24365350</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''
'''How far has the ovary developed by week 8 of gestation?'''
*Week 5- Thickening of mesothelium forms on the mesonephros. Formation of the gonadal ridge results from proliferation of the mesothelium and mesenchymal tissue beneath it <ref name= PMID>17237341<pubmed>17237341</pubmed></ref>
*Projection of finger-like gonadal (epithelial) cords into the mesenchyme. Indifferent gonad segmented medulla )regresses) and cortex (differentiates to form the ovary)
*PGCs migrate through the primitive streak in gastrulation and then reside at the junctional region of the hindgut yolk sac. Migration of the PGCs to the gonadal ridge along the hindgut’s dorsal mesentery <ref name= PMID>17237341<pubmed>17237341</pubmed></ref>
*Week 6- PGCs incorporated into the gonadal cords and are called oogonia, having entered underlying mesenchyme.

'''Fetal stage of ovarian development - from week 8 of gestation onwards:'''

'''Timeline'''
[[File:Fetal ovary morphogenesis (mouse).jpg|300px|right|thumb|Diagramatic representation of fetal mouse ovary morphogenesis]]
*Weeks 8 to 9- Gonad is identifiable as an ovary now due to change in internal structure. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates. Inner ovary; disintegrating blastema surrounded by a thick blastemal layer. Tissue has a cortical region (encloses PGCs) and a central medullary region (reticulum of somatic cells) <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>
*Weeks 10 to 12- Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue <ref name= PMID>22106406<pubmed>22106406</pubmed></ref>
*Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium. Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups. Medulla contains less densely-packed globules, mainly oogonia <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>
*Weeks 14 to 28- In mid-gestation; depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth <ref name= PMID>22106406<pubmed>22106406</pubmed></ref>
*Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium. Primordial follicle formation is the result of active mitosis of oogonia <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>

===Abnormalities===

*Congenital gonadal dysgenesis – Turner Syndrome

Female congenital gonadal dysgenesis syndrome refers to a condition where the fetus undergoes abnormal gonadal development with a presentation of streaks of connective tissue on the developing ovary, also referred to as "streak gonads". Streak ovaries extend from the lateral pelvic wall to the attachment of the utero-ovarian ligaments and are essentially sections of functionless tissue. They vary considerably in size but are usually approximately 4 cm in length and 2–3 mm in width. Dysgenetic ovaries are characterized by also absence of follicular structures and oocytes. In women, the most common cause of congenital gonadal dysgenesis is Turner syndrome, 45X which has a prevalence of approximately 1 in 2500 new born girls worldwide<ref name= PMID15475933><pubmed>15475933</pubmed></ref>. Turner syndrome is a genetic abnormality due to an incomplete or completely missing X chromosome in females. Growth hormones treatments such as estrogen replacement therapy may be used after the child has reached 12-13 years of age to help treat the symptoms<ref name= PMID0001417><pubmed>0001417</pubmed></ref>.

==Testis==
===Fetal development===

'''How far has the testis developed by week 8 of gestation?'''
*By week 8, masculine differentiation is induced in the mesonephric duct and external genitalia. This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>
*Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>

'''Fetal stage of testicular development - from week 8 of gestation onwards'''

'''Timeline'''
*Week 9- Yellowish elongated tube with mesonephros laterally and urinary bladder inferomedially
*Week 13- Testes have acquired the ellipsoidal shape found in the adult and are located above the inguinal canal in the groin region. Convexly curved across all but posterior surface <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*Week 16- Located above deep inguinal ring, convexly curved anterior border and flat posterior border covered by epididymis
*Week 17- Migration of testes begins
*Week 24- Testes grow in size and still located about the deep inguinal ring or inside inguinal canal. The testicular poles seem more prominent. Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26 <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
*Week 30- Testes sinus is towards lower portion of testes and epididymis tail continuous with vas deferens. Testes are located in the scrotum having passed through the superficial inguinal ring
*Week 36- Testes located within scrotal sac, they enlarge in size and are maximally convex <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
===Abnormalities===

*'''Klinefelter’s syndrome'''

Klinefelter’s syndrome is the common form of congenital primary hypogonadism with a prevalence of an estimated 1 in 1000 men. Male hypogonadism is defined as a testicular dysfunction resulting in decreased sperm and testosterone production<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.. This genetic disorder occurs when a male is born with an additional X chromosome causing complications and a general underdevelopment of structures such as the seminiferous tubules and Leydig cells within the testis. As a consequence, the size of the testis is abnormally small and the patient has a low sperm count and testosterone levels. In addition to infertility caused by testosterone deficiency, men born with this disorder frequently have increased length of their long bones, including those in the arms, legs, and hands. Many other complications exist independent of the testosterone deficiency seen with these patients<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''
[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]
*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

*'''Placenta accreta'''

[[File:Placenta accreta.jpg|150px|right|thumb|This image shows an area of profuse bleeding in the human placenta, with a region of placenta accreta indicated by the arrow]]

Placenta accreta (PA )is a rare obstetric abnormality characterised by abnormal insertion of the placenta to the myometrium of the uterus. The 3 types of PA are classified based on the depth of invasion; placenta accreta (superficial- chorionic villi attach to myometrium rather than just decidua basalis), placenta increta (middle layer) or placenta perceta (deep) being the most dire with 1 in 7000 incidence. <ref name= PMID23127895><pubmed>23127895</pubmed></ref> PA has an incidence of 1 in 2500 deliveries and is associated with grand-scale haemorrhage and requires hysterectomy and blood transfusion. <ref name= PMID21280984><pubmed>21280984</pubmed></ref> The condition normally occurs in the lower segment of the uterus which is prone to bleeding being poorly contractile and a site of angiogenesis. Prenatal diagnosis of PA is based on second and third trimester ulstrasound findings indicating; retroplacental zone loss, many lucanue in the vasculature and a very thin (<1mm) retroplacental thickness of the myometrium.<ref name= PMID21280984><pubmed>21280984</pubmed></ref> PA has a 40% likelihood in women aged over 35 who have had Caesarian section with placenta previa in their uterine scars. <ref name= PMID23127895><pubmed>23127895</pubmed></ref>

==Recent Findings==

{|
|-bgcolor="F5FFFA"
|
'''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''<ref><pubmed>22912418</pubmed></ref>

''Jennifer R Gardiner, Abigail L Jackson, Julie Gordon, Heiko Lickert, Nancy R Manley, M Albert Basson '''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''. Development: 2012, 139(18);3456-66 PMID: 22912418''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.
|}

{|
|-bgcolor="F5FFFA"
|'''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''<ref><pubmed>23300903</pubmed></ref>

''Stéphanie Migrenne, Evelyne Moreau, Pirjo Pakarinen, Andrée Dierich, Jorge Merlet, René Habert, Chrystèle Racine '''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''. PLoS ONE: 2012, 7(12);e53257 PMID: 23300903''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.
|}

{|
|-bgcolor="F5FFFA"
|'''Neuropeptide Y in the Adult and Fetal Human Pineal Gland'''<ref><pubmed>24757681</pubmed></ref>

''Morten Møller, Pansiri Phansuwan-Pujito, Corin Badiu '''Neuropeptide Y in the adult and fetal human pineal gland'''. Biomed Res Int: 2014, 2014;868567 PMID: 24757681''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland. Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.
|}

{|
|-bgcolor="F5FFFA"

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, '''Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation.’'' Neuroscience Letters. 556; pp 124–128 http://www.sciencedirect.com/science/article/pii/S0304394013009300</ref>

This study investigates the expression of the voltage operated calcium channels subunits α1A and α1D in the male and female bovine hypothalamus during four embryonic stages of development. The expression of both these subunits have been identified in the brain of adult mammals, however, their distribution and expression during fetal neuronal differentiation has not yet been determined<ref name=Peruffoa>A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, ‘Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation.’ Neuroscience Letters. 556; pp 124–128 http://www.sciencedirect.com/science/article/pii/S0304394013009300</ref>.

The results suggest that expressions of α1A and α1D are correlated with the stage of development, with an increase only in males that peaks on the last period of gestation. Bovine male hypothalami showed significantly higher α1A and α1D expression values in comparison to female ones during the whole developmental period. Additionally immunohistological studies confirmed the presence of the α1A and α1D protein subunits in fetal hypothalamic neurons starting from the third fetal stage.

These calcium channels may have a role in modulating physiological responses of surrounding neural structures during the second trimester of gestation while the hypothalamus is defined and networks start to develop. Due to the long duration of the pregnancy like humans, fetal bovine tissues may represent an important model for translational studies on the human hypothalamic development. In contrast with rodent models, in long gestation species such as the bovine, the critical period for hypothalamic sexual differentiation occurs in earlier gestation phases and thus presents a more relevant model to correlate to human embryonic sexual development<ref name=Peruffoa>A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, ‘Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation.’ Neuroscience Letters. 556; pp 124–128 http://www.sciencedirect.com/science/article/pii/S0304394013009300</ref>.
|}

=References=

<references/>

File:Hypothyroidism.jpg

2014-10-24T02:22:13Z

Z3418702:

==Hyperthyroidism==
This image compares a normal thyroid gland (a) anatomy with a hypothyroidism thyroid gland (b). The histology images reveal in the abnormal thyroid gland, there is less thyroid hormone produced due to irregular epithelium on the surface of the follicles. The researchers in this report found that once thyroid stimulating hormone was added to the hypothyroid follicles, the epithelium became more columnar and the lumens became smaller, similar to healthy thyroid follicles.

===Reference===
<pubmed>22916127</pubmed>

'''Copyright'''
© Endo, Kobayashi. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

{{Template:Student Image}}

2014 Group Project 6

2014-10-23T22:37:20Z

Z3418702:

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

The endocrine system is awesome!

==Pineal gland==
===Fetal development===

[[File:Keith1902 fig167.jpg|200px|thumb|right| Image 1: schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|Image 2: Shows the location of the pineal gland in the adult brain.]]

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon reproductive hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>.

Melatonin plays an important role during fetal development. Both pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammalian fetus, intrinsic circadian rhythms are already established prior to birth.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || Pinealocytes || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

[[File:Primary brain vesicles.jpg|150px|left|thumb|Image 3: Primary brain vesicles]]'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle (Image 3).<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
[[File:Week 6 embryonic development of CNS.jpg|150px|left|thumb|Image 4: Week 6 embryonic development of CNS]]
[[File:Week 11 fetal development of CNS.jpg|150px|right|thumb|Image 5: Week 11 fetal development of CNS]]

*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement and an evagination of the pineal gland is visible (shown in image 4).

[[File:Fetal pineal gland 01.jpg|150px|thumb|right|Image 6: shows a fetal pineal gland at the end of the first trimester of development.]]

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum

*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis (shown in Image 5)

*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

===Abnormalities===

* '''Pineal tumors'''

Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>
[[File:Congenital hydrocephalus MRI02.jpg|150px|thumb|right|Image 7: Infant with obstructive congenital hydrocephalus]]

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signalling pathways, the Hyothalamus-Pituitary-Adrenal (HPA) and the Hypothalamus-Pituitary-Gonad (HPG) and exerts most of it's influence on the body through these two axes.
[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]
[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || (also known as antidiuretic hormone) Controls the body's water balance electrolyte concentration and blood pressure by increasing water permeability in distal convoluted tubules and in the collecting duct of nephrons in the kidney. Results in higher reabsorption of water in kidneys and thus higher blood volume and pressure.
|-
| Oxytocin || || Magnocellular neurosecretory cells || Stimulates lactation, hormone release during labor causes the muscles of the uterus contract
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Releases thyroid-stimulating hormone (TSH) as well as limited prolactin from anterior pituitary
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Inhibits release of prolactin from anterior pituitary
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Stimulates release of growth hormone from anterior pituitary
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Releases adrenocorticotropic hormone (ACTH) from anterior pituitary
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Stimulates release of follicle-stimulating hormone (FSH) as well as luteinizing hormone (LH) from anterior pituitary.
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Stimulates release of growth hormone (GH) from anterior pituitary and also has inhibitory effect on release of thyroid-stimulating hormone (TSH) from the anterior pituitary
|}

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in fetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Fetal oxytocin may initiate or accelerate the course of labor whereas vasopressin plays a role in the adaptation to stress caused by the birth process by redistribution of fetal blood flow.

'''Timeline'''

[[File:Development of hypothalamus.jpg|900px|right|thumb|Image 3: Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).
[[File:Stage 22 image 057.jpg|200x|thumb|Image 1. Histological cross-section of stage 22 embryo]]
* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

===Abnormalities===

*'''Congenital Hypothalamic Hamartoma'''

A hypothalamic hamartoma arises from the region of the tuber cinereum and is commonly associated with isosexual precocious puberty, i.e. puberty that develops unusually early in infants. It involves the alteration of pathways that modulate gonadotropins and contain releasing hormones within the floor of the third ventricle. .<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref> Precocious puberty may either result from a physical manipulation of inhibitory pathways by the hamartoma or a direct neurosecretory process of the hamartoma itself. Seizures are also another common clinical presentation in children with a hypothalamic hamartoma. MR imaging is typically used to identify and monitor the growth of a hypothalamic hamartoma during embryonic and fetal development. Research has shown a trend of congenital hamartomas forming in the embryo within a period of 26 weeks. Because of the known association with other congenital anomalies of the central nervous system, hypothalamic hamartoma is thought to form as early as 4 weeks and may in fact be part of a developmental abnormality spectrum.<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref>. Treatment options are currently limited to post-natal deliver of leuprolide acetate to the infant and in general it is relatively effective in managing and treating the condition.

*

==Pituitary gland==
[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]
=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>
* Anterior pituitary

[[File:Anterior Pituitary Hormones.jpg|300px|right|thumb|Timeline of anterior pituitary hormone expression and synthesis]]

By week 8 of embryological development, the pituitary gland is fully formed and begins functioning as a control centre for release of hormones that are vital for subsequent organ development.

* Week 10 - Growth Hormone and ACTH detectable
* Week 21 - Vasopressin hormone synthesis established

'''Anterior Pituitary - Adenohypophysis'''

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || No function in fetal development. All postnatal action.
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|}

'''Posterior Pituitary - Neurohypophysis'''

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://www.sciencedirect.com/science/article/pii/S030100820900046X#></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Cardiomyogenesis
* Protective action of fetal neurons during brain development
* Neuronal development and plasticity <ref name =Yuzo Murata, Ming-Zi Li, Sadahiko Masuko>Yuzo Murata, Ming-Zi Li, Sadahiko Masuko, 2011, '''Developmental expression of oxytocin receptors in the neonatal medulla
oblongata and pons''', Neuroscience Letters; 502 (2011), pp157-161, http://www.sciencedirect.com/science/article/pii/S0304394011010949#></ref>
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Regulates fetal renal function
* Regulates amniotic fluid content and concentration
* Regulates blood pressure, heart rate, cardiac output and placental blood flow <ref name =M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher >M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher , 1993, '''Vasopressin receptors and effects during fetal development''', Regulatory Peptides; 45, pp203-208, http://www.sciencedirect.com/science/article/pii/016701159390207O#></ref>
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

'''How far has the thyroid gland developed by week 8 of gestation?'''
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

'''Fetal Stage of Thyroid Development - from week 8 of gestation onwards:'''
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis<ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>
* Week 16 - 18 is when fetal thyroid hormone synthesis occurs
** Prior to this, the fetus receives vital maternal thyroid hormones via the placenta

'''Thyroid Hormone Action'''
The following table explains the ontogenic action of thyroid hormone on the developing fetus. Thyroid hormones are essential in brain and central nervous system development in the fetus. A lot of neurological disorders are associated with insufficient thyroid hormone synthesis:

{| class="wikitable"
|-
! Hormone !! Types !! Ontogenic Action
|-
| Thyroid Hormone ||
* T3 - triiodothyronine
* T4 - thyroxine
|| Brain development:
* Central Nervous System development and maturation <ref name =J Patel, K Landers, H Li, R H Mortimer and K Richard>J Patel, K Landers, H Li, R H Mortimer and K Richard, 2011, '''Thyroid hormones and fetal neurological development''', Journal of Endocrinology:209;1-8, http://joe.endocrinology-journals.org.wwwproxy0.library.unsw.edu.au/content/209/1/1.full.pdf+html></ref>
*Glial cell proliferation
*Neural myelination
*Axon and dendrite sprouting
*Synapse formation
|}

{| class="wikitable"
|-
! Header text !! Header text !! Header text
|-
| Example || Example || Example
|}

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|right|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone || Secreted by || Function || Image
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine. || [[File:Active parathyroid hormone assay cartoon.png|200px|thumb|This images shows an active parathyroid hormone and its chemical structure.]]
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

'''Fetal hyperparathyroidism'''

Fetal hyperparathyroidism is a condition that is caused when an excess of parathyroid hormone (PTH) is present the bloodstream.<ref><pubmed> 1745971</pubmed></ref> This may be due to an overstimulated maternal parathyroid gland out of all the four which transfers the over accumulated PTH to the fetus. Normal fetal development requires 25–30 gms of calcium for bone mineralization and around 80% of this calcium accretion is observed in the third trimester of pregnancy. However the calcium gradient of 1.0:1.4 is no longer maintained when there is hyperparathyroidism present.<ref><pubmed> 12140371</pubmed></ref>Instead the gradient is elevated causing fetal parathyroid gland suppression thereby leading to Hypocalcemia. Calcium mobilisation then becomes difficult and hence fetal tetany may occur followed by miscarriage.<ref><pubmed> 25327435</pubmed></ref> In the event that the fetus survives, postnatal problems such as the baby having weak bones will be likely and would require calcium treatment throughout most of their lives.

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

'''Thymic aplasia'''

Thymic aplasia is a condition that has a strong correlation to DiGeorge syndrome. This syndrome is a congenital birth defect which occurs when the fetus either inherits an abnormal chromosome 22 or has a mutation of the same chromosome. In particularly, the mutation is a deletion of the genomic information packaged in the chromosomes and normally occurs when there isn’t proper recombination of chromosomal material during fertilisation.<ref><pubmed>4166528</pubmed></ref> As a result of this deletion, the third and fourth pharyngeal pouches fail to develop in the twelfth gestational week, thereby leading to the absence or partial absence of the thymus and parathyroid glands. Other associated abnormalities with thymic aplasia as a result of the deletion of chromosome 22 genetic material are severe cardiac defects, low immunity, hypocalcaemia and facial abnormalities. <ref><pubmed>5057550</pubmed></ref> Statistics suggest that the thymic aplasia may occur in 1:4000 to 1:6395 of fetuses.<ref><pubmed> 10861201</pubmed></ref> Treatment is normally difficult for fetuses that exhibit thymic aplasia, however calcium levels can be monitored and regulated and heart problems can be resolved though surgery. Immunity defects can be managed from controlling phosphorus levels in the fetus and protecting them from sources of infection.<ref><pubmed>1454183</pubmed></ref>
[[File:Histopathology of the thymus with hyperplasia.jpg|250px|thumb|right|This image shows the histopathology of the thymus with hyperplasia and thymoma]]

'''Thymoma'''

Thymoma is the term given to the neoplasms of the thymus gland. These tumours emerge from the thymic epithelium cells of the thymus gland and do not normally show cytologic characteristics of malignancy, however are considered malignant as they are likely to undergo invasion. Thymomas are classified into different types based on the content and structure of the cells. If the tumour has spindle cell conformation, it is known as type A thymoma and constitutes to 4% to 7% of all thymomas. The tumor is made up of neoplastic thymic epithelial cells that exhibit a spindle oval shape conformation, lack nuclear atypia and have low levels of non-neoplastic lymphocytes. Mixed thymoma, also known as type AB thymoma are similar to a type A thymoma except that the foci is enriched with non-neoplastic lymphocytes. It makes up approximately 28% to 34% of all thymomas.<ref><pubmed>25143131</pubmed></ref>Type B1 thymoma also termed as lymphocytic thymoma is similar to a healthy functional thymus as it contains a large proportion of cells exhibiting features indistinguishable from a healthy thymic cortex with areas similar to thymic medulla. It makes up for approximately 9% to 20% of all thymomas.<ref><pubmed>24672784</pubmed></ref>Cortical thymoma, also known as type B2 thymoma contains neoplastic epithelial cells which appear scattered with vesicular nuclei and distinct nucleoli located in a dense population of non-neoplastic lymphocytes.<ref><pubmed>2698424</pubmed></ref>It is similar to type B1 thymoma but the foci of medullary differentiation are less visible. It makes up for approximately 20% to 36% of all thymomas. Epithelial thymoma, also known as type B3 thymoma is formed mainly from polygonal shaped epithelial cells that show no atypia. The mixture of non-neoplastic lymphocytes gives the tumour a sheet-like appearance. This makes up for approximately 10% to 14% of all thymomas. Since some of these are hard to differentiate from normal thymus tissues, there is poor prognosis.

Thymomas have been closely linked with another disease called myasthenia gravis. It is caused when nerve impulses are disrupted at the neuromuscular junction of skeletal muscles from the lack of binding of acetylcholine (neurotransmitter) to acetylcholine receptors needed to generate muscle contraction. Antibodies produced from the thymus gland destroy the acetylcholine receptors and hence have a strong correlation to myasthenia gravis. <ref><pubmed>21747138</pubmed></ref> Since thymomas contain more cells than normal and are malignant, it is more likely to generate antibodies which target acetylcholine receptors. The formation of these antibodies in B cells is T cell dependent. The T cells involved in this mechanism are generated in the thymus via nontolerogenic thymopoiesis through an abnormal function of thymic epithelial cells.<ref><pubmed> 20402580</pubmed></ref> Overall, incorrect signalling messages could be sent out and hence cause an autoimmune attack.

==Pancreas==
===Fetal development===
[[File:Development of the pancreas during fetal development.jpg|250px|thumb|right|This images shows normal pancreatic development of the fetus.]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
[[File:Ratio of alpha & beta cells at different phases of fetal development.png|350px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref> <ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

*'''Annular Pancreas'''
[[File:Annular pancreas.jpg|200px|thumb|right|This image shows annular pancreas where a ring of the pancreatic tissue encircles the growing duodenum.]]
Annular pancreas is a rare abnormality that can occur during fetal development in which a ring of the pancreatic tissue encircles the growing duodenum.<ref><pubmed>25124266</pubmed></ref> It occurs in 1 out of 7000 birth and is commonly associated with other abnormalities such as esophageal atresia and malrotation of the midgut. It is assumed that annular pancreas occurs when the tip of right ventral bud sticks to the duodenal wall which then forms a ring from the continuous stretching of the wall during rotation.<ref><pubmed> 25165593</pubmed></ref> This part of the pancreas can constrict the duodenum thereby restricting the flow of food to the intestines of the gastrointestinal tract.<ref><pubmed>24890427</pubmed></ref> Furthermore, annular pancreas is divided into two forms. Complete annular pancreas is when the pancreatic parenchyma wraps around the 2nd part of the duodenum completely whereas in incomplete annular pancreas, the tissue only surrounds the duodenum partially.<ref><pubmed> 24741860</pubmed></ref>Treatment for annular pancreas mainly involves surgery to bypass the constricted portion of the duodenum.

*'''Gestational diabetes mellitus'''

Gestational diabetes mellitus (GDM) is a disorder in which women without any history of diabetes show elevated blood glucose levels during pregnancy normally around the third trimester. It is caused when insulin receptors fail to respond correctly due to interference from signalling molecules related to pregnancy such as the interaction between human placental lactogen, prolactin and estradiol with the insulin receptors.<ref><pubmed>2141655</pubmed></ref> As a result, high blood glucose levels are observed. Patients with GDM have high levels of insulin resistance with increased β-cells production of the pancreas since the high levels of blood glucose are not interacting with the abnormal insulin receptors. Glucose is known to diffuse through the placenta via GLUT1 carrier situated in the syncytiotrophoblast of both the microvillus and basal membranes. With GDM, the number of GLUT1 molecules increase and hence placing high levels of glucose to the fetus since insulin itself cannot diffuse across the placenta and counteract this extremity.<ref><pubmed>25333246</pubmed></ref> This mechanism is known to lead to excessive growth at birth with a low glucose environment as it declines and high insulin production overall leading to hypoglycaemia.<ref><pubmed>25315294</pubmed></ref>It can also lead to jaundice and seizures in the new born with mothers having high susceptibility to type 2 diabetes mellitus. GDM can be controlled by monitoring blood sugar levels and controlling levels of glucose and insulin through pharmaceutical drugs.

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*'''Congenital Adrenal Hyperplasia (CAH)'''

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more.[[File:Cushing's syndrome.jpg|150px|right|thumb|This image shows a 3-month old child with classic signs of Cushing’s syndrome; central obesity, chubby cheeks and moon facies]] Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

*'''Cushing's Syndrome'''

Cushing’s Syndrome (CS) is a metabolic disorder characterised by abnormally high production of endogenous cortisol or exogenous levels of corticosteroids, which disrupts the metabolism of macromolecules such as lipids and carbohydrates. It is most common in obese adults aged 20-50 and the most common cause is the therapeutic administration of exogenous ACTH <ref><pubmed>24656295</pubmed></ref>. Cushing’s Syndrome’s two forms are either ACTH-dependent CS (80-85% of patients) or ACTH independent. The etiology of the dependent form is adrenal gland hyperplasia and excessive ACTH secretion by adenomas in the pituitary, however other causes include; small cell lung carcinoma ACTH production ectopically, or medullary thyroid carcinomas. <ref name= PMID24365350><pubmed>24365350</pubmed></ref> The independent form is however caused by neoplastic growths in the adrenal gland such as carcinomas, adenomas and macronodular hyperplasia. Clinical manifestations of this disorder include; moon facies, cataracts, hyperglycaemia, abnormal fat distribution, poor wounding of the skin, obesity in the central body and muscle wasting in 60% of patients. <ref name= PMID24365350><pubmed>24365350</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''
'''How far has the ovary developed by week 8 of gestation?'''
*Week 5- Thickening of mesothelium forms on the mesonephros. Formation of the gonadal ridge results from proliferation of the mesothelium and mesenchymal tissue beneath it <ref name= PMID>17237341<pubmed>17237341</pubmed></ref>
*Projection of finger-like gonadal (epithelial) cords into the mesenchyme. Indifferent gonad segmented medulla )regresses) and cortex (differentiates to form the ovary)
*PGCs migrate through the primitive streak in gastrulation and then reside at the junctional region of the hindgut yolk sac. Migration of the PGCs to the gonadal ridge along the hindgut’s dorsal mesentery <ref name= PMID>17237341<pubmed>17237341</pubmed></ref>
*Week 6- PGCs incorporated into the gonadal cords and are called oogonia, having entered underlying mesenchyme.

'''Fetal stage of ovarian development - from week 8 of gestation onwards:'''

'''Timeline'''
[[File:Fetal ovary morphogenesis (mouse).jpg|300px|right|thumb|Diagramatic representation of fetal mouse ovary morphogenesis]]
*Weeks 8 to 9- Gonad is identifiable as an ovary now due to change in internal structure. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates. Inner ovary; disintegrating blastema surrounded by a thick blastemal layer. Tissue has a cortical region (encloses PGCs) and a central medullary region (reticulum of somatic cells) <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>
*Weeks 10 to 12- Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue <ref name= PMID>22106406<pubmed>22106406</pubmed></ref>
*Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium. Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups. Medulla contains less densely-packed globules, mainly oogonia <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>
*Weeks 14 to 28- In mid-gestation; depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth <ref name= PMID>22106406<pubmed>22106406</pubmed></ref>
*Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium. Primordial follicle formation is the result of active mitosis of oogonia <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>

===Abnormalities===

*Congenital gonadal dysgenesis – Turner Syndrome

Female congenital gonadal dysgenesis syndrome refers to a condition where the fetus undergoes abnormal gonadal development with a presentation of streaks of connective tissue on the developing ovary, also referred to as "streak gonads". Streak ovaries extend from the lateral pelvic wall to the attachment of the utero-ovarian ligaments and are essentially sections of functionless tissue. They vary considerably in size but are usually approximately 4 cm in length and 2–3 mm in width. Dysgenetic ovaries are characterized by also absence of follicular structures and oocytes. In women, the most common cause of congenital gonadal dysgenesis is Turner syndrome, 45X which has a prevalence of approximately 1 in 2500 new born girls worldwide<ref name= PMID15475933><pubmed>15475933</pubmed></ref>. Turner syndrome is a genetic abnormality due to an incomplete or completely missing X chromosome in females. Growth hormones treatments such as estrogen replacement therapy may be used after the child has reached 12-13 years of age to help treat the symptoms<ref name= PMID0001417><pubmed>0001417</pubmed></ref>.

==Testis==
===Fetal development===

'''How far has the testis developed by week 8 of gestation?'''
*By week 8, masculine differentiation is induced in the mesonephric duct and external genitalia. This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>
*Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>

'''Fetal stage of testicular development - from week 8 of gestation onwards'''

'''Timeline'''
*Week 9- Yellowish elongated tube with mesonephros laterally and urinary bladder inferomedially
*Week 13- Testes have acquired the ellipsoidal shape found in the adult and are located above the inguinal canal in the groin region. Convexly curved across all but posterior surface <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*Week 16- Located above deep inguinal ring, convexly curved anterior border and flat posterior border covered by epididymis
*Week 17- Migration of testes begins
*Week 24- Testes grow in size and still located about the deep inguinal ring or inside inguinal canal. The testicular poles seem more prominent. Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26 <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
*Week 30- Testes sinus is towards lower portion of testes and epididymis tail continuous with vas deferens. Testes are located in the scrotum having passed through the superficial inguinal ring
*Week 36- Testes located within scrotal sac, they enlarge in size and are maximally convex <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
===Abnormalities===

*'''Klinefelter’s syndrome'''

Klinefelter’s syndrome is the common form of congenital primary hypogonadism with a prevalence of an estimated 1 in 1000 men. Male hypogonadism is defined as a testicular dysfunction resulting in decreased sperm and testosterone production<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.. This genetic disorder occurs when a male is born with an additional X chromosome causing complications and a general underdevelopment of structures such as the seminiferous tubules and Leydig cells within the testis. As a consequence, the size of the testis is abnormally small and the patient has a low sperm count and testosterone levels. In addition to infertility caused by testosterone deficiency, men born with this disorder frequently have increased length of their long bones, including those in the arms, legs, and hands. Many other complications exist independent of the testosterone deficiency seen with these patients<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''
[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]
*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

*'''Placenta accreta'''

[[File:Placenta accreta.jpg|150px|right|thumb|This image shows an area of profuse bleeding in the human placenta, with a region of placenta accreta indicated by the arrow]]

Placenta accreta (PA )is a rare obstetric abnormality characterised by abnormal insertion of the placenta to the myometrium of the uterus. The 3 types of PA are classified based on the depth of invasion; placenta accreta (superficial- chorionic villi attach to myometrium rather than just decidua basalis), placenta increta (middle layer) or placenta perceta (deep) being the most dire with 1 in 7000 incidence. <ref name= PMID23127895><pubmed>23127895</pubmed></ref> PA has an incidence of 1 in 2500 deliveries and is associated with grand-scale haemorrhage and requires hysterectomy and blood transfusion. <ref name= PMID21280984><pubmed>21280984</pubmed></ref> The condition normally occurs in the lower segment of the uterus which is prone to bleeding being poorly contractile and a site of angiogenesis. Prenatal diagnosis of PA is based on second and third trimester ulstrasound findings indicating; retroplacental zone loss, many lucanue in the vasculature and a very thin (<1mm) retroplacental thickness of the myometrium.<ref name= PMID21280984><pubmed>21280984</pubmed></ref> PA has a 40% likelihood in women aged over 35 who have had Caesarian section with placenta previa in their uterine scars. <ref name= PMID23127895><pubmed>23127895</pubmed></ref>

==Recent Findings==

{|
|-bgcolor="F5FFFA"
|
'''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''<ref><pubmed>22912418</pubmed></ref>

''Jennifer R Gardiner, Abigail L Jackson, Julie Gordon, Heiko Lickert, Nancy R Manley, M Albert Basson '''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''. Development: 2012, 139(18);3456-66 PMID: 22912418''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.
|}

{|
|-bgcolor="F5FFFA"
|'''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''<ref><pubmed>23300903</pubmed></ref>

''Stéphanie Migrenne, Evelyne Moreau, Pirjo Pakarinen, Andrée Dierich, Jorge Merlet, René Habert, Chrystèle Racine '''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''. PLoS ONE: 2012, 7(12);e53257 PMID: 23300903''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.
|}

{|
|-bgcolor="F5FFFA"
|'''Neuropeptide Y in the Adult and Fetal Human Pineal Gland'''<ref><pubmed>24757681</pubmed></ref>

''Morten Møller, Pansiri Phansuwan-Pujito, Corin Badiu '''Neuropeptide Y in the adult and fetal human pineal gland'''. Biomed Res Int: 2014, 2014;868567 PMID: 24757681''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland. Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.
|}

=References=

<references/>

File:Fetal ovary morphogenesis (mouse).jpg

2014-10-23T22:33:05Z

Z3418702: ==Fetal mouse ovary morphogenesis== Image indicating the different component cells in ovary organogenesis in the fetal mouse. PGCs coalesce with somatic cells derived from (1), (2) or (3) in the diagram. (A)- Ovigerous cord formation by PGCs and somat...

==Fetal mouse ovary morphogenesis==

Image indicating the different component cells in ovary organogenesis in the fetal mouse. PGCs coalesce with somatic cells derived from (1), (2) or (3) in the diagram. (A)- Ovigerous cord formation by PGCs and somatic cells. (B)- Formation of germ cell nests. (C)- Germ cell nests broken down at birth by somatic cells. (D)- Primordial follicle formation

This drawing is a student-drawn adaption from <ref><pubmed>20691852</pubmed></ref>

===Reference===

<references/>

'''Copyright'''

Beginning six months after publication, I z3418702 grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode

{{Template:Student Image}}

2014 Group Project 6

2014-10-23T12:42:42Z

Z3418702: /* Ovary */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

[[File:Keith1902 fig167.jpg|200px|thumb|right| Image 1: schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|Image 2: Shows the location of the pineal gland in the adult brain.]]

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon reproductive hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>.

Melatonin plays an important role during fetal development. Both pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammalian fetus, intrinsic circadian rhythms are already established prior to birth.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || Pinealocytes || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

[[File:Primary brain vesicles.jpg|150px|left|thumb|Image 3: Primary brain vesicles]]'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle (Image 3).<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
[[File:Week 6 embryonic development of CNS.jpg|150px|left|thumb|Image 4: Week 6 embryonic development of CNS]]
[[File:Week 11 fetal development of CNS.jpg|150px|right|thumb|Image 5: Week 11 fetal development of CNS]]

*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement and an evagination of the pineal gland is visible (shown in image 4).

[[File:Fetal pineal gland 01.jpg|150px|thumb|right|Image 6: shows a fetal pineal gland at the end of the first trimester of development.]]

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum

*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis (shown in Image 5)

*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

===Abnormalities===

* '''Pineal tumors'''

Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>
[[File:Congenital hydrocephalus MRI02.jpg|150px|thumb|right|Image 7: Infant with obstructive congenital hydrocephalus]]

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signalling pathways, the Hyothalamus-Pituitary-Adrenal (HPA) and the Hypothalamus-Pituitary-Gonad (HPG) and exerts most of it's influence on the body through these two axes.
[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]
[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).
[[File:Stage 22 image 057.jpg|200x|thumb|Image 1. Histological cross-section of stage 22 embryo]]
* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete
[[File:Development of hypothalamus.jpg|850px|left|thumb|Image 3: Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

===Abnormalities===

*'''Congenital Hypothalamic Hamartoma'''

A hypothalamic hamartoma arises from the region of the tuber cinereum and is commonly associated with isosexual precocious puberty, i.e. puberty that develops unusually early in infants. It involves the alteration of pathways that modulate gonadotropins and contain releasing hormones within the floor of the third ventricle. .<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref> Precocious puberty may either result from a physical pertubation of inhibitory pathways by the hamartoma or a direct neurosecretory process of the hamartoma itself. Seizures are also another common clinical presentation in children with a hypothalamic hamartoma. MR imaging is typically used to identify and monitor the growth of a hypothalamic hamartoma during embryonic and fetal development. Research has shown a trend of congenital hamartomas forming in the utero within a period of 26 weeks. Because of the known association with other congenital anomalies of the central nervous system, hypothalamic hamartoma is thought to form as early as 4 weeks and may in fact be part of a developmental abnormality spectrum.<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref>. Treatment options are currently limited to post-natal deliver of leuprolide acetate to the infant and in general it is relatively effective in managing and treating the condition.

*

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==
[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]
=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>
* Anterior pituitary

[[File:Anterior Pituitary Hormones.jpg|300px|right|thumb|Timeline of anterior pituitary hormone expression and synthesis]]

By week 8 of embryological development, the pituitary gland is fully formed and begins functioning as a control centre for release of hormones that are vital for subsequent organ development.

* Week 10 - Growth Hormone and ACTH detectable
* Week 21 - Vasopressin hormone synthesis established

'''Anterior Pituitary - Adenohypophysis'''

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || No function in fetal development. All postnatal action.
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|}

'''Posterior Pituitary - Neurohypophysis'''

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://www.sciencedirect.com/science/article/pii/S030100820900046X#></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Cardiomyogenesis
* Protective action of fetal neurons during brain development
* Neuronal development and plasticity <ref name =Yuzo Murata, Ming-Zi Li, Sadahiko Masuko>Yuzo Murata, Ming-Zi Li, Sadahiko Masuko, 2011, '''Developmental expression of oxytocin receptors in the neonatal medulla
oblongata and pons''', Neuroscience Letters; 502 (2011), pp157-161, http://www.sciencedirect.com/science/article/pii/S0304394011010949#></ref>
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Regulates fetal renal function
* Regulates amniotic fluid content and concentration
* Regulates blood pressure, heart rate, cardiac output and placental blood flow <ref name =M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher >M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher , 1993, '''Vasopressin receptors and effects during fetal development''', Regulatory Peptides; 45, pp203-208, http://www.sciencedirect.com/science/article/pii/016701159390207O#></ref>
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

'''How far has the thyroid gland developed by week 8 of gestation?'''
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

'''Fetal Stage of Thyroid Development - from week 8 of gestation onwards:'''
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis<ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>
* Week 16 - 18 is when fetal thyroid hormone synthesis occurs
** Prior to this, the fetus receives vital maternal thyroid hormones via the placenta

'''Thyroid Hormone Action'''
The following table explains the ontogenic action of thyroid hormone on the developing fetus. Thyroid hormones are essential in brain and central nervous system development in the fetus. A lot of neurological disorders are associated with insufficient thyroid hormone synthesis:

{| class="wikitable"
|-
! Hormone !! Types !! Ontogenic Action
|-
| Thyroid Hormone ||
* T3 - triiodothyronine
* T4 - thyroxine
|| Brain development:
* Central Nervous System development and maturation <ref name =J Patel, K Landers, H Li, R H Mortimer and K Richard>J Patel, K Landers, H Li, R H Mortimer and K Richard, 2011, '''Thyroid hormones and fetal neurological development''', Journal of Endocrinology:209;1-8, http://joe.endocrinology-journals.org.wwwproxy0.library.unsw.edu.au/content/209/1/1.full.pdf+html></ref>
*Glial cell proliferation
*Neural myelination
*Axon and dendrite sprouting
*Synapse formation
|}

{| class="wikitable"
|-
! Header text !! Header text !! Header text
|-
| Example || Example || Example
|}

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|right|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone || Secreted by || Function || Image
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine. || [[File:Active parathyroid hormone assay cartoon.png|200px|thumb|This images shows an active parathyroid hormone and its chemical structure.]]
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

'''Fetal hyperparathyroidism'''

Fetal hyperparathyroidism is a condition that is caused when an excess of parathyroid hormone (PTH) is present the bloodstream.<ref><pubmed> 1745971</pubmed></ref> This may be due to an overstimulated maternal parathyroid gland out of all the four which transfers the over accumulated PTH to the fetus. Normal fetal development requires 25–30 gms of calcium for bone mineralization and around 80% of this calcium accretion is observed in the third trimester of pregnancy. However the calcium gradient of 1.0:1.4 is no longer maintained when there is hyperparathyroidism present.<ref><pubmed> 12140371</pubmed></ref>Instead the gradient is elevated causing fetal parathyroid gland suppression thereby leading to Hypocalcemia. Calcium mobilisation then becomes difficult and hence fetal tetany may occur followed by miscarriage.<ref><pubmed> 25327435</pubmed></ref> In the event that the fetus survives, postnatal problems such as the baby having weak bones will be likely and would require calcium treatment throughout most of their lives.

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

'''Thymic aplasia'''

Thymic aplasia is a condition that has a strong correlation to DiGeorge syndrome. This syndrome is a congenital birth defect which occurs when the fetus either inherits an abnormal chromosome 22 or has a mutation of the same chromosome. In particularly, the mutation is a deletion of the genomic information packaged in the chromosomes and normally occurs when there isn’t proper recombination of chromosomal material during fertilisation.<ref><pubmed>4166528</pubmed></ref> As a result of this deletion, the third and fourth pharyngeal pouches fail to develop in the twelfth gestational week, thereby leading to the absence or partial absence of the thymus and parathyroid glands. Other associated abnormalities with thymic aplasia as a result of the deletion of chromosome 22 genetic material are severe cardiac defects, low immunity, hypocalcaemia and facial abnormalities. <ref><pubmed>5057550</pubmed></ref> Statistics suggest that the thymic aplasia may occur in 1:4000 to 1:6395 of fetuses.<ref><pubmed> 10861201</pubmed></ref> Treatment is normally difficult for fetuses that exhibit thymic aplasia, however calcium levels can be monitored and regulated and heart problems can be resolved though surgery. Immunity defects can be managed from controlling phosphorus levels in the fetus and protecting them from sources of infection.<ref><pubmed>1454183</pubmed></ref>

==Pancreas==
===Fetal development===
[[File:Development of the pancreas during fetal development.jpg|250px|thumb|right|This images shows normal pancreatic development of the fetus.]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
[[File:Ratio of alpha & beta cells at different phases of fetal development.png|350px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref> <ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

*'''Annular Pancreas'''
[[File:Annular pancreas.jpg|200px|thumb|right|This image shows annular pancreas where a ring of the pancreatic tissue encircles the growing duodenum.]]
Annular pancreas is a rare abnormality that can occur during fetal development in which a ring of the pancreatic tissue encircles the growing duodenum.<ref><pubmed>25124266</pubmed></ref> It occurs in 1 out of 7000 birth and is commonly associated with other abnormalities such as esophageal atresia and malrotation of the midgut. It is assumed that annular pancreas occurs when the tip of right ventral bud sticks to the duodenal wall which then forms a ring from the continuous stretching of the wall during rotation.<ref><pubmed> 25165593</pubmed></ref> This part of the pancreas can constrict the duodenum thereby restricting the flow of food to the intestines of the gastrointestinal tract.<ref><pubmed>24890427</pubmed></ref> Furthermore, annular pancreas is divided into two forms. Complete annular pancreas is when the pancreatic parenchyma wraps around the 2nd part of the duodenum completely whereas in incomplete annular pancreas, the tissue only surrounds the duodenum partially.<ref><pubmed> 24741860</pubmed></ref>Treatment for annular pancreas mainly involves surgery to bypass the constricted portion of the duodenum.

*'''Gestational diabetes mellitus'''

Gestational diabetes mellitus (GDM) is a disorder in which women without any history of diabetes show elevated blood glucose levels during pregnancy normally around the third trimester. It is caused when insulin receptors fail to respond correctly due to interference from signalling molecules related to pregnancy such as the interaction between human placental lactogen, prolactin and estradiol with the insulin receptors.<ref><pubmed>2141655</pubmed></ref> As a result, high blood glucose levels are observed. Patients with GDM have high levels of insulin resistance with increased β-cells production of the pancreas since the high levels of blood glucose are not interacting with the abnormal insulin receptors. Glucose is known to diffuse through the placenta via GLUT1 carrier situated in the syncytiotrophoblast of both the microvillus and basal membranes. With GDM, the number of GLUT1 molecules increase and hence placing high levels of glucose to the fetus since insulin itself cannot diffuse across the placenta and counteract this extremity.<ref><pubmed>25333246</pubmed></ref> This mechanism is known to lead to excessive growth at birth with a low glucose environment as it declines and high insulin production overall leading to hypoglycaemia.<ref><pubmed>25315294</pubmed></ref>It can also lead to jaundice and seizures in the new born with mothers having high susceptibility to type 2 diabetes mellitus. GDM can be controlled by monitoring blood sugar levels and controlling levels of glucose and insulin through pharmaceutical drugs.

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*'''Congenital Adrenal Hyperplasia (CAH)'''

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more.[[File:Cushing's syndrome.jpg|150px|right|thumb|This image shows a 3-month old child with classic signs of Cushing’s syndrome; central obesity, chubby cheeks and moon facies]] Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

*'''Cushing's Syndrome'''

Cushing’s Syndrome (CS) is a metabolic disorder characterised by abnormally high production of endogenous cortisol or exogenous levels of corticosteroids, which disrupts the metabolism of macromolecules such as lipids and carbohydrates. It is most common in obese adults aged 20-50 and the most common cause is the therapeutic administration of exogenous ACTH <ref><pubmed>24656295</pubmed></ref>. Cushing’s Syndrome’s two forms are either ACTH-dependent CS (80-85% of patients) or ACTH independent. The etiology of the dependent form is adrenal gland hyperplasia and excessive ACTH secretion by adenomas in the pituitary, however other causes include; small cell lung carcinoma ACTH production ectopically, or medullary thyroid carcinomas. <ref name= PMID24365350><pubmed>24365350</pubmed></ref> The independent form is however caused by neoplastic growths in the adrenal gland such as carcinomas, adenomas and macronodular hyperplasia. Clinical manifestations of this disorder include; moon facies, cataracts, hyperglycaemia, abnormal fat distribution, poor wounding of the skin, obesity in the central body and muscle wasting in 60% of patients. <ref name= PMID24365350><pubmed>24365350</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

===Abnormalities===

*Congenital gonadal dysgenesis – Turner Syndrome

Female congenital gonadal dysgenesis syndrome refers to a condition where the fetus undergoes abnormal gonadal development with a presentation of streaks of connective tissue on the developing ovary, also referred to as "streak gonads". Streak ovaries extend from the lateral pelvic wall to the attachment of the utero-ovarian ligaments and are essentially sections of functionless tissue. They vary considerably in size but are usually approximately 4 cm in length and 2–3 mm in width. Dysgenetic ovaries are characterized by also absence of follicular structures and oocytes. In women, the most common cause of congenital gonadal dysgenesis is Turner syndrome, 45X which has a prevalence of approximately 1 in 2500 new born girls worldwide<ref name= PMID15475933><pubmed>15475933</pubmed></ref>. Turner syndrome is a genetic abnormality due to an incomplete or completely missing X chromosome in females. Growth hormones treatments such as estrogen replacement therapy may be used after the child has reached 12-13 years of age to help treat the symptoms<ref name= PMID0001417><pubmed>0001417</pubmed></ref>.

==Testis==
===Fetal development===

'''How far has the testis developed by week 8 of gestation?'''
*By week 8, masculine differentiation is induced in the mesonephric duct and external genitalia. This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>
*Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>

'''Fetal stage of testicular development - from week 8 of gestation onwards'''

'''Timeline'''
*Week 9- Yellowish elongated tube with mesonephros laterally and urinary bladder inferomedially
*Week 13- Testes have acquired the ellipsoidal shape found in the adult and are located above the inguinal canal in the groin region. Convexly curved across all but posterior surface <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*Week 16- Located above deep inguinal ring, convexly curved anterior border and flat posterior border covered by epididymis
*Week 17- Migration of testes begins
*Week 24- Testes grow in size and still located about the deep inguinal ring or inside inguinal canal. The testicular poles seem more prominent. Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26 <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
*Week 30- Testes sinus is towards lower portion of testes and epididymis tail continuous with vas deferens. Testes are located in the scrotum having passed through the superficial inguinal ring
*Week 36- Testes located within scrotal sac, they enlarge in size and are maximally convex <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
===Abnormalities===

*'''Klinefelter’s syndrome'''

Klinefelter’s syndrome is the common form of congenital primary hypogonadism with a prevalence of an estimated 1 in 1000 men. Male hypogonadism is defined as a testicular dysfunction resulting in decreased sperm and testosterone production<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.. This genetic disorder occurs when a male is born with an additional X chromosome causing complications and a general underdevelopment of structures such as the seminiferous tubules and Leydig cells within the testis. As a consequence, the size of the testis is abnormally small and the patient has a low sperm count and testosterone levels. In addition to infertility caused by testosterone deficiency, men born with this disorder frequently have increased length of their long bones, including those in the arms, legs, and hands. Many other complications exist independent of the testosterone deficiency seen with these patients<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''
[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]
*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

*'''Placenta accreta'''

[[File:Placenta accreta.jpg|150px|right|thumb|This image shows an area of profuse bleeding in the human placenta, with a region of placenta accreta indicated by the arrow]]

Placenta accreta (PA )is a rare obstetric abnormality characterised by abnormal insertion of the placenta to the myometrium of the uterus. The 3 types of PA are classified based on the depth of invasion; placenta accreta (superficial- chorionic villi attach to myometrium rather than just decidua basalis), placenta increta (middle layer) or placenta perceta (deep) being the most dire with 1 in 7000 incidence. <ref name= PMID23127895><pubmed>23127895</pubmed></ref> PA has an incidence of 1 in 2500 deliveries and is associated with grand-scale haemorrhage and requires hysterectomy and blood transfusion. <ref name= PMID21280984><pubmed>21280984</pubmed></ref> The condition normally occurs in the lower segment of the uterus which is prone to bleeding being poorly contractile and a site of angiogenesis. Prenatal diagnosis of PA is based on second and third trimester ulstrasound findings indicating; retroplacental zone loss, many lucanue in the vasculature and a very thin (<1mm) retroplacental thickness of the myometrium.<ref name= PMID21280984><pubmed>21280984</pubmed></ref> PA has a 40% likelihood in women aged over 35 who have had Caesarian section with placenta previa in their uterine scars. <ref name= PMID23127895><pubmed>23127895</pubmed></ref>

==Recent Findings==

{|
|-bgcolor="F5FFFA"
|
'''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''<ref><pubmed>22912418</pubmed></ref>

''Jennifer R Gardiner, Abigail L Jackson, Julie Gordon, Heiko Lickert, Nancy R Manley, M Albert Basson '''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''. Development: 2012, 139(18);3456-66 PMID: 22912418''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.
|}

{|
|-bgcolor="F5FFFA"
|'''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''<ref><pubmed>23300903</pubmed></ref>

''Stéphanie Migrenne, Evelyne Moreau, Pirjo Pakarinen, Andrée Dierich, Jorge Merlet, René Habert, Chrystèle Racine '''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''. PLoS ONE: 2012, 7(12);e53257 PMID: 23300903''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.
|}

{|
|-bgcolor="F5FFFA"
|'''Neuropeptide Y in the Adult and Fetal Human Pineal Gland'''<ref><pubmed>24757681</pubmed></ref>

''Morten Møller, Pansiri Phansuwan-Pujito, Corin Badiu '''Neuropeptide Y in the adult and fetal human pineal gland'''. Biomed Res Int: 2014, 2014;868567 PMID: 24757681''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland. Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.
|}

=References=

<references/>

2014 Group Project 6

2014-10-23T12:34:05Z

Z3418702: /* Ovary */

2014 Group Project 6

2014-10-23T11:34:47Z

Z3418702: /* Testis */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

[[File:Keith1902 fig167.jpg|200px|thumb|right| Image 1: schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|Image 2: Shows the location of the pineal gland in the adult brain.]]

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon reproductive hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>.

Melatonin plays an important role during fetal development. Both pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammalian fetus, intrinsic circadian rhythms are already established prior to birth.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || Pinealocytes || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

[[File:Primary brain vesicles.jpg|150px|left|thumb|Image 3: Primary brain vesicles]]'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle (Image 3).<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
[[File:Week 6 embryonic development of CNS.jpg|150px|left|thumb|Image 4: Week 6 embryonic development of CNS]]
[[File:Week 11 fetal development of CNS.jpg|150px|right|thumb|Image 5: Week 11 fetal development of CNS]]

*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement and an evagination of the pineal gland is visible (shown in image 4).

[[File:Fetal pineal gland 01.jpg|150px|thumb|right|Image 6: shows a fetal pineal gland at the end of the first trimester of development.]]

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum

*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis (shown in Image 5)

*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

===Abnormalities===

* '''Pineal tumors'''

Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>
[[File:Congenital hydrocephalus MRI02.jpg|150px|thumb|right|Image 7: Infant with obstructive congenital hydrocephalus]]

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signalling pathways or "axes":
[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]
[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).
[[File:Stage 22 image 057.jpg|200x|thumb|Image 1. Histological cross-section of stage 22 embryo]]
* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete
[[File:Development of hypothalamus.jpg|900px|left|thumb|Image 3: Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

===Abnormalities===

*'''Congenital Hypothalamic Hamartoma'''

A hypothalamic hamartoma arises from the region of the tuber cinereum and is commonly associated with isosexual precocious puberty, i.e. puberty that develops unusually early in infants. It involves the alteration of pathways that modulate gonadotropins and contain releasing hormones within the floor of the third ventricle. .<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref> Precocious puberty may either result from a physical pertubation of inhibitory pathways by the hamartoma or a direct neurosecretory process of the hamartoma itself. Seizures are also another common clinical presentation in children with a hypothalamic hamartoma. MR imaging is typically used to identify and monitor the growth of a hypothalamic hamartoma during embryonic and fetal development. Research has shown a trend of congenital hamartomas forming in the utero within a period of 26 weeks. Because of the known association with other congenital anomalies of the central nervous system, hypothalamic hamartoma is thought to form as early as 4 weeks and may in fact be part of a developmental abnormality spectrum.<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref>. Treatment options are currently limited to post-natal deliver of leuprolide acetate to the infant and in general it is relatively effective in managing and treating the condition.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==
[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]
=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>
* Anterior pituitary

[[File:Anterior Pituitary Hormones.jpg|300px|right|thumb|Timeline of anterior pituitary hormone expression and synthesis]]

By week 8 of embryological development, the pituitary gland is fully formed and begins functioning as a control centre for release of hormones that are vital for subsequent organ development.

* Week 10 - Growth Hormone and ACTH detectable
* Week 21 - Vasopressin hormone synthesis established

'''Anterior Pituitary - Adenohypophysis'''

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || No function in fetal development. All postnatal action.
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|}

'''Posterior Pituitary - Neurohypophysis'''

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://www.sciencedirect.com/science/article/pii/S030100820900046X#></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Cardiomyogenesis
* Protective action of fetal neurons during brain development
* Neuronal development and plasticity <ref name =Yuzo Murata, Ming-Zi Li, Sadahiko Masuko>Yuzo Murata, Ming-Zi Li, Sadahiko Masuko, 2011, '''Developmental expression of oxytocin receptors in the neonatal medulla
oblongata and pons''', Neuroscience Letters; 502 (2011), pp157-161, http://www.sciencedirect.com/science/article/pii/S0304394011010949#></ref>
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Regulates fetal renal function
* Regulates amniotic fluid content and concentration
* Regulates blood pressure, heart rate, cardiac output and placental blood flow <ref name =M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher >M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher , 1993, '''Vasopressin receptors and effects during fetal development''', Regulatory Peptides; 45, pp203-208, http://www.sciencedirect.com/science/article/pii/016701159390207O#></ref>
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

'''How far has the thyroid gland developed by week 8 of gestation?'''
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

'''Fetal Stage of Thyroid Development - from week 8 of gestation onwards:'''
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis<ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>
* Week 16 - 18 is when fetal thyroid hormone synthesis occurs
** Prior to this, the fetus receives vital maternal thyroid hormones via the placenta

'''Thyroid Hormone Action'''
The following table explains the ontogenic action of thyroid hormone on the developing fetus. Thyroid hormones are essential in brain and central nervous system development in the fetus. A lot of neurological disorders are associated with insufficient thyroid hormone synthesis:

{| class="wikitable"
|-
! Hormone !! Types !! Ontogenic Action
|-
| Thyroid Hormone ||
* T3 - triiodothyronine
* T4 - thyroxine
|| Brain development:
* Central Nervous System development and maturation <ref name =J Patel, K Landers, H Li, R H Mortimer and K Richard>J Patel, K Landers, H Li, R H Mortimer and K Richard, 2011, '''Thyroid hormones and fetal neurological development''', Journal of Endocrinology:209;1-8, http://joe.endocrinology-journals.org.wwwproxy0.library.unsw.edu.au/content/209/1/1.full.pdf+html></ref>
*Glial cell proliferation
*Neural myelination
*Axon and dendrite sprouting
*Synapse formation
|}

{| class="wikitable"
|-
! Header text !! Header text !! Header text
|-
| Example || Example || Example
|}

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|right|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone || Secreted by || Function || Image
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine. || [[File:Active parathyroid hormone assay cartoon.png|200px|thumb|This images shows an active parathyroid hormone and its chemical structure.]]
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

'''Fetal hyperparathyroidism'''

Fetal hyperparathyroidism is a condition that is caused when an excess of parathyroid hormone (PTH) is present the bloodstream.<ref><pubmed> 1745971</pubmed></ref> This may be due to an overstimulated maternal parathyroid gland out of all the four which transfers the over accumulated PTH to the fetus. Normal fetal development requires 25–30 gms of calcium for bone mineralization and around 80% of this calcium accretion is observed in the third trimester of pregnancy. However the calcium gradient of 1.0:1.4 is no longer maintained when there is hyperparathyroidism present.<ref><pubmed> 12140371</pubmed></ref>Instead the gradient is elevated causing fetal parathyroid gland suppression thereby leading to Hypocalcemia. Calcium mobilisation then becomes difficult and hence fetal tetany may occur followed by miscarriage.<ref><pubmed> 25327435</pubmed></ref> In the event that the fetus survives, postnatal problems such as the baby having weak bones will be likely and would require calcium treatment throughout most of their lives.

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

'''Thymic aplasia'''

Thymic aplasia is a condition that has a strong correlation to DiGeorge syndrome. This syndrome is a congenital birth defect which occurs when the fetus either inherits an abnormal chromosome 22 or has a mutation of the same chromosome. In particularly, the mutation is a deletion of the genomic information packaged in the chromosomes and normally occurs when there isn’t proper recombination of chromosomal material during fertilisation.<ref><pubmed>4166528</pubmed></ref> As a result of this deletion, the third and fourth pharyngeal pouches fail to develop in the twelfth gestational week, thereby leading to the absence or partial absence of the thymus and parathyroid glands. Other associated abnormalities with thymic aplasia as a result of the deletion of chromosome 22 genetic material are severe cardiac defects, low immunity, hypocalcaemia and facial abnormalities. <ref><pubmed>5057550</pubmed></ref> Statistics suggest that the thymic aplasia may occur in 1:4000 to 1:6395 of fetuses.<ref><pubmed> 10861201</pubmed></ref> Treatment is normally difficult for fetuses that exhibit thymic aplasia, however calcium levels can be monitored and regulated and heart problems can be resolved though surgery. Immunity defects can be managed from controlling phosphorus levels in the fetus and protecting them from sources of infection.<ref><pubmed>1454183</pubmed></ref>

==Pancreas==
===Fetal development===
[[File:Development of the pancreas during fetal development.jpg|250px|thumb|right|This images shows normal pancreatic development of the fetus.]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
[[File:Ratio of alpha & beta cells at different phases of fetal development.png|350px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref> <ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

*'''Annular Pancreas'''
[[File:Annular pancreas.jpg|200px|thumb|right|This image shows annular pancreas where a ring of the pancreatic tissue encircles the growing duodenum.]]
Annular pancreas is a rare abnormality that can occur during fetal development in which a ring of the pancreatic tissue encircles the growing duodenum.<ref><pubmed>25124266</pubmed></ref> It occurs in 1 out of 7000 birth and is commonly associated with other abnormalities such as esophageal atresia and malrotation of the midgut. It is assumed that annular pancreas occurs when the tip of right ventral bud sticks to the duodenal wall which then forms a ring from the continuous stretching of the wall during rotation.<ref><pubmed> 25165593</pubmed></ref> This part of the pancreas can constrict the duodenum thereby restricting the flow of food to the intestines of the gastrointestinal tract.<ref><pubmed>24890427</pubmed></ref> Furthermore, annular pancreas is divided into two forms. Complete annular pancreas is when the pancreatic parenchyma wraps around the 2nd part of the duodenum completely whereas in incomplete annular pancreas, the tissue only surrounds the duodenum partially.<ref><pubmed> 24741860</pubmed></ref>Treatment for annular pancreas mainly involves surgery to bypass the constricted portion of the duodenum.

*'''Gestational diabetes mellitus'''

Gestational diabetes mellitus (GDM) is a disorder in which women without any history of diabetes show elevated blood glucose levels during pregnancy normally around the third trimester. It is caused when insulin receptors fail to respond correctly due to interference from signalling molecules related to pregnancy such as the interaction between human placental lactogen, prolactin and estradiol with the insulin receptors.<ref><pubmed>2141655</pubmed></ref> As a result, high blood glucose levels are observed. Patients with GDM have high levels of insulin resistance with increased β-cells production of the pancreas since the high levels of blood glucose are not interacting with the abnormal insulin receptors. Glucose is known to diffuse through the placenta via GLUT1 carrier situated in the syncytiotrophoblast of both the microvillus and basal membranes. With GDM, the number of GLUT1 molecules increase and hence placing high levels of glucose to the fetus since insulin itself cannot diffuse across the placenta and counteract this extremity.<ref><pubmed>25333246</pubmed></ref> This mechanism is known to lead to excessive growth at birth with a low glucose environment as it declines and high insulin production overall leading to hypoglycaemia.<ref><pubmed>25315294</pubmed></ref>It can also lead to jaundice and seizures in the new born with mothers having high susceptibility to type 2 diabetes mellitus. GDM can be controlled by monitoring blood sugar levels and controlling levels of glucose and insulin through pharmaceutical drugs.

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*'''Congenital Adrenal Hyperplasia (CAH)'''

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more.[[File:Cushing's syndrome.jpg|150px|right|thumb|This image shows a 3-month old child with classic signs of Cushing’s syndrome; central obesity, chubby cheeks and moon facies]] Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

*'''Cushing's Syndrome'''

Cushing’s Syndrome (CS) is a metabolic disorder characterised by abnormally high production of endogenous cortisol or exogenous levels of corticosteroids, which disrupts the metabolism of macromolecules such as lipids and carbohydrates. It is most common in obese adults aged 20-50 and the most common cause is the therapeutic administration of exogenous ACTH <ref><pubmed>24656295</pubmed></ref>. Cushing’s Syndrome’s two forms are either ACTH-dependent CS (80-85% of patients) or ACTH independent. The etiology of the dependent form is adrenal gland hyperplasia and excessive ACTH secretion by adenomas in the pituitary, however other causes include; small cell lung carcinoma ACTH production ectopically, or medullary thyroid carcinomas. <ref name= PMID24365350><pubmed>24365350</pubmed></ref> The independent form is however caused by neoplastic growths in the adrenal gland such as carcinomas, adenomas and macronodular hyperplasia. Clinical manifestations of this disorder include; moon facies, cataracts, hyperglycaemia, abnormal fat distribution, poor wounding of the skin, obesity in the central body and muscle wasting in 60% of patients. <ref name= PMID24365350><pubmed>24365350</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

===Abnormalities===

==Testis==
===Fetal development===

'''How far has the testis developed by week 8 of gestation?'''
*By week 8, masculine differentiation is induced in the mesonephric duct and external genitalia. This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>
*Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>

'''Fetal stage of testicular development - from week 8 of gestation onwards'''

'''Timeline'''
*Week 9- Yellowish elongated tube with mesonephros laterally and urinary bladder inferomedially
*Week 13- Testes have acquired the ellipsoidal shape found in the adult and are located above the inguinal canal in the groin region. Convexly curved across all but posterior surface <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*Week 16- Located above deep inguinal ring, convexly curved anterior border and flat posterior border covered by epididymis
*Week 17- Migration of testes begins
*Week 24- Testes grow in size and still located about the deep inguinal ring or inside inguinal canal. The testicular poles seem more prominent. Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26 <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
*Week 30- Testes sinus is towards lower portion of testes and epididymis tail continuous with vas deferens. Testes are located in the scrotum having passed through the superficial inguinal ring
*Week 36- Testes located within scrotal sac, they enlarge in size and are maximally convex <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
===Abnormalities===

*'''Klinefelter’s syndrome'''

Klinefelter’s syndrome is the common form of congenital primary hypogonadism with a prevalence of an estimated 1 in 1000 men. Male hypogonadism is defined as a testicular dysfunction resulting in decreased sperm and testosterone production<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.. This genetic disorder occurs when a male is born with an additional X chromosome causing complications and a general underdevelopment of structures such as the seminiferous tubules and Leydig cells within the testis. As a consequence, the size of the testis is abnormally small and the patient has a low sperm count and testosterone levels. In addition to infertility caused by testosterone deficiency, men born with this disorder frequently have increased length of their long bones, including those in the arms, legs, and hands. Many other complications exist independent of the testosterone deficiency seen with these patients<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''
[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]
*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

*'''Placenta accreta'''

[[File:Placenta accreta.jpg|150px|right|thumb|This image shows an area of profuse bleeding in the human placenta, with a region of placenta accreta indicated by the arrow]]

Placenta accreta (PA )is a rare obstetric abnormality characterised by abnormal insertion of the placenta to the myometrium of the uterus. The 3 types of PA are classified based on the depth of invasion; placenta accreta (superficial- chorionic villi attach to myometrium rather than just decidua basalis), placenta increta (middle layer) or placenta perceta (deep) being the most dire with 1 in 7000 incidence. <ref name= PMID23127895><pubmed>23127895</pubmed></ref> PA has an incidence of 1 in 2500 deliveries and is associated with grand-scale haemorrhage and requires hysterectomy and blood transfusion. <ref name= PMID21280984><pubmed>21280984</pubmed></ref> The condition normally occurs in the lower segment of the uterus which is prone to bleeding being poorly contractile and a site of angiogenesis. Prenatal diagnosis of PA is based on second and third trimester ulstrasound findings indicating; retroplacental zone loss, many lucanue in the vasculature and a very thin (<1mm) retroplacental thickness of the myometrium.<ref name= PMID21280984><pubmed>21280984</pubmed></ref> PA has a 40% likelihood in women aged over 35 who have had Caesarian section with placenta previa in their uterine scars. <ref name= PMID23127895><pubmed>23127895</pubmed></ref>

==Recent Findings==

{|
|-bgcolor="F5FFFA"
|
'''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''<ref><pubmed>22912418</pubmed></ref>

''Jennifer R Gardiner, Abigail L Jackson, Julie Gordon, Heiko Lickert, Nancy R Manley, M Albert Basson '''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''. Development: 2012, 139(18);3456-66 PMID: 22912418''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.
|}

{|
|-bgcolor="F5FFFA"
|'''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''<ref><pubmed>23300903</pubmed></ref>

''Stéphanie Migrenne, Evelyne Moreau, Pirjo Pakarinen, Andrée Dierich, Jorge Merlet, René Habert, Chrystèle Racine '''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''. PLoS ONE: 2012, 7(12);e53257 PMID: 23300903''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.
|}

{|
|-bgcolor="F5FFFA"
|'''Neuropeptide Y in the Adult and Fetal Human Pineal Gland'''<ref><pubmed>24757681</pubmed></ref>

''Morten Møller, Pansiri Phansuwan-Pujito, Corin Badiu '''Neuropeptide Y in the adult and fetal human pineal gland'''. Biomed Res Int: 2014, 2014;868567 PMID: 24757681''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland. Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.
|}

=References=

<references/>

2014 Group Project 6

2014-10-23T11:29:51Z

Z3418702: /* Testis */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

[[File:Keith1902 fig167.jpg|200px|thumb|right| Image 1: schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|Image 2: Shows the location of the pineal gland in the adult brain.]]

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon reproductive hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>.

Melatonin plays an important role during fetal development. Both pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammalian fetus, intrinsic circadian rhythms are already established prior to birth.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || Pinealocytes || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

[[File:Primary brain vesicles.jpg|150px|left|thumb|Image 3: Primary brain vesicles]]'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle (Image 3).<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
[[File:Week 6 embryonic development of CNS.jpg|150px|left|thumb|Image 4: Week 6 embryonic development of CNS]]
[[File:Week 11 fetal development of CNS.jpg|150px|right|thumb|Image 5: Week 11 fetal development of CNS]]

*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement and an evagination of the pineal gland is visible (shown in image 4).

[[File:Fetal pineal gland 01.jpg|150px|thumb|right|Image 6: shows a fetal pineal gland at the end of the first trimester of development.]]

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum

*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis (shown in Image 5)

*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

===Abnormalities===

* '''Pineal tumors'''

Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>
[[File:Congenital hydrocephalus MRI02.jpg|150px|thumb|right|Image 7: Infant with obstructive congenital hydrocephalus]]

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signalling pathways or "axes":
[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]
[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).
[[File:Stage 22 image 057.jpg|200x|thumb|Image 1. Histological cross-section of stage 22 embryo]]
* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete
[[File:Development of hypothalamus.jpg|900px|left|thumb|Image 3: Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

===Abnormalities===

*'''Congenital Hypothalamic Hamartoma'''

A hypothalamic hamartoma arises from the region of the tuber cinereum and is commonly associated with isosexual precocious puberty, i.e. puberty that develops unusually early in infants. It involves the alteration of pathways that modulate gonadotropins and contain releasing hormones within the floor of the third ventricle. .<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref> Precocious puberty may either result from a physical pertubation of inhibitory pathways by the hamartoma or a direct neurosecretory process of the hamartoma itself. Seizures are also another common clinical presentation in children with a hypothalamic hamartoma. MR imaging is typically used to identify and monitor the growth of a hypothalamic hamartoma during embryonic and fetal development. Research has shown a trend of congenital hamartomas forming in the utero within a period of 26 weeks. Because of the known association with other congenital anomalies of the central nervous system, hypothalamic hamartoma is thought to form as early as 4 weeks and may in fact be part of a developmental abnormality spectrum.<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref>. Treatment options are currently limited to post-natal deliver of leuprolide acetate to the infant and in general it is relatively effective in managing and treating the condition.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==
[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]
=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>
* Anterior pituitary

[[File:Anterior Pituitary Hormones.jpg|300px|right|thumb|Timeline of anterior pituitary hormone expression and synthesis]]

By week 8 of embryological development, the pituitary gland is fully formed and begins functioning as a control centre for release of hormones that are vital for subsequent organ development.

* Week 10 - Growth Hormone and ACTH detectable
* Week 21 - Vasopressin hormone synthesis established

'''Anterior Pituitary - Adenohypophysis'''

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || No function in fetal development. All postnatal action.
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|}

'''Posterior Pituitary - Neurohypophysis'''

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://www.sciencedirect.com/science/article/pii/S030100820900046X#></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Cardiomyogenesis
* Protective action of fetal neurons during brain development
* Neuronal development and plasticity <ref name =Yuzo Murata, Ming-Zi Li, Sadahiko Masuko>Yuzo Murata, Ming-Zi Li, Sadahiko Masuko, 2011, '''Developmental expression of oxytocin receptors in the neonatal medulla
oblongata and pons''', Neuroscience Letters; 502 (2011), pp157-161, http://www.sciencedirect.com/science/article/pii/S0304394011010949#></ref>
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Regulates fetal renal function
* Regulates amniotic fluid content and concentration
* Regulates blood pressure, heart rate, cardiac output and placental blood flow <ref name =M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher >M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher , 1993, '''Vasopressin receptors and effects during fetal development''', Regulatory Peptides; 45, pp203-208, http://www.sciencedirect.com/science/article/pii/016701159390207O#></ref>
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

'''How far has the thyroid gland developed by week 8 of gestation?'''
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

'''Fetal Stage of Thyroid Development - from week 8 of gestation onwards:'''
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis<ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>
* Week 16 - 18 is when fetal thyroid hormone synthesis occurs
** Prior to this, the fetus receives vital maternal thyroid hormones via the placenta

'''Thyroid Hormone Action'''
The following table explains the ontogenic action of thyroid hormone on the developing fetus. Thyroid hormones are essential in brain and central nervous system development in the fetus. A lot of neurological disorders are associated with insufficient thyroid hormone synthesis:

{| class="wikitable"
|-
! Hormone !! Types !! Ontogenic Action
|-
| Thyroid Hormone ||
* T3 - triiodothyronine
* T4 - thyroxine
|| Brain development:
* Central Nervous System development and maturation <ref name =J Patel, K Landers, H Li, R H Mortimer and K Richard>J Patel, K Landers, H Li, R H Mortimer and K Richard, 2011, '''Thyroid hormones and fetal neurological development''', Journal of Endocrinology:209;1-8, http://joe.endocrinology-journals.org.wwwproxy0.library.unsw.edu.au/content/209/1/1.full.pdf+html></ref>
*Glial cell proliferation
*Neural myelination
*Axon and dendrite sprouting
*Synapse formation
|}

{| class="wikitable"
|-
! Header text !! Header text !! Header text
|-
| Example || Example || Example
|}

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|right|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone || Secreted by || Function || Image
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine. || [[File:Active parathyroid hormone assay cartoon.png|200px|thumb|This images shows an active parathyroid hormone and its chemical structure.]]
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

'''Fetal hyperparathyroidism'''

Fetal hyperparathyroidism is a condition that is caused when an excess of parathyroid hormone (PTH) is present the bloodstream.<ref><pubmed> 1745971</pubmed></ref> This may be due to an overstimulated maternal parathyroid gland out of all the four which transfers the over accumulated PTH to the fetus. Normal fetal development requires 25–30 gms of calcium for bone mineralization and around 80% of this calcium accretion is observed in the third trimester of pregnancy. However the calcium gradient of 1.0:1.4 is no longer maintained when there is hyperparathyroidism present.<ref><pubmed> 12140371</pubmed></ref>Instead the gradient is elevated causing fetal parathyroid gland suppression thereby leading to Hypocalcemia. Calcium mobilisation then becomes difficult and hence fetal tetany may occur followed by miscarriage.<ref><pubmed> 25327435</pubmed></ref> In the event that the fetus survives, postnatal problems such as the baby having weak bones will be likely and would require calcium treatment throughout most of their lives.

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

'''Thymic aplasia'''

Thymic aplasia is a condition that has a strong correlation to DiGeorge syndrome. This syndrome is a congenital birth defect which occurs when the fetus either inherits an abnormal chromosome 22 or has a mutation of the same chromosome. In particularly, the mutation is a deletion of the genomic information packaged in the chromosomes and normally occurs when there isn’t proper recombination of chromosomal material during fertilisation.<ref><pubmed>4166528</pubmed></ref> As a result of this deletion, the third and fourth pharyngeal pouches fail to develop in the twelfth gestational week, thereby leading to the absence or partial absence of the thymus and parathyroid glands. Other associated abnormalities with thymic aplasia as a result of the deletion of chromosome 22 genetic material are severe cardiac defects, low immunity, hypocalcaemia and facial abnormalities. <ref><pubmed>5057550</pubmed></ref> Statistics suggest that the thymic aplasia may occur in 1:4000 to 1:6395 of fetuses.<ref><pubmed> 10861201</pubmed></ref> Treatment is normally difficult for fetuses that exhibit thymic aplasia, however calcium levels can be monitored and regulated and heart problems can be resolved though surgery. Immunity defects can be managed from controlling phosphorus levels in the fetus and protecting them from sources of infection.<ref><pubmed>1454183</pubmed></ref>

==Pancreas==
===Fetal development===
[[File:Development of the pancreas during fetal development.jpg|250px|thumb|right|This images shows normal pancreatic development of the fetus.]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
[[File:Ratio of alpha & beta cells at different phases of fetal development.png|350px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref> <ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

*'''Annular Pancreas'''
[[File:Annular pancreas.jpg|200px|thumb|right|This image shows annular pancreas where a ring of the pancreatic tissue encircles the growing duodenum.]]
Annular pancreas is a rare abnormality that can occur during fetal development in which a ring of the pancreatic tissue encircles the growing duodenum.<ref><pubmed>25124266</pubmed></ref> It occurs in 1 out of 7000 birth and is commonly associated with other abnormalities such as esophageal atresia and malrotation of the midgut. It is assumed that annular pancreas occurs when the tip of right ventral bud sticks to the duodenal wall which then forms a ring from the continuous stretching of the wall during rotation.<ref><pubmed> 25165593</pubmed></ref> This part of the pancreas can constrict the duodenum thereby restricting the flow of food to the intestines of the gastrointestinal tract.<ref><pubmed>24890427</pubmed></ref> Furthermore, annular pancreas is divided into two forms. Complete annular pancreas is when the pancreatic parenchyma wraps around the 2nd part of the duodenum completely whereas in incomplete annular pancreas, the tissue only surrounds the duodenum partially.<ref><pubmed> 24741860</pubmed></ref>Treatment for annular pancreas mainly involves surgery to bypass the constricted portion of the duodenum.

*'''Gestational diabetes mellitus'''

Gestational diabetes mellitus (GDM) is a disorder in which women without any history of diabetes show elevated blood glucose levels during pregnancy normally around the third trimester. It is caused when insulin receptors fail to respond correctly due to interference from signalling molecules related to pregnancy such as the interaction between human placental lactogen, prolactin and estradiol with the insulin receptors.<ref><pubmed>2141655</pubmed></ref> As a result, high blood glucose levels are observed. Patients with GDM have high levels of insulin resistance with increased β-cells production of the pancreas since the high levels of blood glucose are not interacting with the abnormal insulin receptors. Glucose is known to diffuse through the placenta via GLUT1 carrier situated in the syncytiotrophoblast of both the microvillus and basal membranes. With GDM, the number of GLUT1 molecules increase and hence placing high levels of glucose to the fetus since insulin itself cannot diffuse across the placenta and counteract this extremity.<ref><pubmed>25333246</pubmed></ref> This mechanism is known to lead to excessive growth at birth with a low glucose environment as it declines and high insulin production overall leading to hypoglycaemia.<ref><pubmed>25315294</pubmed></ref>It can also lead to jaundice and seizures in the new born with mothers having high susceptibility to type 2 diabetes mellitus. GDM can be controlled by monitoring blood sugar levels and controlling levels of glucose and insulin through pharmaceutical drugs.

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*'''Congenital Adrenal Hyperplasia (CAH)'''

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more.[[File:Cushing's syndrome.jpg|150px|right|thumb|This image shows a 3-month old child with classic signs of Cushing’s syndrome; central obesity, chubby cheeks and moon facies]] Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

*'''Cushing's Syndrome'''

Cushing’s Syndrome (CS) is a metabolic disorder characterised by abnormally high production of endogenous cortisol or exogenous levels of corticosteroids, which disrupts the metabolism of macromolecules such as lipids and carbohydrates. It is most common in obese adults aged 20-50 and the most common cause is the therapeutic administration of exogenous ACTH <ref><pubmed>24656295</pubmed></ref>. Cushing’s Syndrome’s two forms are either ACTH-dependent CS (80-85% of patients) or ACTH independent. The etiology of the dependent form is adrenal gland hyperplasia and excessive ACTH secretion by adenomas in the pituitary, however other causes include; small cell lung carcinoma ACTH production ectopically, or medullary thyroid carcinomas. <ref name= PMID24365350><pubmed>24365350</pubmed></ref> The independent form is however caused by neoplastic growths in the adrenal gland such as carcinomas, adenomas and macronodular hyperplasia. Clinical manifestations of this disorder include; moon facies, cataracts, hyperglycaemia, abnormal fat distribution, poor wounding of the skin, obesity in the central body and muscle wasting in 60% of patients. <ref name= PMID24365350><pubmed>24365350</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

===Abnormalities===

==Testis==
===Fetal development===

'''How far has the testis developed by week 8 of gestation?'''
*By week 8, masculine differentiation is induced in the mesonephric duct and external genitalia. This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>
*Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>

'''Fetal stage of testicular development - from week 8 of gestation onwards'''

'''Timeline'''
*Week 9- Yellowish elongated tube with mesonephros laterally and urinary bladder inferomedially
*Week 13- Testes have acquired the ellipsoidal shape found in the adult and are located above the inguinal canal in the groin region. Convexly curved across all but posterior surface <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*Week 16- Located above deep inguinal ring, convexly curved anterior border and flat posterior border covered by epididymis
*Week 17- Migration of testes begins from
*Week 24- Testes grow in size and still located about the deep inguinal ring or inside inguinal canal. The testicular poles seem more prominent. Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
*Week 30- Testes sinus is towards lower portion of testes and epididymis tail continuous with vas deferens. Testes are located in the scrotum having passed through the superficial inguinal ring
Week 36- Testes located within scrotal sac, they enlarge in size and are maximally convex <ref name= Subhalakshmi>Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti '''Development and Morphogenesis of Testis in Human Fetuses'''. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171</ref>
===Abnormalities===

*'''Klinefelter’s syndrome'''

Klinefelter’s syndrome is the common form of congenital primary hypogonadism with a prevalence of an estimated 1 in 1000 men. Male hypogonadism is defined as a testicular dysfunction resulting in decreased sperm and testosterone production<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.. This genetic disorder occurs when a male is born with an additional X chromosome causing complications and a general underdevelopment of structures such as the seminiferous tubules and Leydig cells within the testis. As a consequence, the size of the testis is abnormally small and the patient has a low sperm count and testosterone levels. In addition to infertility caused by testosterone deficiency, men born with this disorder frequently have increased length of their long bones, including those in the arms, legs, and hands. Many other complications exist independent of the testosterone deficiency seen with these patients<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''
[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]
*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

*'''Placenta accreta'''

[[File:Placenta accreta.jpg|150px|right|thumb|This image shows an area of profuse bleeding in the human placenta, with a region of placenta accreta indicated by the arrow]]

Placenta accreta (PA )is a rare obstetric abnormality characterised by abnormal insertion of the placenta to the myometrium of the uterus. The 3 types of PA are classified based on the depth of invasion; placenta accreta (superficial- chorionic villi attach to myometrium rather than just decidua basalis), placenta increta (middle layer) or placenta perceta (deep) being the most dire with 1 in 7000 incidence. <ref name= PMID23127895><pubmed>23127895</pubmed></ref> PA has an incidence of 1 in 2500 deliveries and is associated with grand-scale haemorrhage and requires hysterectomy and blood transfusion. <ref name= PMID21280984><pubmed>21280984</pubmed></ref> The condition normally occurs in the lower segment of the uterus which is prone to bleeding being poorly contractile and a site of angiogenesis. Prenatal diagnosis of PA is based on second and third trimester ulstrasound findings indicating; retroplacental zone loss, many lucanue in the vasculature and a very thin (<1mm) retroplacental thickness of the myometrium.<ref name= PMID21280984><pubmed>21280984</pubmed></ref> PA has a 40% likelihood in women aged over 35 who have had Caesarian section with placenta previa in their uterine scars. <ref name= PMID23127895><pubmed>23127895</pubmed></ref>

==Recent Findings==

{|
|-bgcolor="F5FFFA"
|
'''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''<ref><pubmed>22912418</pubmed></ref>

''Jennifer R Gardiner, Abigail L Jackson, Julie Gordon, Heiko Lickert, Nancy R Manley, M Albert Basson '''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''. Development: 2012, 139(18);3456-66 PMID: 22912418''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.
|}

{|
|-bgcolor="F5FFFA"
|'''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''<ref><pubmed>23300903</pubmed></ref>

''Stéphanie Migrenne, Evelyne Moreau, Pirjo Pakarinen, Andrée Dierich, Jorge Merlet, René Habert, Chrystèle Racine '''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''. PLoS ONE: 2012, 7(12);e53257 PMID: 23300903''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.
|}

{|
|-bgcolor="F5FFFA"
|'''Neuropeptide Y in the Adult and Fetal Human Pineal Gland'''<ref><pubmed>24757681</pubmed></ref>

''Morten Møller, Pansiri Phansuwan-Pujito, Corin Badiu '''Neuropeptide Y in the adult and fetal human pineal gland'''. Biomed Res Int: 2014, 2014;868567 PMID: 24757681''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland. Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.
|}

=References=

<references/>

2014 Group Project 6

2014-10-23T11:22:52Z

Z3418702: /* Testis */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

[[File:Keith1902 fig167.jpg|200px|thumb|right| Image 1: schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|Image 2: Shows the location of the pineal gland in the adult brain.]]

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon reproductive hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>.

Melatonin plays an important role during fetal development. Both pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammalian fetus, intrinsic circadian rhythms are already established prior to birth.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || Pinealocytes || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

[[File:Primary brain vesicles.jpg|150px|left|thumb|Image 3: Primary brain vesicles]]'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle (Image 3).<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
[[File:Week 6 embryonic development of CNS.jpg|150px|left|thumb|Image 4: Week 6 embryonic development of CNS]]
[[File:Week 11 fetal development of CNS.jpg|150px|right|thumb|Image 5: Week 11 fetal development of CNS]]

*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement and an evagination of the pineal gland is visible (shown in image 4).

[[File:Fetal pineal gland 01.jpg|150px|thumb|right|Image 6: shows a fetal pineal gland at the end of the first trimester of development.]]

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum

*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis (shown in Image 5)

*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

===Abnormalities===

* '''Pineal tumors'''

Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>
[[File:Congenital hydrocephalus MRI02.jpg|150px|thumb|right|Image 7: Infant with obstructive congenital hydrocephalus]]

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signalling pathways or "axes":
[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]
[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).
[[File:Stage 22 image 057.jpg|200x|thumb|Image 1. Histological cross-section of stage 22 embryo]]
* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete
[[File:Development of hypothalamus.jpg|900px|left|thumb|Image 3: Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

===Abnormalities===

*'''Congenital Hypothalamic Hamartoma'''

A hypothalamic hamartoma arises from the region of the tuber cinereum and is commonly associated with isosexual precocious puberty, i.e. puberty that develops unusually early in infants. It involves the alteration of pathways that modulate gonadotropins and contain releasing hormones within the floor of the third ventricle. .<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref> Precocious puberty may either result from a physical pertubation of inhibitory pathways by the hamartoma or a direct neurosecretory process of the hamartoma itself. Seizures are also another common clinical presentation in children with a hypothalamic hamartoma. MR imaging is typically used to identify and monitor the growth of a hypothalamic hamartoma during embryonic and fetal development. Research has shown a trend of congenital hamartomas forming in the utero within a period of 26 weeks. Because of the known association with other congenital anomalies of the central nervous system, hypothalamic hamartoma is thought to form as early as 4 weeks and may in fact be part of a developmental abnormality spectrum.<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref>. Treatment options are currently limited to post-natal deliver of leuprolide acetate to the infant and in general it is relatively effective in managing and treating the condition.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==
[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]
=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>
* Anterior pituitary

[[File:Anterior Pituitary Hormones.jpg|300px|right|thumb|Timeline of anterior pituitary hormone expression and synthesis]]

By week 8 of embryological development, the pituitary gland is fully formed and begins functioning as a control centre for release of hormones that are vital for subsequent organ development.

* Week 10 - Growth Hormone and ACTH detectable
* Week 21 - Vasopressin hormone synthesis established

'''Anterior Pituitary - Adenohypophysis'''

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || No function in fetal development. All postnatal action.
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|}

'''Posterior Pituitary - Neurohypophysis'''

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://www.sciencedirect.com/science/article/pii/S030100820900046X#></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Cardiomyogenesis
* Protective action of fetal neurons during brain development
* Neuronal development and plasticity <ref name =Yuzo Murata, Ming-Zi Li, Sadahiko Masuko>Yuzo Murata, Ming-Zi Li, Sadahiko Masuko, 2011, '''Developmental expression of oxytocin receptors in the neonatal medulla
oblongata and pons''', Neuroscience Letters; 502 (2011), pp157-161, http://www.sciencedirect.com/science/article/pii/S0304394011010949#></ref>
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Regulates fetal renal function
* Regulates amniotic fluid content and concentration
* Regulates blood pressure, heart rate, cardiac output and placental blood flow <ref name =M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher >M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher , 1993, '''Vasopressin receptors and effects during fetal development''', Regulatory Peptides; 45, pp203-208, http://www.sciencedirect.com/science/article/pii/016701159390207O#></ref>
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

'''How far has the thyroid gland developed by week 8 of gestation?'''
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

'''Fetal Stage of Thyroid Development - from week 8 of gestation onwards:'''
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis<ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>
* Week 16 - 18 is when fetal thyroid hormone synthesis occurs
** Prior to this, the fetus receives vital maternal thyroid hormones via the placenta

'''Thyroid Hormone Action'''
The following table explains the ontogenic action of thyroid hormone on the developing fetus. Thyroid hormones are essential in brain and central nervous system development in the fetus. A lot of neurological disorders are associated with insufficient thyroid hormone synthesis:

{| class="wikitable"
|-
! Hormone !! Types !! Ontogenic Action
|-
| Thyroid Hormone ||
* T3 - triiodothyronine
* T4 - thyroxine
|| Brain development:
* Central Nervous System development and maturation <ref name =J Patel, K Landers, H Li, R H Mortimer and K Richard>J Patel, K Landers, H Li, R H Mortimer and K Richard, 2011, '''Thyroid hormones and fetal neurological development''', Journal of Endocrinology:209;1-8, http://joe.endocrinology-journals.org.wwwproxy0.library.unsw.edu.au/content/209/1/1.full.pdf+html></ref>
*Glial cell proliferation
*Neural myelination
*Axon and dendrite sprouting
*Synapse formation
|}

{| class="wikitable"
|-
! Header text !! Header text !! Header text
|-
| Example || Example || Example
|}

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|right|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone || Secreted by || Function || Image
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine. || [[File:Active parathyroid hormone assay cartoon.png|200px|thumb|This images shows an active parathyroid hormone and its chemical structure.]]
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

'''Fetal hyperparathyroidism'''

Fetal hyperparathyroidism is a condition that is caused when an excess of parathyroid hormone (PTH) is present the bloodstream.<ref><pubmed> 1745971</pubmed></ref> This may be due to an overstimulated maternal parathyroid gland out of all the four which transfers the over accumulated PTH to the fetus. Normal fetal development requires 25–30 gms of calcium for bone mineralization and around 80% of this calcium accretion is observed in the third trimester of pregnancy. However the calcium gradient of 1.0:1.4 is no longer maintained when there is hyperparathyroidism present.<ref><pubmed> 12140371</pubmed></ref>Instead the gradient is elevated causing fetal parathyroid gland suppression thereby leading to Hypocalcemia. Calcium mobilisation then becomes difficult and hence fetal tetany may occur followed by miscarriage.<ref><pubmed> 25327435</pubmed></ref> In the event that the fetus survives, postnatal problems such as the baby having weak bones will be likely and would require calcium treatment throughout most of their lives.

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

'''Thymic aplasia'''

Thymic aplasia is a condition that has a strong correlation to DiGeorge syndrome. This syndrome is a congenital birth defect which occurs when the fetus either inherits an abnormal chromosome 22 or has a mutation of the same chromosome. In particularly, the mutation is a deletion of the genomic information packaged in the chromosomes and normally occurs when there isn’t proper recombination of chromosomal material during fertilisation.<ref><pubmed>4166528</pubmed></ref> As a result of this deletion, the third and fourth pharyngeal pouches fail to develop in the twelfth gestational week, thereby leading to the absence or partial absence of the thymus and parathyroid glands. Other associated abnormalities with thymic aplasia as a result of the deletion of chromosome 22 genetic material are severe cardiac defects, low immunity, hypocalcaemia and facial abnormalities. <ref><pubmed>5057550</pubmed></ref> Statistics suggest that the thymic aplasia may occur in 1:4000 to 1:6395 of fetuses.<ref><pubmed> 10861201</pubmed></ref> Treatment is normally difficult for fetuses that exhibit thymic aplasia, however calcium levels can be monitored and regulated and heart problems can be resolved though surgery. Immunity defects can be managed from controlling phosphorus levels in the fetus and protecting them from sources of infection.<ref><pubmed>1454183</pubmed></ref>

==Pancreas==
===Fetal development===
[[File:Development of the pancreas during fetal development.jpg|250px|thumb|right|This images shows normal pancreatic development of the fetus.]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
[[File:Ratio of alpha & beta cells at different phases of fetal development.png|350px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref> <ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

*'''Annular Pancreas'''
[[File:Annular pancreas.jpg|200px|thumb|right|This image shows annular pancreas where a ring of the pancreatic tissue encircles the growing duodenum.]]
Annular pancreas is a rare abnormality that can occur during fetal development in which a ring of the pancreatic tissue encircles the growing duodenum.<ref><pubmed>25124266</pubmed></ref> It occurs in 1 out of 7000 birth and is commonly associated with other abnormalities such as esophageal atresia and malrotation of the midgut. It is assumed that annular pancreas occurs when the tip of right ventral bud sticks to the duodenal wall which then forms a ring from the continuous stretching of the wall during rotation.<ref><pubmed> 25165593</pubmed></ref> This part of the pancreas can constrict the duodenum thereby restricting the flow of food to the intestines of the gastrointestinal tract.<ref><pubmed>24890427</pubmed></ref> Furthermore, annular pancreas is divided into two forms. Complete annular pancreas is when the pancreatic parenchyma wraps around the 2nd part of the duodenum completely whereas in incomplete annular pancreas, the tissue only surrounds the duodenum partially.<ref><pubmed> 24741860</pubmed></ref>Treatment for annular pancreas mainly involves surgery to bypass the constricted portion of the duodenum.

*'''Gestational diabetes mellitus'''

Gestational diabetes mellitus (GDM) is a disorder in which women without any history of diabetes show elevated blood glucose levels during pregnancy normally around the third trimester. It is caused when insulin receptors fail to respond correctly due to interference from signalling molecules related to pregnancy such as the interaction between human placental lactogen, prolactin and estradiol with the insulin receptors.<ref><pubmed>2141655</pubmed></ref> As a result, high blood glucose levels are observed. Patients with GDM have high levels of insulin resistance with increased β-cells production of the pancreas since the high levels of blood glucose are not interacting with the abnormal insulin receptors. Glucose is known to diffuse through the placenta via GLUT1 carrier situated in the syncytiotrophoblast of both the microvillus and basal membranes. With GDM, the number of GLUT1 molecules increase and hence placing high levels of glucose to the fetus since insulin itself cannot diffuse across the placenta and counteract this extremity.<ref><pubmed>25333246</pubmed></ref> This mechanism is known to lead to excessive growth at birth with a low glucose environment as it declines and high insulin production overall leading to hypoglycaemia.<ref><pubmed>25315294</pubmed></ref>It can also lead to jaundice and seizures in the new born with mothers having high susceptibility to type 2 diabetes mellitus. GDM can be controlled by monitoring blood sugar levels and controlling levels of glucose and insulin through pharmaceutical drugs.

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*'''Congenital Adrenal Hyperplasia (CAH)'''

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more.[[File:Cushing's syndrome.jpg|150px|right|thumb|This image shows a 3-month old child with classic signs of Cushing’s syndrome; central obesity, chubby cheeks and moon facies]] Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

*'''Cushing's Syndrome'''

Cushing’s Syndrome (CS) is a metabolic disorder characterised by abnormally high production of endogenous cortisol or exogenous levels of corticosteroids, which disrupts the metabolism of macromolecules such as lipids and carbohydrates. It is most common in obese adults aged 20-50 and the most common cause is the therapeutic administration of exogenous ACTH <ref><pubmed>24656295</pubmed></ref>. Cushing’s Syndrome’s two forms are either ACTH-dependent CS (80-85% of patients) or ACTH independent. The etiology of the dependent form is adrenal gland hyperplasia and excessive ACTH secretion by adenomas in the pituitary, however other causes include; small cell lung carcinoma ACTH production ectopically, or medullary thyroid carcinomas. <ref name= PMID24365350><pubmed>24365350</pubmed></ref> The independent form is however caused by neoplastic growths in the adrenal gland such as carcinomas, adenomas and macronodular hyperplasia. Clinical manifestations of this disorder include; moon facies, cataracts, hyperglycaemia, abnormal fat distribution, poor wounding of the skin, obesity in the central body and muscle wasting in 60% of patients. <ref name= PMID24365350><pubmed>24365350</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

===Abnormalities===

==Testis==
===Fetal development===

'''How far has the testis developed by week 8 of gestation?'''
*By week 8, masculine differentiation is induced in the mesonephric duct and external genitalia. This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>
*Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>

'''Fetal stage of testicular development - from week 8 of gestation onwards'''

'''Timeline'''
*Week 9- Yellowish elongated tube with mesonephros laterally and urinary bladder inferomedially
*Week 13- Testes have acquired the ellipsoidal shape found in the adult and are located above the inguinal canal in the groin region. Convexly curved across all but posterior surface <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*Week 16- Located above deep inguinal ring, convexly curved anterior border and flat posterior border covered by epididymis
*Week 17- Migration of testes begins from
*Week 24- Testes grow in size and still located about the deep inguinal ring or inside inguinal canal. The testicular poles seem more prominent. Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum <ref name= Subhalakshmi><Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti ‘’’Development and Morphogenesis of Testis in Human Fetuses’’’. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171></ref>
*Week 30- Testes sinus is towards lower portion of testes and epididymis tail continuous with vas deferens. Testes are located in the scrotum having passed through the superficial inguinal ring
Week 36- Testes located within scrotal sac, they enlarge in size and are maximally convex <ref name= Subhalakshmi><Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti ‘’’Development and Morphogenesis of Testis in Human Fetuses’’’. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171></ref>
===Abnormalities===

*'''Klinefelter’s syndrome'''

Klinefelter’s syndrome is the common form of congenital primary hypogonadism with a prevalence of an estimated 1 in 1000 men. Male hypogonadism is defined as a testicular dysfunction resulting in decreased sperm and testosterone production<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.. This genetic disorder occurs when a male is born with an additional X chromosome causing complications and a general underdevelopment of structures such as the seminiferous tubules and Leydig cells within the testis. As a consequence, the size of the testis is abnormally small and the patient has a low sperm count and testosterone levels. In addition to infertility caused by testosterone deficiency, men born with this disorder frequently have increased length of their long bones, including those in the arms, legs, and hands. Many other complications exist independent of the testosterone deficiency seen with these patients<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''
[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]
*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

*'''Placenta accreta'''

[[File:Placenta accreta.jpg|150px|right|thumb|This image shows an area of profuse bleeding in the human placenta, with a region of placenta accreta indicated by the arrow]]

Placenta accreta (PA )is a rare obstetric abnormality characterised by abnormal insertion of the placenta to the myometrium of the uterus. The 3 types of PA are classified based on the depth of invasion; placenta accreta (superficial- chorionic villi attach to myometrium rather than just decidua basalis), placenta increta (middle layer) or placenta perceta (deep) being the most dire with 1 in 7000 incidence. <ref name= PMID23127895><pubmed>23127895</pubmed></ref> PA has an incidence of 1 in 2500 deliveries and is associated with grand-scale haemorrhage and requires hysterectomy and blood transfusion. <ref name= PMID21280984><pubmed>21280984</pubmed></ref> The condition normally occurs in the lower segment of the uterus which is prone to bleeding being poorly contractile and a site of angiogenesis. Prenatal diagnosis of PA is based on second and third trimester ulstrasound findings indicating; retroplacental zone loss, many lucanue in the vasculature and a very thin (<1mm) retroplacental thickness of the myometrium.<ref name= PMID21280984><pubmed>21280984</pubmed></ref> PA has a 40% likelihood in women aged over 35 who have had Caesarian section with placenta previa in their uterine scars. <ref name= PMID23127895><pubmed>23127895</pubmed></ref>

==Recent Findings==

{|
|-bgcolor="F5FFFA"
|
'''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''<ref><pubmed>22912418</pubmed></ref>

''Jennifer R Gardiner, Abigail L Jackson, Julie Gordon, Heiko Lickert, Nancy R Manley, M Albert Basson '''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''. Development: 2012, 139(18);3456-66 PMID: 22912418''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.
|}

{|
|-bgcolor="F5FFFA"
|'''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''<ref><pubmed>23300903</pubmed></ref>

''Stéphanie Migrenne, Evelyne Moreau, Pirjo Pakarinen, Andrée Dierich, Jorge Merlet, René Habert, Chrystèle Racine '''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''. PLoS ONE: 2012, 7(12);e53257 PMID: 23300903''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.
|}

{|
|-bgcolor="F5FFFA"
|'''Neuropeptide Y in the Adult and Fetal Human Pineal Gland'''<ref><pubmed>24757681</pubmed></ref>

''Morten Møller, Pansiri Phansuwan-Pujito, Corin Badiu '''Neuropeptide Y in the adult and fetal human pineal gland'''. Biomed Res Int: 2014, 2014;868567 PMID: 24757681''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland. Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.
|}

=References=

<references/>

2014 Group Project 6

2014-10-23T11:16:47Z

Z3418702: /* Testis */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

[[File:Keith1902 fig167.jpg|200px|thumb|right| Image 1: schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|Image 2: Shows the location of the pineal gland in the adult brain.]]

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon reproductive hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>.

Melatonin plays an important role during fetal development. Both pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammalian fetus, intrinsic circadian rhythms are already established prior to birth.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || Pinealocytes || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

[[File:Primary brain vesicles.jpg|150px|left|thumb|Image 3: Primary brain vesicles]]'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle (Image 3).<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
[[File:Week 6 embryonic development of CNS.jpg|150px|left|thumb|Image 4: Week 6 embryonic development of CNS]]
[[File:Week 11 fetal development of CNS.jpg|150px|right|thumb|Image 5: Week 11 fetal development of CNS]]

*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement and an evagination of the pineal gland is visible (shown in image 4).

[[File:Fetal pineal gland 01.jpg|150px|thumb|right|Image 6: shows a fetal pineal gland at the end of the first trimester of development.]]

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum

*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis (shown in Image 5)

*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

===Abnormalities===

* '''Pineal tumors'''

Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>
[[File:Congenital hydrocephalus MRI02.jpg|150px|thumb|right|Image 7: Infant with obstructive congenital hydrocephalus]]

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signalling pathways or "axes":
[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]
[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).
[[File:Stage 22 image 057.jpg|200x|thumb|Image 1. Histological cross-section of stage 22 embryo]]
* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete
[[File:Development of hypothalamus.jpg|900px|left|thumb|Image 3: Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

===Abnormalities===

*'''Congenital Hypothalamic Hamartoma'''

A hypothalamic hamartoma arises from the region of the tuber cinereum and is commonly associated with isosexual precocious puberty, i.e. puberty that develops unusually early in infants. It involves the alteration of pathways that modulate gonadotropins and contain releasing hormones within the floor of the third ventricle. .<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref> Precocious puberty may either result from a physical pertubation of inhibitory pathways by the hamartoma or a direct neurosecretory process of the hamartoma itself. Seizures are also another common clinical presentation in children with a hypothalamic hamartoma. MR imaging is typically used to identify and monitor the growth of a hypothalamic hamartoma during embryonic and fetal development. Research has shown a trend of congenital hamartomas forming in the utero within a period of 26 weeks. Because of the known association with other congenital anomalies of the central nervous system, hypothalamic hamartoma is thought to form as early as 4 weeks and may in fact be part of a developmental abnormality spectrum.<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref>. Treatment options are currently limited to post-natal deliver of leuprolide acetate to the infant and in general it is relatively effective in managing and treating the condition.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==
[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]
=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>
* Anterior pituitary

[[File:Anterior Pituitary Hormones.jpg|300px|right|thumb|Timeline of anterior pituitary hormone expression and synthesis]]

By week 8 of embryological development, the pituitary gland is fully formed and begins functioning as a control centre for release of hormones that are vital for subsequent organ development.

* Week 10 - Growth Hormone and ACTH detectable
* Week 21 - Vasopressin hormone synthesis established

'''Anterior Pituitary - Adenohypophysis'''

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || No function in fetal development. All postnatal action.
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|}

'''Posterior Pituitary - Neurohypophysis'''

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://www.sciencedirect.com/science/article/pii/S030100820900046X#></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Cardiomyogenesis
* Protective action of fetal neurons during brain development
* Neuronal development and plasticity <ref name =Yuzo Murata, Ming-Zi Li, Sadahiko Masuko>Yuzo Murata, Ming-Zi Li, Sadahiko Masuko, 2011, '''Developmental expression of oxytocin receptors in the neonatal medulla
oblongata and pons''', Neuroscience Letters; 502 (2011), pp157-161, http://www.sciencedirect.com/science/article/pii/S0304394011010949#></ref>
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Regulates fetal renal function
* Regulates amniotic fluid content and concentration
* Regulates blood pressure, heart rate, cardiac output and placental blood flow <ref name =M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher >M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher , 1993, '''Vasopressin receptors and effects during fetal development''', Regulatory Peptides; 45, pp203-208, http://www.sciencedirect.com/science/article/pii/016701159390207O#></ref>
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

'''How far has the thyroid gland developed by week 8 of gestation?'''
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

'''Fetal Stage of Thyroid Development - from week 8 of gestation onwards:'''
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis<ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>
* Week 16 - 18 is when fetal thyroid hormone synthesis occurs
** Prior to this, the fetus receives vital maternal thyroid hormones via the placenta

'''Thyroid Hormone Action'''
The following table explains the ontogenic action of thyroid hormone on the developing fetus. Thyroid hormones are essential in brain and central nervous system development in the fetus. A lot of neurological disorders are associated with insufficient thyroid hormone synthesis:

{| class="wikitable"
|-
! Hormone !! Types !! Ontogenic Action
|-
| Thyroid Hormone ||
* T3 - triiodothyronine
* T4 - thyroxine
|| Brain development:
* Central Nervous System development and maturation <ref name =J Patel, K Landers, H Li, R H Mortimer and K Richard>J Patel, K Landers, H Li, R H Mortimer and K Richard, 2011, '''Thyroid hormones and fetal neurological development''', Journal of Endocrinology:209;1-8, http://joe.endocrinology-journals.org.wwwproxy0.library.unsw.edu.au/content/209/1/1.full.pdf+html></ref>
*Glial cell proliferation
*Neural myelination
*Axon and dendrite sprouting
*Synapse formation
|}

{| class="wikitable"
|-
! Header text !! Header text !! Header text
|-
| Example || Example || Example
|}

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|right|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone || Secreted by || Function || Image
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine. || [[File:Active parathyroid hormone assay cartoon.png|200px|thumb|This images shows an active parathyroid hormone and its chemical structure.]]
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

'''Fetal hyperparathyroidism'''

Fetal hyperparathyroidism is a condition that is caused when an excess of parathyroid hormone (PTH) is present the bloodstream.<ref><pubmed> 1745971</pubmed></ref> This may be due to an overstimulated maternal parathyroid gland out of all the four which transfers the over accumulated PTH to the fetus. Normal fetal development requires 25–30 gms of calcium for bone mineralization and around 80% of this calcium accretion is observed in the third trimester of pregnancy. However the calcium gradient of 1.0:1.4 is no longer maintained when there is hyperparathyroidism present.<ref><pubmed> 12140371</pubmed></ref>Instead the gradient is elevated causing fetal parathyroid gland suppression thereby leading to Hypocalcemia. Calcium mobilisation then becomes difficult and hence fetal tetany may occur followed by miscarriage.<ref><pubmed> 25327435</pubmed></ref> In the event that the fetus survives, postnatal problems such as the baby having weak bones will be likely and would require calcium treatment throughout most of their lives.

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

'''Thymic aplasia'''

Thymic aplasia is a condition that has a strong correlation to DiGeorge syndrome. This syndrome is a congenital birth defect which occurs when the fetus either inherits an abnormal chromosome 22 or has a mutation of the same chromosome. In particularly, the mutation is a deletion of the genomic information packaged in the chromosomes and normally occurs when there isn’t proper recombination of chromosomal material during fertilisation.<ref><pubmed>4166528</pubmed></ref> As a result of this deletion, the third and fourth pharyngeal pouches fail to develop in the twelfth gestational week, thereby leading to the absence or partial absence of the thymus and parathyroid glands. Other associated abnormalities with thymic aplasia as a result of the deletion of chromosome 22 genetic material are severe cardiac defects, low immunity, hypocalcaemia and facial abnormalities. <ref><pubmed>5057550</pubmed></ref> Statistics suggest that the thymic aplasia may occur in 1:4000 to 1:6395 of fetuses.<ref><pubmed> 10861201</pubmed></ref> Treatment is normally difficult for fetuses that exhibit thymic aplasia, however calcium levels can be monitored and regulated and heart problems can be resolved though surgery. Immunity defects can be managed from controlling phosphorus levels in the fetus and protecting them from sources of infection.<ref><pubmed>1454183</pubmed></ref>

==Pancreas==
===Fetal development===
[[File:Development of the pancreas during fetal development.jpg|250px|thumb|right|This images shows normal pancreatic development of the fetus.]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
[[File:Ratio of alpha & beta cells at different phases of fetal development.png|350px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref> <ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

*'''Annular Pancreas'''
[[File:Annular pancreas.jpg|200px|thumb|right|This image shows annular pancreas where a ring of the pancreatic tissue encircles the growing duodenum.]]
Annular pancreas is a rare abnormality that can occur during fetal development in which a ring of the pancreatic tissue encircles the growing duodenum.<ref><pubmed>25124266</pubmed></ref> It occurs in 1 out of 7000 birth and is commonly associated with other abnormalities such as esophageal atresia and malrotation of the midgut. It is assumed that annular pancreas occurs when the tip of right ventral bud sticks to the duodenal wall which then forms a ring from the continuous stretching of the wall during rotation.<ref><pubmed> 25165593</pubmed></ref> This part of the pancreas can constrict the duodenum thereby restricting the flow of food to the intestines of the gastrointestinal tract.<ref><pubmed>24890427</pubmed></ref> Furthermore, annular pancreas is divided into two forms. Complete annular pancreas is when the pancreatic parenchyma wraps around the 2nd part of the duodenum completely whereas in incomplete annular pancreas, the tissue only surrounds the duodenum partially.<ref><pubmed> 24741860</pubmed></ref>Treatment for annular pancreas mainly involves surgery to bypass the constricted portion of the duodenum.

*'''Gestational diabetes mellitus'''

Gestational diabetes mellitus (GDM) is a disorder in which women without any history of diabetes show elevated blood glucose levels during pregnancy normally around the third trimester. It is caused when insulin receptors fail to respond correctly due to interference from signalling molecules related to pregnancy such as the interaction between human placental lactogen, prolactin and estradiol with the insulin receptors.<ref><pubmed>2141655</pubmed></ref> As a result, high blood glucose levels are observed. Patients with GDM have high levels of insulin resistance with increased β-cells production of the pancreas since the high levels of blood glucose are not interacting with the abnormal insulin receptors. Glucose is known to diffuse through the placenta via GLUT1 carrier situated in the syncytiotrophoblast of both the microvillus and basal membranes. With GDM, the number of GLUT1 molecules increase and hence placing high levels of glucose to the fetus since insulin itself cannot diffuse across the placenta and counteract this extremity.<ref><pubmed>25333246</pubmed></ref> This mechanism is known to lead to excessive growth at birth with a low glucose environment as it declines and high insulin production overall leading to hypoglycaemia.<ref><pubmed>25315294</pubmed></ref>It can also lead to jaundice and seizures in the new born with mothers having high susceptibility to type 2 diabetes mellitus. GDM can be controlled by monitoring blood sugar levels and controlling levels of glucose and insulin through pharmaceutical drugs.

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*'''Congenital Adrenal Hyperplasia (CAH)'''

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more.[[File:Cushing's syndrome.jpg|150px|right|thumb|This image shows a 3-month old child with classic signs of Cushing’s syndrome; central obesity, chubby cheeks and moon facies]] Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

*'''Cushing's Syndrome'''

Cushing’s Syndrome (CS) is a metabolic disorder characterised by abnormally high production of endogenous cortisol or exogenous levels of corticosteroids, which disrupts the metabolism of macromolecules such as lipids and carbohydrates. It is most common in obese adults aged 20-50 and the most common cause is the therapeutic administration of exogenous ACTH <ref><pubmed>24656295</pubmed></ref>. Cushing’s Syndrome’s two forms are either ACTH-dependent CS (80-85% of patients) or ACTH independent. The etiology of the dependent form is adrenal gland hyperplasia and excessive ACTH secretion by adenomas in the pituitary, however other causes include; small cell lung carcinoma ACTH production ectopically, or medullary thyroid carcinomas. <ref name= PMID24365350><pubmed>24365350</pubmed></ref> The independent form is however caused by neoplastic growths in the adrenal gland such as carcinomas, adenomas and macronodular hyperplasia. Clinical manifestations of this disorder include; moon facies, cataracts, hyperglycaemia, abnormal fat distribution, poor wounding of the skin, obesity in the central body and muscle wasting in 60% of patients. <ref name= PMID24365350><pubmed>24365350</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

===Abnormalities===

==Testis==
===Fetal development===

'''How far has the testis developed by week 8 of gestation?'''
*By week 8, masculine differentiation is induced in the mesonephric duct and external genitalia. This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>
*Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct. <ref name= PMID1769902><pubmed>1769902</pubmed></ref>

'''Fetal stage of testicular development - from week 8 of gestation onwards'''

'''Timeline'''
*Week 9- Yellowish elongated tube with mesonephros laterally and urinary bladder inferomedially
*Week 13- Testes have acquired the ellipsoidal shape found in the adult and are located above the inguinal canal in the groin region. Convexly curved across all but posterior surface <ref name= PMID10510117><pubmed>10510117</pubmed></ref>
*Week 16- Located above deep inguinal ring, convexly curved anterior border and flat posterior border covered by epididymis
*Week 17- Migration of testes begins from
*Week 24- Testes grow in size and still located about the deep inguinal ring or inside inguinal canal. The testicular poles seem more prominent. Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum <ref name= Subhalakshmi Wahengbam><Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti ‘’’Development and Morphogenesis of Testis in Human Fetuses’’’. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171></ref>
*Week 30- Testes sinus is towards lower portion of testes and epididymis tail continuous with vas deferens. Testes are located in the scrotum having passed through the superficial inguinal ring
Week 36- Testes located within scrotal sac, they enlarge in size and are maximally convex <ref name= Subhalakshmi Wahengbam><Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti ‘’’Development and Morphogenesis of Testis in Human Fetuses’’’. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171></ref>
===Abnormalities===

*Klinefelter’s syndrome

Klinefelter’s syndrome is the common form of congenital primary hypogonadism with a prevalence of an estimated 1 in 1000 men. Male hypogonadism is defined as a testicular dysfunction resulting in decreased sperm and testosterone production<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.. This genetic disorder occurs when a male is born with an additional X chromosome causing complications and a general underdevelopment of structures such as the seminiferous tubules and Leydig cells within the testis. As a consequence, the size of the testis is abnormally small and the patient has a low sperm count and testosterone levels. In addition to infertility caused by testosterone deficiency, men born with this disorder frequently have increased length of their long bones, including those in the arms, legs, and hands. Many other complications exist independent of the testosterone deficiency seen with these patients<ref name=Sexson>E. Sexson, J. Knezevich, ‘Male Hypogonadism: A Review of the Disease and Its Treatment’, U.S. Pharmacist:2010, http://www.uspharmacist.com/content/d/health%20systems/c/21150/</ref>.

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''
[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]
*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

*'''Placenta accreta'''

[[File:Placenta accreta.jpg|150px|right|thumb|This image shows an area of profuse bleeding in the human placenta, with a region of placenta accreta indicated by the arrow]]

Placenta accreta (PA )is a rare obstetric abnormality characterised by abnormal insertion of the placenta to the myometrium of the uterus. The 3 types of PA are classified based on the depth of invasion; placenta accreta (superficial- chorionic villi attach to myometrium rather than just decidua basalis), placenta increta (middle layer) or placenta perceta (deep) being the most dire with 1 in 7000 incidence. <ref name= PMID23127895><pubmed>23127895</pubmed></ref> PA has an incidence of 1 in 2500 deliveries and is associated with grand-scale haemorrhage and requires hysterectomy and blood transfusion. <ref name= PMID21280984><pubmed>21280984</pubmed></ref> The condition normally occurs in the lower segment of the uterus which is prone to bleeding being poorly contractile and a site of angiogenesis. Prenatal diagnosis of PA is based on second and third trimester ulstrasound findings indicating; retroplacental zone loss, many lucanue in the vasculature and a very thin (<1mm) retroplacental thickness of the myometrium.<ref name= PMID21280984><pubmed>21280984</pubmed></ref> PA has a 40% likelihood in women aged over 35 who have had Caesarian section with placenta previa in their uterine scars. <ref name= PMID23127895><pubmed>23127895</pubmed></ref>

==Recent Findings==

{|
|-bgcolor="F5FFFA"
|
'''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''<ref><pubmed>22912418</pubmed></ref>

''Jennifer R Gardiner, Abigail L Jackson, Julie Gordon, Heiko Lickert, Nancy R Manley, M Albert Basson '''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''. Development: 2012, 139(18);3456-66 PMID: 22912418''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.
|}

{|
|-bgcolor="F5FFFA"
|'''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''<ref><pubmed>23300903</pubmed></ref>

''Stéphanie Migrenne, Evelyne Moreau, Pirjo Pakarinen, Andrée Dierich, Jorge Merlet, René Habert, Chrystèle Racine '''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''. PLoS ONE: 2012, 7(12);e53257 PMID: 23300903''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.
|}

{|
|-bgcolor="F5FFFA"
|'''Neuropeptide Y in the Adult and Fetal Human Pineal Gland'''<ref><pubmed>24757681</pubmed></ref>

''Morten Møller, Pansiri Phansuwan-Pujito, Corin Badiu '''Neuropeptide Y in the adult and fetal human pineal gland'''. Biomed Res Int: 2014, 2014;868567 PMID: 24757681''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland. Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.
|}

=References=

<references/>

2014 Group Project 6

2014-10-23T11:04:05Z

Z3418702: /* Fetal development */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

[[File:Keith1902 fig167.jpg|200px|thumb|right| Image 1: schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|Image 2: Shows the location of the pineal gland in the adult brain.]]

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon reproductive hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>.

Melatonin plays an important role during fetal development. Both pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammalian fetus, intrinsic circadian rhythms are already established prior to birth.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || Pinealocytes || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

[[File:Primary brain vesicles.jpg|150px|left|thumb|Image 3: Primary brain vesicles]]'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle (Image 3).<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
[[File:Week 6 embryonic development of CNS.jpg|150px|left|thumb|Image 4: Week 6 embryonic development of CNS]]
[[File:Week 11 fetal development of CNS.jpg|150px|right|thumb|Image 5: Week 11 fetal development of CNS]]

*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement and an evagination of the pineal gland is visible (shown in image 4).

[[File:Fetal pineal gland 01.jpg|150px|thumb|right|Image 6: shows a fetal pineal gland at the end of the first trimester of development.]]

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum

*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis (shown in Image 5)

*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

===Abnormalities===

* '''Pineal tumors'''

Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>
[[File:Congenital hydrocephalus MRI02.jpg|150px|thumb|right|Image 7: Infant with obstructive congenital hydrocephalus]]

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signalling pathways or "axes":
[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]
[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).
[[File:Stage 22 image 057.jpg|200x|thumb|Image 1. Histological cross-section of stage 22 embryo]]
* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete
[[File:Development of hypothalamus.jpg|900px|left|thumb|Image 3: Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

===Abnormalities===

*'''Congenital Hypothalamic Hamartoma'''

A hypothalamic hamartoma arises from the region of the tuber cinereum and is commonly associated with isosexual precocious puberty, i.e. puberty that develops unusually early in infants. It involves the alteration of pathways that modulate gonadotropins and contain releasing hormones within the floor of the third ventricle. .<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref> Precocious puberty may either result from a physical pertubation of inhibitory pathways by the hamartoma or a direct neurosecretory process of the hamartoma itself. Seizures are also another common clinical presentation in children with a hypothalamic hamartoma. MR imaging is typically used to identify and monitor the growth of a hypothalamic hamartoma during embryonic and fetal development. Research has shown a trend of congenital hamartomas forming in the utero within a period of 26 weeks. Because of the known association with other congenital anomalies of the central nervous system, hypothalamic hamartoma is thought to form as early as 4 weeks and may in fact be part of a developmental abnormality spectrum.<ref name=Booth>T. Booth, C. Timmons, K. Shapiro, N.K. Rollins, ‘Pre- and Postnatal MR Imaging of Hypothalamic Hamartomas Associated with Arachnoid Cysts’, Americal Jounral of Neuroradiology:2004, http://www.ajnr.org/content/25/7/1283.full</ref>. Treatment options are currently limited to post-natal deliver of leuprolide acetate to the infant and in general it is relatively effective in managing and treating the condition.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==
[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]
=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>
* Anterior pituitary

[[File:Anterior Pituitary Hormones.jpg|300px|right|thumb|Timeline of anterior pituitary hormone expression and synthesis]]

By week 8 of embryological development, the pituitary gland is fully formed and begins functioning as a control centre for release of hormones that are vital for subsequent organ development.

* Week 10 - Growth Hormone and ACTH detectable
* Week 21 - Vasopressin hormone synthesis established

'''Anterior Pituitary - Adenohypophysis'''

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || No function in fetal development. All postnatal action.
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|}

'''Posterior Pituitary - Neurohypophysis'''

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://www.sciencedirect.com/science/article/pii/S030100820900046X#></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Cardiomyogenesis
* Protective action of fetal neurons during brain development
* Neuronal development and plasticity <ref name =Yuzo Murata, Ming-Zi Li, Sadahiko Masuko>Yuzo Murata, Ming-Zi Li, Sadahiko Masuko, 2011, '''Developmental expression of oxytocin receptors in the neonatal medulla
oblongata and pons''', Neuroscience Letters; 502 (2011), pp157-161, http://www.sciencedirect.com/science/article/pii/S0304394011010949#></ref>
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Regulates fetal renal function
* Regulates amniotic fluid content and concentration
* Regulates blood pressure, heart rate, cardiac output and placental blood flow <ref name =M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher >M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher , 1993, '''Vasopressin receptors and effects during fetal development''', Regulatory Peptides; 45, pp203-208, http://www.sciencedirect.com/science/article/pii/016701159390207O#></ref>
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

'''How far has the thyroid gland developed by week 8 of gestation?'''
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

'''Fetal Stage of Thyroid Development - from week 8 of gestation onwards:'''
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis<ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>
* Week 16 - 18 is when fetal thyroid hormone synthesis occurs
** Prior to this, the fetus receives vital maternal thyroid hormones via the placenta

'''Thyroid Hormone Action'''
The following table explains the ontogenic action of thyroid hormone on the developing fetus. Thyroid hormones are essential in brain and central nervous system development in the fetus. A lot of neurological disorders are associated with insufficient thyroid hormone synthesis:

{| class="wikitable"
|-
! Hormone !! Types !! Ontogenic Action
|-
| Thyroid Hormone ||
* T3 - triiodothyronine
* T4 - thyroxine
|| Brain development:
* Central Nervous System development and maturation <ref name =J Patel, K Landers, H Li, R H Mortimer and K Richard>J Patel, K Landers, H Li, R H Mortimer and K Richard, 2011, '''Thyroid hormones and fetal neurological development''', Journal of Endocrinology:209;1-8, http://joe.endocrinology-journals.org.wwwproxy0.library.unsw.edu.au/content/209/1/1.full.pdf+html></ref>
*Glial cell proliferation
*Neural myelination
*Axon and dendrite sprouting
*Synapse formation
|}

{| class="wikitable"
|-
! Header text !! Header text !! Header text
|-
| Example || Example || Example
|}

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|right|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone || Secreted by || Function || Image
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine. || [[File:Active parathyroid hormone assay cartoon.png|200px|thumb|This images shows an active parathyroid hormone and its chemical structure.]]
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

'''Fetal hyperparathyroidism'''

Fetal hyperparathyroidism is a condition that is caused when an excess of parathyroid hormone (PTH) is present the bloodstream.<ref><pubmed> 1745971</pubmed></ref> This may be due to an overstimulated maternal parathyroid gland out of all the four which transfers the over accumulated PTH to the fetus. Normal fetal development requires 25–30 gms of calcium for bone mineralization and around 80% of this calcium accretion is observed in the third trimester of pregnancy. However the calcium gradient of 1.0:1.4 is no longer maintained when there is hyperparathyroidism present.<ref><pubmed> 12140371</pubmed></ref>Instead the gradient is elevated causing fetal parathyroid gland suppression thereby leading to Hypocalcemia. Calcium mobilisation then becomes difficult and hence fetal tetany may occur followed by miscarriage.<ref><pubmed> 25327435</pubmed></ref> In the event that the fetus survives, postnatal problems such as the baby having weak bones will be likely and would require calcium treatment throughout most of their lives.

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

'''Thymic aplasia'''

Thymic aplasia is a condition that has a strong correlation to DiGeorge syndrome. This syndrome is a congenital birth defect which occurs when the fetus either inherits an abnormal chromosome 22 or has a mutation of the same chromosome. In particularly, the mutation is a deletion of the genomic information packaged in the chromosomes and normally occurs when there isn’t proper recombination of chromosomal material during fertilisation.<ref><pubmed>4166528</pubmed></ref> As a result of this deletion, the third and fourth pharyngeal pouches fail to develop in the twelfth gestational week, thereby leading to the absence or partial absence of the thymus and parathyroid glands. Other associated abnormalities with thymic aplasia as a result of the deletion of chromosome 22 genetic material are severe cardiac defects, low immunity, hypocalcaemia and facial abnormalities. <ref><pubmed>5057550</pubmed></ref> Statistics suggest that the thymic aplasia may occur in 1:4000 to 1:6395 of fetuses.<ref><pubmed> 10861201</pubmed></ref> Treatment is normally difficult for fetuses that exhibit thymic aplasia, however calcium levels can be monitored and regulated and heart problems can be resolved though surgery. Immunity defects can be managed from controlling phosphorus levels in the fetus and protecting them from sources of infection.<ref><pubmed>1454183</pubmed></ref>

==Pancreas==
===Fetal development===
[[File:Development of the pancreas during fetal development.jpg|250px|thumb|right|This images shows normal pancreatic development of the fetus.]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
[[File:Ratio of alpha & beta cells at different phases of fetal development.png|350px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref> <ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

*'''Annular Pancreas'''
[[File:Annular pancreas.jpg|200px|thumb|right|This image shows annular pancreas where a ring of the pancreatic tissue encircles the growing duodenum.]]
Annular pancreas is a rare abnormality that can occur during fetal development in which a ring of the pancreatic tissue encircles the growing duodenum.<ref><pubmed>25124266</pubmed></ref> It occurs in 1 out of 7000 birth and is commonly associated with other abnormalities such as esophageal atresia and malrotation of the midgut. It is assumed that annular pancreas occurs when the tip of right ventral bud sticks to the duodenal wall which then forms a ring from the continuous stretching of the wall during rotation.<ref><pubmed> 25165593</pubmed></ref> This part of the pancreas can constrict the duodenum thereby restricting the flow of food to the intestines of the gastrointestinal tract.<ref><pubmed>24890427</pubmed></ref> Furthermore, annular pancreas is divided into two forms. Complete annular pancreas is when the pancreatic parenchyma wraps around the 2nd part of the duodenum completely whereas in incomplete annular pancreas, the tissue only surrounds the duodenum partially.<ref><pubmed> 24741860</pubmed></ref>Treatment for annular pancreas mainly involves surgery to bypass the constricted portion of the duodenum.

*'''Gestational diabetes mellitus'''

Gestational diabetes mellitus (GDM) is a disorder in which women without any history of diabetes show elevated blood glucose levels during pregnancy normally around the third trimester. It is caused when insulin receptors fail to respond correctly due to interference from signalling molecules related to pregnancy such as the interaction between human placental lactogen, prolactin and estradiol with the insulin receptors.<ref><pubmed>2141655</pubmed></ref> As a result, high blood glucose levels are observed. Patients with GDM have high levels of insulin resistance with increased β-cells production of the pancreas since the high levels of blood glucose are not interacting with the abnormal insulin receptors. Glucose is known to diffuse through the placenta via GLUT1 carrier situated in the syncytiotrophoblast of both the microvillus and basal membranes. With GDM, the number of GLUT1 molecules increase and hence placing high levels of glucose to the fetus since insulin itself cannot diffuse across the placenta and counteract this extremity.<ref><pubmed>25333246</pubmed></ref> This mechanism is known to lead to excessive growth at birth with a low glucose environment as it declines and high insulin production overall leading to hypoglycaemia.<ref><pubmed>25315294</pubmed></ref>It can also lead to jaundice and seizures in the new born with mothers having high susceptibility to type 2 diabetes mellitus. GDM can be controlled by monitoring blood sugar levels and controlling levels of glucose and insulin through pharmaceutical drugs.

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*'''Congenital Adrenal Hyperplasia (CAH)'''

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more.[[File:Cushing's syndrome.jpg|150px|right|thumb|This image shows a 3-month old child with classic signs of Cushing’s syndrome; central obesity, chubby cheeks and moon facies]] Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

*'''Cushing's Syndrome'''

Cushing’s Syndrome (CS) is a metabolic disorder characterised by abnormally high production of endogenous cortisol or exogenous levels of corticosteroids, which disrupts the metabolism of macromolecules such as lipids and carbohydrates. It is most common in obese adults aged 20-50 and the most common cause is the therapeutic administration of exogenous ACTH <ref><pubmed>24656295</pubmed></ref>. Cushing’s Syndrome’s two forms are either ACTH-dependent CS (80-85% of patients) or ACTH independent. The etiology of the dependent form is adrenal gland hyperplasia and excessive ACTH secretion by adenomas in the pituitary, however other causes include; small cell lung carcinoma ACTH production ectopically, or medullary thyroid carcinomas. <ref name= PMID24365350><pubmed>24365350</pubmed></ref> The independent form is however caused by neoplastic growths in the adrenal gland such as carcinomas, adenomas and macronodular hyperplasia. Clinical manifestations of this disorder include; moon facies, cataracts, hyperglycaemia, abnormal fat distribution, poor wounding of the skin, obesity in the central body and muscle wasting in 60% of patients. <ref name= PMID24365350><pubmed>24365350</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

===Abnormalities===

==Testis==
===Fetal development===

'''How far has the testis developed by week 8 of gestation?'''
*By week 8, masculine differentiation is induced in the mesonephric duct and external genitalia. This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12.<ref><pubmed>8292535</pubmed></ref>
*Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1260417><pubmed>1260417</pubmed></ref>
*The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct. <ref name= PMID1260417><pubmed>1260417</pubmed></ref>

'''Fetal stage of testicular development - from week 8 of gestation onwards'''

'''Timeline'''
*Week 9- Yellowish elongated tube with mesonephros laterally and urinary bladder inferomedially <ref name= PMID1769902><pubmed>1260417</pubmed></ref>
*Week 13- Testes have acquired the ellipsoidal shape found in the adult and are located above the inguinal canal in the groin region. Convexly curved across all but posterior surface <ref name= Subhalakshmi Wahengbam><Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti ‘’’Development and Morphogenesis of Testis in Human Fetuses’’’. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171></ref>
*Week 16- Located above deep inguinal ring, convexly curved anterior border and flat posterior border covered by epididymis
*Week 17- Migration of testes begins from
*Week 24- Testes grow in size and still located about the deep inguinal ring or inside inguinal canal. The testicular poles seem more prominent. Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26 <ref name= Subhalakshmi Wahengbam><Subhalakshmi Wahengbam, S. Arunchandra Singh, Ningthoujam Damayanti ‘’’Development and Morphogenesis of Testis in Human Fetuses’’’. Journal of Anatomical Society of India: 2011, 60(2); 160-167, http://www.sciencedirect.com/science/article/pii/S0003277811800171></ref>
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 30- Testes sinus is towards lower portion of testes and epididymis tail continuous with vas deferens. Testes are located in the scrotum having passed through the superficial inguinal ring <ref name= PMID1769902><pubmed>1260417</pubmed></ref>
Week 36- Testes located within scrotal sac, they enlarge in size and are maximally convex <ref name= PMID1260417><pubmed>1260417</pubmed></ref>

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''
[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]
*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

*'''Placenta accreta'''

[[File:Placenta accreta.jpg|150px|right|thumb|This image shows an area of profuse bleeding in the human placenta, with a region of placenta accreta indicated by the arrow]]

Placenta accreta (PA )is a rare obstetric abnormality characterised by abnormal insertion of the placenta to the myometrium of the uterus. The 3 types of PA are classified based on the depth of invasion; placenta accreta (superficial- chorionic villi attach to myometrium rather than just decidua basalis), placenta increta (middle layer) or placenta perceta (deep) being the most dire with 1 in 7000 incidence. <ref name= PMID23127895><pubmed>23127895</pubmed></ref> PA has an incidence of 1 in 2500 deliveries and is associated with grand-scale haemorrhage and requires hysterectomy and blood transfusion. <ref name= PMID21280984><pubmed>21280984</pubmed></ref> The condition normally occurs in the lower segment of the uterus which is prone to bleeding being poorly contractile and a site of angiogenesis. Prenatal diagnosis of PA is based on second and third trimester ulstrasound findings indicating; retroplacental zone loss, many lucanue in the vasculature and a very thin (<1mm) retroplacental thickness of the myometrium.<ref name= PMID21280984><pubmed>21280984</pubmed></ref> PA has a 40% likelihood in women aged over 35 who have had Caesarian section with placenta previa in their uterine scars. <ref name= PMID23127895><pubmed>23127895</pubmed></ref>

==Recent Findings==

{|
|-bgcolor="F5FFFA"
|
'''''*Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''<ref><pubmed>22912418</pubmed></ref>

''Jennifer R Gardiner, Abigail L Jackson, Julie Gordon, Heiko Lickert, Nancy R Manley, M Albert Basson Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis. Development: 2012, 139(18);3456-66 PMID: 22912418''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.
|}

{|
|-bgcolor="F5FFFA"
|'''''*Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''<ref><pubmed>23300903</pubmed></ref>

''Stéphanie Migrenne, Evelyne Moreau, Pirjo Pakarinen, Andrée Dierich, Jorge Merlet, René Habert, Chrystèle Racine Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life. PLoS ONE: 2012, 7(12);e53257 PMID: 23300903
''
This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.
|}

{|
|-bgcolor="F5FFFA"
|''''*Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''<ref><pubmed>24757681</pubmed></ref>

''Morten Møller, Pansiri Phansuwan-Pujito, Corin Badiu Neuropeptide Y in the adult and fetal human pineal gland. Biomed Res Int: 2014, 2014;868567 PMID: 24757681
''
Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland. Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.
|}

=References=

<references/>

2014 Group Project 6

2014-10-23T09:52:22Z

Z3418702: /* Placenta */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

[[File:Keith1902 fig167.jpg|200px|thumb|right| Image 1: schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|Image 2: Shows the location of the pineal gland in the adult brain.]]

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon reproductive hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>.

Melatonin plays an important role during fetal development. Both pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammalian fetus, intrinsic circadian rhythms are already established prior to birth.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || Pinealocytes || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

[[File:Primary brain vesicles.jpg|150px|left|thumb|Image 3: Primary brain vesicles]]'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle (Image 3).<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
[[File:Week 6 embryonic development of CNS.jpg|150px|left|thumb|Image 4: Week 6 embryonic development of CNS]]
[[File:Week 11 fetal development of CNS.jpg|150px|right|thumb|Image 5: Week 11 fetal development of CNS]]

*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement and an evagination of the pineal gland is visible (shown in image 4).

[[File:Fetal pineal gland 01.jpg|150px|thumb|right|Image 6: shows a fetal pineal gland at the end of the first trimester of development.]]

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum

*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis (shown in Image 5)

*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

===Abnormalities===

* '''Pineal tumors'''

Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>
[[File:Congenital hydrocephalus MRI02.jpg|150px|thumb|right|Image 7: Infant with obstructive congenital hydrocephalus]]

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

[[File:Development of hypothalamus.jpg|340px|thumb|Image 3: Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

===Abnormalities===

*Hypothalamus

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==
[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]
=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>
* Anterior pituitary

[[File:Anterior Pituitary Hormones.jpg|300px|right|thumb|Timeline of anterior pituitary hormone expression and synthesis]]

By week 8 of embryological development, the pituitary gland is fully formed and begins functioning as a control centre for release of hormones that are vital for subsequent organ development.

* Week 10 - Growth Hormone and ACTH detectable
* Week 21 - Vasopressin hormone synthesis established

'''Anterior Pituitary - Adenohypophysis'''

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || No function in fetal development. All postnatal action.
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|}

'''Posterior Pituitary - Neurohypophysis'''

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://www.sciencedirect.com/science/article/pii/S030100820900046X#></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Cardiomyogenesis
* Protective action of fetal neurons during brain development
* Neuronal development and plasticity <ref name =Yuzo Murata, Ming-Zi Li, Sadahiko Masuko>Yuzo Murata, Ming-Zi Li, Sadahiko Masuko, 2011, '''Developmental expression of oxytocin receptors in the neonatal medulla
oblongata and pons''', Neuroscience Letters; 502 (2011), pp157-161, http://www.sciencedirect.com/science/article/pii/S0304394011010949#></ref>
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Regulates fetal renal function
* Regulates amniotic fluid content and concentration
* Regulates blood pressure, heart rate, cardiac output and placental blood flow <ref name =M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher >M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher , 1993, '''Vasopressin receptors and effects during fetal development''', Regulatory Peptides; 45, pp203-208, http://www.sciencedirect.com/science/article/pii/016701159390207O#></ref>
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

'''How far has the thyroid gland developed by week 8 of gestation?'''
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

'''Fetal Stage of Thyroid Development - from week 8 of gestation onwards:'''
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis<ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>
* Week 16 - 18 is when fetal thyroid hormone synthesis occurs
** Prior to this, the fetus receives vital maternal thyroid hormones via the placenta

The following table explains the ontogenic action of thyroid hormone on the developing fetus. Thyroid hormones are essential in brain and central nervous system development in the fetus. A lot of neurological disorders are associated with insufficient thyroid hormone synthesis:

{| class="wikitable"
|-
! Hormone !! Types !! Ontogenic Action
|-
| Thyroid Hormone ||
* T3 - triiodothyronine
* T4 - thyroxine || Brain development:
* Central Nervous System development and maturation <ref name =J Patel, K Landers, H Li, R H Mortimer and K Richard>J Patel, K Landers, H Li, R H Mortimer and K Richard, 2011, '''Thyroid hormones and fetal neurological development''', Journal of Endocrinology:209;1-8, http://joe.endocrinology-journals.org.wwwproxy0.library.unsw.edu.au/content/209/1/1.full.pdf+html></ref>
**Glial cell proliferation
**Neural myelination
**Axon and dendrite sprouting
**Synapse formation
|}

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|right|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone || Secreted by || Function || Image
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine. || [[File:Active parathyroid hormone assay cartoon.png|200px|thumb|This images shows an active parathyroid hormone and its chemical structure.]]
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

'''Fetal hyperparathyroidism'''

Fetal hyperparathyroidism is a condition that is caused when an excess of parathyroid hormone (PTH) is present the bloodstream.<ref><pubmed> 1745971</pubmed></ref> This may be due to an overstimulated maternal parathyroid gland out of all the four which transfers the over accumulated PTH to the fetus. Normal fetal development requires 25–30 gms of calcium for bone mineralization and around 80% of this calcium accretion is observed in the third trimester of pregnancy. However the calcium gradient of 1.0:1.4 is no longer maintained when there is hyperparathyroidism present.<ref><pubmed> 12140371</pubmed></ref>Instead the gradient is elevated causing fetal parathyroid gland suppression thereby leading to Hypocalcemia. Calcium mobilisation then becomes difficult and hence fetal tetany may occur followed by miscarriage.<ref><pubmed> 25327435</pubmed></ref> In the event that the fetus survives, postnatal problems such as the baby having weak bones will be likely and would require calcium treatment throughout most of their lives.

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

'''Thymic aplasia'''

Thymic aplasia is a condition that has a strong correlation to DiGeorge syndrome. This syndrome is a congenital birth defect which occurs when the fetus either inherits an abnormal chromosome 22 or has a mutation of the same chromosome. In particularly, the mutation is a deletion of the genomic information packaged in the chromosomes and normally occurs when there isn’t proper recombination of chromosomal material during fertilisation.<ref><pubmed>4166528</pubmed></ref> As a result of this deletion, the third and fourth pharyngeal pouches fail to develop in the twelfth gestational week, thereby leading to the absence or partial absence of the thymus and parathyroid glands. Other associated abnormalities with thymic aplasia as a result of the deletion of chromosome 22 genetic material are severe cardiac defects, low immunity, hypocalcaemia and facial abnormalities. <ref><pubmed>5057550</pubmed></ref> Statistics suggest that the thymic aplasia may occur in 1:4000 to 1:6395 of fetuses.<ref><pubmed> 10861201</pubmed></ref> Treatment is normally difficult for fetuses that exhibit thymic aplasia, however calcium levels can be monitored and regulated and heart problems can be resolved though surgery. Immunity defects can be managed from controlling phosphorus levels in the fetus and protecting them from sources of infection.<ref><pubmed>1454183</pubmed></ref>

==Pancreas==
===Fetal development===
[[File:Development of the pancreas during fetal development.jpg|250px|thumb|right|This images shows normal pancreatic development of the fetus.]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
[[File:Ratio of alpha & beta cells at different phases of fetal development.png|350px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref> <ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

*'''Annular Pancreas'''
[[File:Annular pancreas.jpg|200px|thumb|right|This image shows annular pancreas where a ring of the pancreatic tissue encircles the growing duodenum.]]
Annular pancreas is a rare abnormality that can occur during fetal development in which a ring of the pancreatic tissue encircles the growing duodenum.<ref><pubmed>25124266</pubmed></ref> It occurs in 1 out of 7000 birth and is commonly associated with other abnormalities such as esophageal atresia and malrotation of the midgut. It is assumed that annular pancreas occurs when the tip of right ventral bud sticks to the duodenal wall which then forms a ring from the continuous stretching of the wall during rotation.<ref><pubmed> 25165593</pubmed></ref> This part of the pancreas can constrict the duodenum thereby restricting the flow of food to the intestines of the gastrointestinal tract.<ref><pubmed>24890427</pubmed></ref> Furthermore, annular pancreas is divided into two forms. Complete annular pancreas is when the pancreatic parenchyma wraps around the 2nd part of the duodenum completely whereas in incomplete annular pancreas, the tissue only surrounds the duodenum partially.<ref><pubmed> 24741860</pubmed></ref>Treatment for annular pancreas mainly involves surgery to bypass the constricted portion of the duodenum.

*'''Gestational diabetes mellitus'''

Gestational diabetes mellitus (GDM) is a disorder in which women without any history of diabetes show elevated blood glucose levels during pregnancy normally around the third trimester. It is caused when insulin receptors fail to respond correctly due to interference from signalling molecules related to pregnancy such as the interaction between human placental lactogen, prolactin and estradiol with the insulin receptors.<ref><pubmed>2141655</pubmed></ref> As a result, high blood glucose levels are observed. Patients with GDM have high levels of insulin resistance with increased β-cells production of the pancreas since the high levels of blood glucose are not interacting with the abnormal insulin receptors. Glucose is known to diffuse through the placenta via GLUT1 carrier situated in the syncytiotrophoblast of both the microvillus and basal membranes. With GDM, the number of GLUT1 molecules increase and hence placing high levels of glucose to the fetus since insulin itself cannot diffuse across the placenta and counteract this extremity.<ref><pubmed>25333246</pubmed></ref> This mechanism is known to lead to excessive growth at birth with a low glucose environment as it declines and high insulin production overall leading to hypoglycaemia.<ref><pubmed>25315294</pubmed></ref>It can also lead to jaundice and seizures in the new born with mothers having high susceptibility to type 2 diabetes mellitus. GDM can be controlled by monitoring blood sugar levels and controlling levels of glucose and insulin through pharmaceutical drugs.

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*'''Congenital Adrenal Hyperplasia (CAH)'''

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more.[[File:Cushing's syndrome.jpg|150px|right|thumb|This image shows a 3-month old child with classic signs of Cushing’s syndrome; central obesity, chubby cheeks and moon facies]] Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

*'''Cushing's Syndrome'''

Cushing’s Syndrome (CS) is a metabolic disorder characterised by abnormally high production of endogenous cortisol or exogenous levels of corticosteroids, which disrupts the metabolism of macromolecules such as lipids and carbohydrates. It is most common in obese adults aged 20-50 and the most common cause is the therapeutic administration of exogenous ACTH <ref><pubmed>24656295</pubmed></ref>. Cushing’s Syndrome’s two forms are either ACTH-dependent CS (80-85% of patients) or ACTH independent. The etiology of the dependent form is adrenal gland hyperplasia and excessive ACTH secretion by adenomas in the pituitary, however other causes include; small cell lung carcinoma ACTH production ectopically, or medullary thyroid carcinomas. <ref name= PMID24365350><pubmed>24365350</pubmed></ref> The independent form is however caused by neoplastic growths in the adrenal gland such as carcinomas, adenomas and macronodular hyperplasia. Clinical manifestations of this disorder include; moon facies, cataracts, hyperglycaemia, abnormal fat distribution, poor wounding of the skin, obesity in the central body and muscle wasting in 60% of patients. <ref name= PMID24365350><pubmed>24365350</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone). <ref><pubmed>8292535</pubmed></ref>

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''
[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]
*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

*'''Placenta accreta'''

[[File:Placenta accreta.jpg|150px|right|thumb|This image shows an area of profuse bleeding in the human placenta, with a region of placenta accreta indicated by the arrow]]

Placenta accreta (PA )is a rare obstetric abnormality characterised by abnormal insertion of the placenta to the myometrium of the uterus. The 3 types of PA are classified based on the depth of invasion; placenta accreta (superficial- chorionic villi attach to myometrium rather than just decidua basalis), placenta increta (middle layer) or placenta perceta (deep) being the most dire with 1 in 7000 incidence. <ref name= PMID23127895><pubmed>23127895</pubmed></ref> PA has an incidence of 1 in 2500 deliveries and is associated with grand-scale haemorrhage and requires hysterectomy and blood transfusion. <ref name= PMID21280984><pubmed>21280984</pubmed></ref> The condition normally occurs in the lower segment of the uterus which is prone to bleeding being poorly contractile and a site of angiogenesis. Prenatal diagnosis of PA is based on second and third trimester ulstrasound findings indicating; retroplacental zone loss, many lucanue in the vasculature and a very thin (<1mm) retroplacental thickness of the myometrium.<ref name= PMID21280984><pubmed>21280984</pubmed></ref> PA has a 40% likelihood in women aged over 35 who have had Caesarian section with placenta previa in their uterine scars. <ref name= PMID23127895><pubmed>23127895</pubmed></ref>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland. Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.

<ref><pubmed>24757681</pubmed></ref>

=References=

<references/>

2014 Group Project 6

2014-10-23T09:47:37Z

Z3418702: /* Placenta */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

[[File:Keith1902 fig167.jpg|200px|thumb|right| Image 1: schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|Image 2: Shows the location of the pineal gland in the adult brain.]]

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon reproductive hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>.

Melatonin plays an important role during fetal development. Both pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammalian fetus, intrinsic circadian rhythms are already established prior to birth.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || Pinealocytes || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

[[File:Primary brain vesicles.jpg|150px|left|thumb|Image 3: Primary brain vesicles]]'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle (Image 3).<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
[[File:Week 6 embryonic development of CNS.jpg|150px|left|thumb|Image 4: Week 6 embryonic development of CNS]]
[[File:Week 11 fetal development of CNS.jpg|150px|right|thumb|Image 5: Week 11 fetal development of CNS]]

*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement and an evagination of the pineal gland is visible (shown in image 4).

[[File:Fetal pineal gland 01.jpg|150px|thumb|right|Image 6: shows a fetal pineal gland at the end of the first trimester of development.]]

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum

*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis (shown in Image 5)

*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

===Abnormalities===

* '''Pineal tumors'''

Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>
[[File:Congenital hydrocephalus MRI02.jpg|150px|thumb|right|Image 7: Infant with obstructive congenital hydrocephalus]]

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

[[File:Development of hypothalamus.jpg|340px|thumb|Image 3: Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

===Abnormalities===

*Hypothalamus

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==
[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]
=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>
* Anterior pituitary

[[File:Anterior Pituitary Hormones.jpg|300px|right|thumb|Timeline of anterior pituitary hormone expression and synthesis]]

By week 8 of embryological development, the pituitary gland is fully formed and begins functioning as a control centre for release of hormones that are vital for subsequent organ development.

* Week 10 - Growth Hormone and ACTH detectable
* Week 21 - Vasopressin hormone synthesis established

'''Anterior Pituitary - Adenohypophysis'''

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || No function in fetal development. All postnatal action.
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|}

'''Posterior Pituitary - Neurohypophysis'''

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://www.sciencedirect.com/science/article/pii/S030100820900046X#></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Cardiomyogenesis
* Protective action of fetal neurons during brain development
* Neuronal development and plasticity <ref name =Yuzo Murata, Ming-Zi Li, Sadahiko Masuko>Yuzo Murata, Ming-Zi Li, Sadahiko Masuko, 2011, '''Developmental expression of oxytocin receptors in the neonatal medulla
oblongata and pons''', Neuroscience Letters; 502 (2011), pp157-161, http://www.sciencedirect.com/science/article/pii/S0304394011010949#></ref>
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Regulates fetal renal function
* Regulates amniotic fluid content and concentration
* Regulates blood pressure, heart rate, cardiac output and placental blood flow <ref name =M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher >M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher , 1993, '''Vasopressin receptors and effects during fetal development''', Regulatory Peptides; 45, pp203-208, http://www.sciencedirect.com/science/article/pii/016701159390207O#></ref>
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|right|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone || Secreted by || Function || Image
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine. || [[File:Active parathyroid hormone assay cartoon.png|200px|thumb|This images shows an active parathyroid hormone and its chemical structure.]]
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

'''Fetal hyperparathyroidism'''

Fetal hyperparathyroidism is a condition that is caused when an excess of parathyroid hormone (PTH) is present the bloodstream.<ref><pubmed> 1745971</pubmed></ref> This may be due to an overstimulated maternal parathyroid gland out of all the four which transfers the over accumulated PTH to the fetus. Normal fetal development requires 25–30 gms of calcium for bone mineralization and around 80% of this calcium accretion is observed in the third trimester of pregnancy. However the calcium gradient of 1.0:1.4 is no longer maintained when there is hyperparathyroidism present.<ref><pubmed> 12140371</pubmed></ref>Instead the gradient is elevated causing fetal parathyroid gland suppression thereby leading to Hypocalcemia. Calcium mobilisation then becomes difficult and hence fetal tetany may occur followed by miscarriage.<ref><pubmed> 25327435</pubmed></ref> In the event that the fetus survives, postnatal problems such as the baby having weak bones will be likely and would require calcium treatment throughout most of their lives.

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

'''Thymic aplasia'''

Thymic aplasia is a condition that has a strong correlation to DiGeorge syndrome. This syndrome is a congenital birth defect which occurs when the fetus either inherits an abnormal chromosome 22 or has a mutation of the same chromosome. In particularly, the mutation is a deletion of the genomic information packaged in the chromosomes and normally occurs when there isn’t proper recombination of chromosomal material during fertilisation.<ref><pubmed>4166528</pubmed></ref> As a result of this deletion, the third and fourth pharyngeal pouches fail to develop in the twelfth gestational week, thereby leading to the absence or partial absence of the thymus and parathyroid glands. Other associated abnormalities with thymic aplasia as a result of the deletion of chromosome 22 genetic material are severe cardiac defects, low immunity, hypocalcaemia and facial abnormalities. <ref><pubmed>5057550</pubmed></ref> Statistics suggest that the thymic aplasia may occur in 1:4000 to 1:6395 of fetuses.<ref><pubmed> 10861201</pubmed></ref> Treatment is normally difficult for fetuses that exhibit thymic aplasia, however calcium levels can be monitored and regulated and heart problems can be resolved though surgery. Immunity defects can be managed from controlling phosphorus levels in the fetus and protecting them from sources of infection.<ref><pubmed>1454183</pubmed></ref>

==Pancreas==
===Fetal development===
[[File:Development of the pancreas during fetal development.jpg|250px|thumb|right|This images shows normal pancreatic development of the fetus.]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
[[File:Ratio of alpha & beta cells at different phases of fetal development.png|350px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref> <ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

*'''Annular Pancreas'''
[[File:Annular pancreas.jpg|200px|thumb|right|This image shows annular pancreas where a ring of the pancreatic tissue encircles the growing duodenum.]]
Annular pancreas is a rare abnormality that can occur during fetal development in which a ring of the pancreatic tissue encircles the growing duodenum.<ref><pubmed>25124266</pubmed></ref> It occurs in 1 out of 7000 birth and is commonly associated with other abnormalities such as esophageal atresia and malrotation of the midgut. It is assumed that annular pancreas occurs when the tip of right ventral bud sticks to the duodenal wall which then forms a ring from the continuous stretching of the wall during rotation.<ref><pubmed> 25165593</pubmed></ref> This part of the pancreas can constrict the duodenum thereby restricting the flow of food to the intestines of the gastrointestinal tract.<ref><pubmed>24890427</pubmed></ref> Furthermore, annular pancreas is divided into two forms. Complete annular pancreas is when the pancreatic parenchyma wraps around the 2nd part of the duodenum completely whereas in incomplete annular pancreas, the tissue only surrounds the duodenum partially.<ref><pubmed> 24741860</pubmed></ref>Treatment for annular pancreas mainly involves surgery to bypass the constricted portion of the duodenum.

*'''Gestational diabetes mellitus'''

Gestational diabetes mellitus (GDM) is a disorder in which women without any history of diabetes show elevated blood glucose levels during pregnancy normally around the third trimester. It is caused when insulin receptors fail to respond correctly due to interference from signalling molecules related to pregnancy such as the interaction between human placental lactogen, prolactin and estradiol with the insulin receptors.<ref><pubmed>2141655</pubmed></ref> As a result, high blood glucose levels are observed. Patients with GDM have high levels of insulin resistance with increased β-cells production of the pancreas since the high levels of blood glucose are not interacting with the abnormal insulin receptors. Glucose is known to diffuse through the placenta via GLUT1 carrier situated in the syncytiotrophoblast of both the microvillus and basal membranes. With GDM, the number of GLUT1 molecules increase and hence placing high levels of glucose to the fetus since insulin itself cannot diffuse across the placenta and counteract this extremity.<ref><pubmed>25333246</pubmed></ref> This mechanism is known to lead to excessive growth at birth with a low glucose environment as it declines and high insulin production overall leading to hypoglycaemia.<ref><pubmed>25315294</pubmed></ref>It can also lead to jaundice and seizures in the new born with mothers having high susceptibility to type 2 diabetes mellitus. GDM can be controlled by monitoring blood sugar levels and controlling levels of glucose and insulin through pharmaceutical drugs.

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*'''Congenital Adrenal Hyperplasia (CAH)'''

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more.[[File:Cushing's syndrome.jpg|150px|right|thumb|This image shows a 3-month old child with classic signs of Cushing’s syndrome; central obesity, chubby cheeks and moon facies]] Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

*'''Cushing's Syndrome'''

Cushing’s Syndrome (CS) is a metabolic disorder characterised by abnormally high production of endogenous cortisol or exogenous levels of corticosteroids, which disrupts the metabolism of macromolecules such as lipids and carbohydrates. It is most common in obese adults aged 20-50 and the most common cause is the therapeutic administration of exogenous ACTH <ref><pubmed>24656295</pubmed></ref>. Cushing’s Syndrome’s two forms are either ACTH-dependent CS (80-85% of patients) or ACTH independent. The etiology of the dependent form is adrenal gland hyperplasia and excessive ACTH secretion by adenomas in the pituitary, however other causes include; small cell lung carcinoma ACTH production ectopically, or medullary thyroid carcinomas. <ref name= PMID24365350><pubmed>24365350</pubmed></ref> The independent form is however caused by neoplastic growths in the adrenal gland such as carcinomas, adenomas and macronodular hyperplasia. Clinical manifestations of this disorder include; moon facies, cataracts, hyperglycaemia, abnormal fat distribution, poor wounding of the skin, obesity in the central body and muscle wasting in 60% of patients. <ref name= PMID24365350><pubmed>24365350</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone). <ref><pubmed>8292535</pubmed></ref>

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

*'''Placenta accreta'''

[[File:Placenta accreta.jpg|150px|right|thumb|This image shows an area of profuse bleeding in the human placenta, with a region of placenta accreta indicated by the arrow]]

Placenta accreta (PA )is a rare obstetric abnormality characterised by abnormal insertion of the placenta to the myometrium of the uterus. The 3 types of PA are classified based on the depth of invasion; placenta accreta (superficial- chorionic villi attach to myometrium rather than just decidua basalis), placenta increta (middle layer) or placenta perceta (deep) being the most dire with 1 in 7000 incidence. <ref name= PMID23127895><pubmed>23127895</pubmed></ref> PA has an incidence of 1 in 2500 deliveries and is associated with grand-scale haemorrhage and requires hysterectomy and blood transfusion. <ref name= PMID21280984><pubmed>21280984</pubmed></ref> The condition normally occurs in the lower segment of the uterus which is prone to bleeding being poorly contractile and a site of angiogenesis. Prenatal diagnosis of PA is based on second and third trimester ulstrasound findings indicating; retroplacental zone loss, many lucanue in the vasculature and a very thin (<1mm) retroplacental thickness of the myometrium.<ref name= PMID21280984><pubmed>21280984</pubmed></ref> PA has a 40% likelihood in women aged over 35 who have had Caesarian section with placenta previa in their uterine scars. <ref name= PMID23127895><pubmed>23127895</pubmed></ref>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland. Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.

<ref><pubmed>24757681</pubmed></ref>

=References=

<references/>

File:Placenta accreta.jpg

2014-10-23T09:41:26Z

Z3418702: ==Placenta accreta== This image shows an area of profuse bleeding in the human placenta, with an arrow indicating an area of placenta accreta ===Reference=== <pubmed>21867547</pubmed> '''Copyright''' ©2011 Tikkanen et al; licensee BioMed Central L...

==Placenta accreta==
This image shows an area of profuse bleeding in the human placenta, with an arrow indicating an area of placenta accreta

===Reference===
<pubmed>21867547</pubmed>

'''Copyright'''

©2011 Tikkanen et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

{{Template:Student Image}}

2014 Group Project 6

2014-10-23T08:21:00Z

Z3418702: /* Abnormalities */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

[[File:Keith1902 fig167.jpg|200px|thumb|right| Image 1: schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|Image 2: Shows the location of the pineal gland in the adult brain.]]

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon reproductive hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>.

Melatonin plays an important role during fetal development. Both pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammalian fetus, intrinsic circadian rhythms are already established prior to birth.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || Pinealocytes || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

[[File:Primary brain vesicles.jpg|150px|left|thumb|Image 3: Primary brain vesicles]]'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle (Image 3).<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
[[File:Week 6 embryonic development of CNS.jpg|150px|left|thumb|Image 4: Week 6 embryonic development of CNS]]
[[File:Week 11 fetal development of CNS.jpg|150px|right|thumb|Image 5: Week 11 fetal development of CNS]]

*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement and an evagination of the pineal gland is visible (shown in image 4).

[[File:Fetal pineal gland 01.jpg|150px|thumb|right|Image 6: shows a fetal pineal gland at the end of the first trimester of development.]]

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum

*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis (shown in Image 5)

*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

===Abnormalities===

* '''Pineal tumors'''

Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>
[[File:Congenital hydrocephalus MRI02.jpg|150px|thumb|right|Image 7: Infant with obstructive congenital hydrocephalus]]

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

[[File:Development of hypothalamus.jpg|340px|thumb|Image 3: Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

===Abnormalities===

*Hypothalamus

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==
[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]
=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>
* Anterior pituitary

[[File:Anterior Pituitary Hormones.jpg|300px|right|thumb|Timeline of anterior pituitary hormone expression and synthesis]]

By week 8 of embryological development, the pituitary gland is fully formed and begins functioning as a control centre for release of hormones that are vital for subsequent organ development.

* Week 10 - Growth Hormone and ACTH detectable
* Week 21 - Vasopressin hormone synthesis established

'''Anterior Pituitary - Adenohypophysis'''

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || No function in fetal development. All postnatal action.
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|}

'''Posterior Pituitary - Neurohypophysis'''

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://www.sciencedirect.com/science/article/pii/S030100820900046X#></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Cardiomyogenesis
* Protective action of fetal neurons during brain development
* Neuronal development and plasticity <ref name =Yuzo Murata, Ming-Zi Li, Sadahiko Masuko>Yuzo Murata, Ming-Zi Li, Sadahiko Masuko, 2011, '''Developmental expression of oxytocin receptors in the neonatal medulla
oblongata and pons''', Neuroscience Letters; 502 (2011), pp157-161, http://www.sciencedirect.com/science/article/pii/S0304394011010949#></ref>
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Regulates fetal renal function
* Regulates amniotic fluid content and concentration
* Regulates blood pressure, heart rate, cardiac output and placental blood flow <ref name =M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher >M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher , 1993, '''Vasopressin receptors and effects during fetal development''', Regulatory Peptides; 45, pp203-208, http://www.sciencedirect.com/science/article/pii/016701159390207O#></ref>
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|right|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone || Secreted by || Function || Image
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine. || [[File:Active parathyroid hormone assay cartoon.png|200px|thumb|This images shows an active parathyroid hormone and its chemical structure.]]
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

'''Fetal hyperparathyroidism'''

Fetal hyperparathyroidism is a condition that is caused when an excess of parathyroid hormone (PTH) is present the bloodstream.<ref><pubmed> 1745971</pubmed></ref> This may be due to an overstimulated maternal parathyroid gland out of all the four which transfers the over accumulated PTH to the fetus. Normal fetal development requires 25–30 gms of calcium for bone mineralization and around 80% of this calcium accretion is observed in the third trimester of pregnancy. However the calcium gradient of 1.0:1.4 is no longer maintained when there is hyperparathyroidism present.<ref><pubmed> 12140371</pubmed></ref>Instead the gradient is elevated causing fetal parathyroid gland suppression thereby leading to Hypocalcemia. Calcium mobilisation then becomes difficult and hence fetal tetany may occur followed by miscarriage.<ref><pubmed> 25327435</pubmed></ref> In the event that the fetus survives, postnatal problems such as the baby having weak bones will be likely and would require calcium treatment throughout most of their lives.

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===
[[File:Development of the pancreas during fetal development.jpg|250px|thumb|right|This images shows normal pancreatic development of the fetus.]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
[[File:Ratio of alpha & beta cells at different phases of fetal development.png|350px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref> <ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

*'''Annular Pancreas'''
[[File:Annular pancreas.jpg|200px|thumb|right|This image shows annular pancreas where a ring of the pancreatic tissue encircles the growing duodenum.]]
Annular pancreas is a rare abnormality that can occur during fetal development in which a ring of the pancreatic tissue encircles the growing duodenum.<ref><pubmed>25124266</pubmed></ref> It occurs in 1 out of 7000 birth and is commonly associated with other abnormalities such as esophageal atresia and malrotation of the midgut. It is assumed that annular pancreas occurs when the tip of right ventral bud sticks to the duodenal wall which then forms a ring from the continuous stretching of the wall during rotation.<ref><pubmed> 25165593</pubmed></ref> This part of the pancreas can constrict the duodenum thereby restricting the flow of food to the intestines of the gastrointestinal tract.<ref><pubmed>24890427</pubmed></ref> Furthermore, annular pancreas is divided into two forms. Complete annular pancreas is when the pancreatic parenchyma wraps around the 2nd part of the duodenum completely whereas in incomplete annular pancreas, the tissue only surrounds the duodenum partially.<ref><pubmed> 24741860</pubmed></ref>Treatment for annular pancreas mainly involves surgery to bypass the constricted portion of the duodenum.

*'''Gestational diabetes mellitus'''

Gestational diabetes mellitus (GDM) is a disorder in which women without any history of diabetes show elevated blood glucose levels during pregnancy normally around the third trimester. It is caused when insulin receptors fail to respond correctly due to interference from signalling molecules related to pregnancy such as the interaction between human placental lactogen, prolactin and estradiol with the insulin receptors.<ref><pubmed>2141655</pubmed></ref> As a result, high blood glucose levels are observed. Patients with GDM have high levels of insulin resistance with increased β-cells production of the pancreas since the high levels of blood glucose are not interacting with the abnormal insulin receptors. Glucose is known to diffuse through the placenta via GLUT1 carrier situated in the syncytiotrophoblast of both the microvillus and basal membranes. With GDM, the number of GLUT1 molecules increase and hence placing high levels of glucose to the fetus since insulin itself cannot diffuse across the placenta and counteract this extremity.<ref><pubmed>25333246</pubmed></ref> This mechanism is known to lead to excessive growth at birth with a low glucose environment as it declines and high insulin production overall leading to hypoglycaemia.<ref><pubmed>25315294</pubmed></ref>It can also lead to jaundice and seizures in the new born with mothers having high susceptibility to type 2 diabetes mellitus. GDM can be controlled by monitoring blood sugar levels and controlling levels of glucose and insulin through pharmaceutical drugs.

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*'''Congenital Adrenal Hyperplasia (CAH)'''

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

*'''Cushing's Syndrome'''

[[File:Cushing's syndrome.jpg|300px|right|thumb|This image shows a 3-month old child with classic signs of Cushing’s syndrome; central obesity, chubby cheeks and moon facies]]

Cushing’s Syndrome (CS) is a metabolic disorder characterised by abnormally high production of endogenous cortisol or exogenous levels of corticosteroids, which disrupts the metabolism of macromolecules such as lipids and carbohydrates. It is most common in obese adults aged 20-50 and the most common cause is the therapeutic administration of exogenous ACTH <ref><pubmed>24656295</pubmed></ref>. Cushing’s Syndrome’s two forms are either ACTH-dependent CS (80-85% of patients) or ACTH independent. The etiology of the dependent form is adrenal gland hyperplasia and excessive ACTH secretion by adenomas in the pituitary, however other causes include; small cell lung carcinoma ACTH production ectopically, or medullary thyroid carcinomas. <ref name= PMID24365350><pubmed>24365350</pubmed></ref> The independent form is however caused by neoplastic growths in the adrenal gland such as carcinomas, adenomas and macronodular hyperplasia. Clinical manifestations of this disorder include; moon facies, cataracts, hyperglycaemia, abnormal fat distribution, poor wounding of the skin, obesity in the central body and muscle wasting in 60% of patients. <ref name= PMID24365350><pubmed>24365350</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone). <ref><pubmed>8292535</pubmed></ref>

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland. Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.

<ref><pubmed>24757681</pubmed></ref>

=References=

<references/>

2014 Group Project 6

2014-10-23T08:14:53Z

Z3418702: /* Adrenal gland */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

[[File:Keith1902 fig167.jpg|200px|thumb|right| Image 1: schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|Image 2: Shows the location of the pineal gland in the adult brain.]]

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon reproductive hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>.

Melatonin plays an important role during fetal development. Both pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammalian fetus, intrinsic circadian rhythms are already established prior to birth.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || Pinealocytes || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

[[File:Primary brain vesicles.jpg|150px|left|thumb|Image 3: Primary brain vesicles]]'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle (Image 3).<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
[[File:Week 6 embryonic development of CNS.jpg|150px|left|thumb|Image 4: Week 6 embryonic development of CNS]]
[[File:Week 11 fetal development of CNS.jpg|150px|right|thumb|Image 5: Week 11 fetal development of CNS]]

*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement and an evagination of the pineal gland is visible (shown in image 4).

[[File:Fetal pineal gland 01.jpg|150px|thumb|right|Image 6: shows a fetal pineal gland at the end of the first trimester of development.]]

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum

*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis (shown in Image 5)

*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

===Abnormalities===

* '''Pineal tumors'''

Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>
[[File:Congenital hydrocephalus MRI02.jpg|150px|thumb|right|Image 7: Infant with obstructive congenital hydrocephalus]]

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

[[File:Development of hypothalamus.jpg|340px|thumb|Image 3: Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

===Abnormalities===

*Hypothalamus

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==
[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]
=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>
* Anterior pituitary

[[File:Anterior Pituitary Hormones.jpg|300px|right|thumb|Timeline of anterior pituitary hormone expression and synthesis]]

By week 8 of embryological development, the pituitary gland is fully formed and begins functioning as a control centre for release of hormones that are vital for subsequent organ development.

* Week 10 - Growth Hormone and ACTH detectable
* Week 21 - Vasopressin hormone synthesis established

'''Anterior Pituitary - Adenohypophysis'''

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || No function in fetal development. All postnatal action.
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|}

'''Posterior Pituitary - Neurohypophysis'''

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://www.sciencedirect.com/science/article/pii/S030100820900046X#></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Cardiomyogenesis
* Protective action of fetal neurons during brain development
* Neuronal development and plasticity <ref name =Yuzo Murata, Ming-Zi Li, Sadahiko Masuko>Yuzo Murata, Ming-Zi Li, Sadahiko Masuko, 2011, '''Developmental expression of oxytocin receptors in the neonatal medulla
oblongata and pons''', Neuroscience Letters; 502 (2011), pp157-161, http://www.sciencedirect.com/science/article/pii/S0304394011010949#></ref>
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Regulates fetal renal function
* Regulates amniotic fluid content and concentration
* Regulates blood pressure, heart rate, cardiac output and placental blood flow <ref name =M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher >M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher , 1993, '''Vasopressin receptors and effects during fetal development''', Regulatory Peptides; 45, pp203-208, http://www.sciencedirect.com/science/article/pii/016701159390207O#></ref>
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|right|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone || Secreted by || Function || Image
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine. || [[File:Active parathyroid hormone assay cartoon.png|200px|thumb|This images shows an active parathyroid hormone and its chemical structure.]]
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

'''Fetal hyperparathyroidism'''

Fetal hyperparathyroidism is a condition that is caused when an excess of parathyroid hormone (PTH) is present the bloodstream.<ref><pubmed> 1745971</pubmed></ref> This may be due to an overstimulated maternal parathyroid gland out of all the four which transfers the over accumulated PTH to the fetus. Normal fetal development requires 25–30 gms of calcium for bone mineralization and around 80% of this calcium accretion is observed in the third trimester of pregnancy. However the calcium gradient of 1.0:1.4 is no longer maintained when there is hyperparathyroidism present.<ref><pubmed> 12140371</pubmed></ref>Instead the gradient is elevated causing fetal parathyroid gland suppression thereby leading to Hypocalcemia. Calcium mobilisation then becomes difficult and hence fetal tetany may occur followed by miscarriage.<ref><pubmed> 25327435</pubmed></ref> In the event that the fetus survives, postnatal problems such as the baby having weak bones will be likely and would require calcium treatment throughout most of their lives.

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===
[[File:Development of the pancreas during fetal development.jpg|250px|thumb|right|This images shows normal pancreatic development of the fetus.]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
[[File:Ratio of alpha & beta cells at different phases of fetal development.png|350px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref> <ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

*'''Annular Pancreas'''
[[File:Annular pancreas.jpg|200px|thumb|right|This image shows annular pancreas where a ring of the pancreatic tissue encircles the growing duodenum.]]
Annular pancreas is a rare abnormality that can occur during fetal development in which a ring of the pancreatic tissue encircles the growing duodenum.<ref><pubmed>25124266</pubmed></ref> It occurs in 1 out of 7000 birth and is commonly associated with other abnormalities such as esophageal atresia and malrotation of the midgut. It is assumed that annular pancreas occurs when the tip of right ventral bud sticks to the duodenal wall which then forms a ring from the continuous stretching of the wall during rotation.<ref><pubmed> 25165593</pubmed></ref> This part of the pancreas can constrict the duodenum thereby restricting the flow of food to the intestines of the gastrointestinal tract.<ref><pubmed>24890427</pubmed></ref> Furthermore, annular pancreas is divided into two forms. Complete annular pancreas is when the pancreatic parenchyma wraps around the 2nd part of the duodenum completely whereas in incomplete annular pancreas, the tissue only surrounds the duodenum partially.<ref><pubmed> 24741860</pubmed></ref>Treatment for annular pancreas mainly involves surgery to bypass the constricted portion of the duodenum.

*'''Gestational diabetes mellitus'''

Gestational diabetes mellitus (GDM) is a disorder in which women without any history of diabetes show elevated blood glucose levels during pregnancy normally around the third trimester. It is caused when insulin receptors fail to respond correctly due to interference from signalling molecules related to pregnancy such as the interaction between human placental lactogen, prolactin and estradiol with the insulin receptors.<ref><pubmed>2141655</pubmed></ref> As a result, high blood glucose levels are observed. Patients with GDM have high levels of insulin resistance with increased β-cells production of the pancreas since the high levels of blood glucose are not interacting with the abnormal insulin receptors. Glucose is known to diffuse through the placenta via GLUT1 carrier situated in the syncytiotrophoblast of both the microvillus and basal membranes. With GDM, the number of GLUT1 molecules increase and hence placing high levels of glucose to the fetus since insulin itself cannot diffuse across the placenta and counteract this extremity.<ref><pubmed>25333246</pubmed></ref> This mechanism is known to lead to excessive growth at birth with a low glucose environment as it declines and high insulin production overall leading to hypoglycaemia.<ref><pubmed>25315294</pubmed></ref>It can also lead to jaundice and seizures in the new born with mothers having high susceptibility to type 2 diabetes mellitus. GDM can be controlled by monitoring blood sugar levels and controlling levels of glucose and insulin through pharmaceutical drugs.

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*'''Congenital Adrenal Hyperplasia (CAH)'''

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

*'''Cushing's Syndrome'''

[[File:Cushing's syndrome.jpg|300px|right|thumb|This image shows a 3-month old child with classic signs of Cushing’s syndrome; central obesity, chubby cheeks and moon facies]]

Cushing’s Syndrome (CS) is a metabolic disorder characterised by abnormally high production of endogenous cortisol or exogenous levels of corticosteroids, which disrupts the metabolism of macromolecules such as lipids and carbohydrates. It is most common in obese adults aged 20-50 and the most common cause is the therapeutic administration of exogenous ACTH <ref><pubmed>24656295</pubmed></ref>. Cushing’s Syndrome’s two forms are either ACTH-dependent CS (80-85% of patients) or ACTH independent. The etiology of the dependent form is adrenal gland hyperplasia and excessive ACTH secretion by adenomas in the pituitary, however other causes include; small cell lung carcinoma ACTH production ectopically, or medullary thyroid carcinomas. <ref name= PMID24365350><pubmed>24365350</pubmed></ref> The independent form is however caused by neoplastic growths in the adrenal gland such as carcinomas, adenomas and macronodular hyperplasia. Clinical manifestations of this disorder include; moon facies, cataracts, hyperglycaemia, abnormal fat distribution, poor wounding of the skin, obesity in the central body and muscle wasting in 60% of patients. <ref name= PMID24365350><pubmed>24365350</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone). <ref><pubmed>8292535</pubmed></ref>

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland. Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.

<ref><pubmed>24757681</pubmed></ref>

=References=

<references/>

File:Cushing's syndrome.jpg

2014-10-23T08:08:26Z

Z3418702: ==Clinical manifestations of Cushing’s Syndrome== This image shows a child at 3 months of age showing central obesity, moon facies and chubby cheeks; classic signs of Cushing’s Syndrome in infants. ===Reference=== <pubmed>22985617</pubmed> '''Co...

==Clinical manifestations of Cushing’s Syndrome==
This image shows a child at 3 months of age showing central obesity, moon facies and chubby cheeks; classic signs of Cushing’s Syndrome in infants.

===Reference===
<pubmed>22985617</pubmed>

'''Copyright'''

© Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

{{Template:Student Image}}

2014 Group Project 6

2014-10-23T07:36:53Z

Z3418702:

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

[[File:Keith1902 fig167.jpg|200px|thumb|right| Image 1: schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|Image 2: Shows the location of the pineal gland in the adult brain.]]

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon reproductive hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>.

Melatonin plays an important role during fetal development. Both pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammalian fetus, intrinsic circadian rhythms are already established prior to birth.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || Pinealocytes || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

[[File:Primary brain vesicles.jpg|150px|left|thumb|Image 3: Primary brain vesicles]]'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle (Image 3).<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
[[File:Week 6 embryonic development of CNS.jpg|150px|left|thumb|Image 4: Week 6 embryonic development of CNS]]
[[File:Week 11 fetal development of CNS.jpg|150px|right|thumb|Image 5: Week 11 fetal development of CNS]]

*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement and an evagination of the pineal gland is visible (shown in image 4).

[[File:Fetal pineal gland 01.jpg|150px|thumb|right|Image 6: shows a fetal pineal gland at the end of the first trimester of development.]]

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum

*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis (shown in Image 5)

*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

===Abnormalities===

* '''Pineal tumors'''

Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>
[[File:Congenital hydrocephalus MRI02.jpg|150px|thumb|right|Image 7: Infant with obstructive congenital hydrocephalus]]

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

[[File:Development of hypothalamus.jpg|340px|thumb|Image 3: Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

===Abnormalities===

*Hypothalamus

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==
[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]
=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>
* Anterior pituitary

[[File:Anterior Pituitary Hormones.jpg|300px|right|thumb|Timeline of anterior pituitary hormone expression and synthesis]]

By week 8 of embryological development, the pituitary gland is fully formed and begins functioning as a control centre for release of hormones that are vital for subsequent organ development.

* Week 10 - Growth Hormone and ACTH detectable
* Week 21 - Vasopressin hormone synthesis established

'''Anterior Pituitary - Adenohypophysis'''

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || No function in fetal development. All postnatal action.
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|}

'''Posterior Pituitary - Neurohypophysis'''

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://www.sciencedirect.com/science/article/pii/S030100820900046X#></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Cardiomyogenesis
* Protective action of fetal neurons during brain development
* Neuronal development and plasticity <ref name =Yuzo Murata, Ming-Zi Li, Sadahiko Masuko>Yuzo Murata, Ming-Zi Li, Sadahiko Masuko, 2011, '''Developmental expression of oxytocin receptors in the neonatal medulla
oblongata and pons''', Neuroscience Letters; 502 (2011), pp157-161, http://www.sciencedirect.com/science/article/pii/S0304394011010949#></ref>
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei ||
* Regulates fetal renal function
* Regulates amniotic fluid content and concentration
* Regulates blood pressure, heart rate, cardiac output and placental blood flow <ref name =M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher >M. Gore Ervin, Linda K. Kullama, Michael G. Ross, Rosemary D. Leake and Delbert A. Fisher , 1993, '''Vasopressin receptors and effects during fetal development''', Regulatory Peptides; 45, pp203-208, http://www.sciencedirect.com/science/article/pii/016701159390207O#></ref>
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|right|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone || Secreted by || Function || Image
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine. || [[File:Active parathyroid hormone assay cartoon.png|200px|thumb|This images shows an active parathyroid hormone and its chemical structure.]]
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

'''Fetal hyperparathyroidism'''

Fetal hyperparathyroidism is a condition that is caused when an excess of parathyroid hormone (PTH) is present the bloodstream.<ref><pubmed> 1745971</pubmed></ref> This may be due to an overstimulated maternal parathyroid gland out of all the four which transfers the over accumulated PTH to the fetus. Normal fetal development requires 25–30 gms of calcium for bone mineralization and around 80% of this calcium accretion is observed in the third trimester of pregnancy. However the calcium gradient of 1.0:1.4 is no longer maintained when there is hyperparathyroidism present.<ref><pubmed> 12140371</pubmed></ref>Instead the gradient is elevated causing fetal parathyroid gland suppression thereby leading to Hypocalcemia. Calcium mobilisation then becomes difficult and hence fetal tetany may occur followed by miscarriage.<ref><pubmed> 25327435</pubmed></ref> In the event that the fetus survives, postnatal problems such as the baby having weak bones will be likely and would require calcium treatment throughout most of their lives.

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===
[[File:Development of the pancreas during fetal development.jpg|250px|thumb|right|This images shows normal pancreatic development of the fetus.]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
[[File:Ratio of alpha & beta cells at different phases of fetal development.png|350px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref> <ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

*'''Annular Pancreas'''
[[File:Annular pancreas.jpg|200px|thumb|right|This image shows annular pancreas where a ring of the pancreatic tissue encircles the growing duodenum.]]
Annular pancreas is a rare abnormality that can occur during fetal development in which a ring of the pancreatic tissue encircles the growing duodenum.<ref><pubmed>25124266</pubmed></ref> It occurs in 1 out of 7000 birth and is commonly associated with other abnormalities such as esophageal atresia and malrotation of the midgut. It is assumed that annular pancreas occurs when the tip of right ventral bud sticks to the duodenal wall which then forms a ring from the continuous stretching of the wall during rotation.<ref><pubmed> 25165593</pubmed></ref> This part of the pancreas can constrict the duodenum thereby restricting the flow of food to the intestines of the gastrointestinal tract.<ref><pubmed>24890427</pubmed></ref> Furthermore, annular pancreas is divided into two forms. Complete annular pancreas is when the pancreatic parenchyma wraps around the 2nd part of the duodenum completely whereas in incomplete annular pancreas, the tissue only surrounds the duodenum partially.<ref><pubmed> 24741860</pubmed></ref>Treatment for annular pancreas mainly involves surgery to bypass the constricted portion of the duodenum.

*'''Gestational diabetes mellitus'''

Gestational diabetes mellitus (GDM) is a disorder in which women without any history of diabetes show elevated blood glucose levels during pregnancy normally around the third trimester. It is caused when insulin receptors fail to respond correctly due to interference from signalling molecules related to pregnancy such as the interaction between human placental lactogen, prolactin and estradiol with the insulin receptors.<ref><pubmed>2141655</pubmed></ref> As a result, high blood glucose levels are observed. Patients with GDM have high levels of insulin resistance with increased β-cells production of the pancreas since the high levels of blood glucose are not interacting with the abnormal insulin receptors. Glucose is known to diffuse through the placenta via GLUT1 carrier situated in the syncytiotrophoblast of both the microvillus and basal membranes. With GDM, the number of GLUT1 molecules increase and hence placing high levels of glucose to the fetus since insulin itself cannot diffuse across the placenta and counteract this extremity.<ref><pubmed>25333246</pubmed></ref> This mechanism is known to lead to excessive growth at birth with a low glucose environment as it declines and high insulin production overall leading to hypoglycaemia.<ref><pubmed>25315294</pubmed></ref>It can also lead to jaundice and seizures in the new born with mothers having high susceptibility to type 2 diabetes mellitus. GDM can be controlled by monitoring blood sugar levels and controlling levels of glucose and insulin through pharmaceutical drugs.

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*'''Congenital Adrenal Hyperplasia (CAH)'''

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

*'''Cushing's Syndrome'''

Cushing’s Syndrome (CS) is a metabolic disorder characterised by abnormally high production of endogenous cortisol or exogenous levels of corticosteroids, which disrupts the metabolism of macromolecules such as lipids and carbohydrates. It is most common in obese adults aged 20-50 and the most common cause is the therapeutic administration of exogenous ACTH <ref><pubmed>24656295</pubmed></ref>. Cushing’s Syndrome’s two forms are either ACTH-dependent CS (80-85% of patients) or ACTH independent. The etiology of the dependent form is adrenal gland hyperplasia and excessive ACTH secretion by adenomas in the pituitary, however other causes include; small cell lung carcinoma ACTH production ectopically, or medullary thyroid carcinomas. <ref name= PMID24365350><pubmed>24365350</pubmed></ref> The independent form is however caused by neoplastic growths in the adrenal gland such as carcinomas, adenomas and macronodular hyperplasia. Clinical manifestations of this disorder include; cataracts, hyperglycaemia, abnormal fat distribution, poor wounding of the skin, obesity in the central body and muscle wasting in 60% of patients. <ref name= PMID24365350><pubmed>24365350</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone). <ref><pubmed>8292535</pubmed></ref>

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland. Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.

<ref><pubmed>24757681</pubmed></ref>

=References=

<references/>

2014 Group Project 6

2014-10-22T12:44:03Z

Z3418702: /* Fetal development */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. however it also has a role in reproductive development. Recent findings have shown that the pineal gland does play an important role during fetal development through the production of it's primary hormone, melatonin.

[[File:Keith1902 fig167.jpg|300px|thumb| Image 1: schematic of a developing pineal gland in week 6 of gestation]]

Pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammilian fetus, intrinsic circadian rhythms are already established prior to birth. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || pinealocytes; The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement.

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum
*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis
*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

[[File:Fetal pineal gland 01.jpg|300px|thumb|Image 5: shows a fetal pineal gland at the end of the first trimester of development.]]

===Abnormalities===

* '''Pineal tumors'''
Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>

[[File:Pineal-body.jpg|250px|thumb| Image 6: Shows the location of the pineal gland in the adult brain.]]
''

[[File:Congenital hydrocephalus MRI02.jpg|250px|thumb|Image 7: Infant with obstructive congenital hydrocephalus]]
''

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

===Abnormalities===

Complications in development of these nuclei regions lead to disorders characteristic to those regions affected.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==

<pubmed>10.1016/j.acthis.2014.04.003</pubmed>

<pubmed>10.1371/journal.pone.0004815</pubmed>

<pubmed>10.1371/journal.pone.0004513</pubmed>

[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]

=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || Example
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|-
| Example || Example || Example || Example
|}

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://ac.els-cdn.com/S030100820900046X/1-s2.0-S030100820900046X-main.pdf?_tid=42bc9e94-59ac-11e4-acd8-00000aacb361&acdnat=1413955891_77158b95d9eb4f3e4942d81440455daa></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Neurophysin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|left|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone !! Secreted by ||Function
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine.
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===

[[File:Ratio of alpha & beta cells at different phases of fetal development.png|400px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref>

<ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone). <ref><pubmed>8292535</pubmed></ref>

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref> Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref>

M. Møller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland, 2014, BioMed Research International, http://www.hindawi.com/journals/bmri/2014/868567/

[[IMAGE 8 http://www.hindawi.com/journals/bmri/2014/868567/fig2/]]

=References=

<references/>

2014 Group Project 6

2014-10-22T12:41:04Z

Z3418702: /* Fetal development */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. however it also has a role in reproductive development. Recent findings have shown that the pineal gland does play an important role during fetal development through the production of it's primary hormone, melatonin.

[[File:Keith1902 fig167.jpg|300px|thumb| Image 1: schematic of a developing pineal gland in week 6 of gestation]]

Pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammilian fetus, intrinsic circadian rhythms are already established prior to birth. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || pinealocytes; The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement.

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum
*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis
*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

[[File:Fetal pineal gland 01.jpg|300px|thumb|Image 5: shows a fetal pineal gland at the end of the first trimester of development.]]

===Abnormalities===

* '''Pineal tumors'''
Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>

[[File:Pineal-body.jpg|250px|thumb| Image 6: Shows the location of the pineal gland in the adult brain.]]
''

[[File:Congenital hydrocephalus MRI02.jpg|250px|thumb|Image 7: Infant with obstructive congenital hydrocephalus]]
''

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

===Abnormalities===

Complications in development of these nuclei regions lead to disorders characteristic to those regions affected.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==

<pubmed>10.1016/j.acthis.2014.04.003</pubmed>

<pubmed>10.1371/journal.pone.0004815</pubmed>

<pubmed>10.1371/journal.pone.0004513</pubmed>

[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]

=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || Example
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|-
| Example || Example || Example || Example
|}

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://ac.els-cdn.com/S030100820900046X/1-s2.0-S030100820900046X-main.pdf?_tid=42bc9e94-59ac-11e4-acd8-00000aacb361&acdnat=1413955891_77158b95d9eb4f3e4942d81440455daa></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Neurophysin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|left|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone !! Secreted by ||Function
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine.
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===

[[File:Ratio of alpha & beta cells at different phases of fetal development.png|400px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref>

<ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates. <ref name= PMID>17237341<pubmed>17237341</pubmed></ref>
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells <ref name= PMID>22106406<pubmed>22106406</pubmed></ref>
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue. <ref name= PMID>17237341<pubmed>17237341</pubmed></ref>
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium. <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium <ref name= PMID>22106406<pubmed>22106406</pubmed></ref>
**Primordial follicle formation is the result of active mitosis of oogonia

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone). <ref><pubmed>8292535</pubmed></ref>

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref> Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref>

M. Møller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland, 2014, BioMed Research International, http://www.hindawi.com/journals/bmri/2014/868567/

[[IMAGE 8 http://www.hindawi.com/journals/bmri/2014/868567/fig2/]]

=References=

<references/>

2014 Group Project 6

2014-10-22T12:37:49Z

Z3418702:

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. however it also has a role in reproductive development. Recent findings have shown that the pineal gland does play an important role during fetal development through the production of it's primary hormone, melatonin.

[[File:Keith1902 fig167.jpg|300px|thumb| Image 1: schematic of a developing pineal gland in week 6 of gestation]]

Pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammilian fetus, intrinsic circadian rhythms are already established prior to birth. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || pinealocytes; The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement.

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum
*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis
*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

[[File:Fetal pineal gland 01.jpg|300px|thumb|Image 5: shows a fetal pineal gland at the end of the first trimester of development.]]

===Abnormalities===

* '''Pineal tumors'''
Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>

[[File:Pineal-body.jpg|250px|thumb| Image 6: Shows the location of the pineal gland in the adult brain.]]
''

[[File:Congenital hydrocephalus MRI02.jpg|250px|thumb|Image 7: Infant with obstructive congenital hydrocephalus]]
''

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

===Abnormalities===

Complications in development of these nuclei regions lead to disorders characteristic to those regions affected.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==

<pubmed>10.1016/j.acthis.2014.04.003</pubmed>

<pubmed>10.1371/journal.pone.0004815</pubmed>

<pubmed>10.1371/journal.pone.0004513</pubmed>

[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]

=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || Example
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|-
| Example || Example || Example || Example
|}

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://ac.els-cdn.com/S030100820900046X/1-s2.0-S030100820900046X-main.pdf?_tid=42bc9e94-59ac-11e4-acd8-00000aacb361&acdnat=1413955891_77158b95d9eb4f3e4942d81440455daa></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Neurophysin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|left|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone !! Secreted by ||Function
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine.
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===

[[File:Ratio of alpha & beta cells at different phases of fetal development.png|400px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref>

<ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates. <ref name= PMID>17237341<pubmed>17237341</pubmed></ref>
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue. <ref name= PMID>17237341<pubmed>17237341</pubmed></ref>
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone). <ref><pubmed>8292535</pubmed></ref>

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref> Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref>

M. Møller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland, 2014, BioMed Research International, http://www.hindawi.com/journals/bmri/2014/868567/

[[IMAGE 8 http://www.hindawi.com/journals/bmri/2014/868567/fig2/]]

=References=

<references/>

2014 Group Project 6

2014-10-22T12:26:12Z

Z3418702: /* Fetal development */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. however it also has a role in reproductive development. Recent findings have shown that the pineal gland does play an important role during fetal development through the production of it's primary hormone, melatonin.

[[File:Keith1902 fig167.jpg|300px|thumb| Image 1: schematic of a developing pineal gland in week 6 of gestation]]

Pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammilian fetus, intrinsic circadian rhythms are already established prior to birth. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || pinealocytes; The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement.

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum
*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis
*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

[[File:Fetal pineal gland 01.jpg|300px|thumb|Image 5: shows a fetal pineal gland at the end of the first trimester of development.]]

===Abnormalities===

* '''Pineal tumors'''
Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>

[[File:Pineal-body.jpg|250px|thumb| Image 6: Shows the location of the pineal gland in the adult brain.]]
''

[[File:Congenital hydrocephalus MRI02.jpg|250px|thumb|Image 7: Infant with obstructive congenital hydrocephalus]]
''

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

===Abnormalities===

Complications in development of these nuclei regions lead to disorders characteristic to those regions affected.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==

<pubmed>10.1016/j.acthis.2014.04.003</pubmed>

<pubmed>10.1371/journal.pone.0004815</pubmed>

<pubmed>10.1371/journal.pone.0004513</pubmed>

[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]

=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || Example
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|-
| Example || Example || Example || Example
|}

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://ac.els-cdn.com/S030100820900046X/1-s2.0-S030100820900046X-main.pdf?_tid=42bc9e94-59ac-11e4-acd8-00000aacb361&acdnat=1413955891_77158b95d9eb4f3e4942d81440455daa></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Neurophysin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|left|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone !! Secreted by ||Function
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine.
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===

[[File:Ratio of alpha & beta cells at different phases of fetal development.png|400px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref>

<ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates. <ref name= PMID>17237341<pubmed>17237341</pubmed></ref>
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue. <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium. <ref name= PMID17237341><pubmed>17237341</pubmed></ref>
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups. <ref name= PMID>22106406<pubmed>22106406</pubmed></ref>
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium <ref name= PMID>17237341<pubmed>17237341</pubmed></ref>
**Primordial follicle formation is the result of active mitosis of oogonia <ref name= PMID>22106406<pubmed>22106406</pubmed></ref>

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone). <ref><pubmed>8292535</pubmed></ref>

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref> Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref>

M. Møller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland, 2014, BioMed Research International, http://www.hindawi.com/journals/bmri/2014/868567/

[[IMAGE 8 http://www.hindawi.com/journals/bmri/2014/868567/fig2/]]

=References=

<references/>

2014 Group Project 6

2014-10-22T12:21:56Z

Z3418702: /* Fetal development */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. however it also has a role in reproductive development. Recent findings have shown that the pineal gland does play an important role during fetal development through the production of it's primary hormone, melatonin.

[[File:Keith1902 fig167.jpg|300px|thumb| Image 1: schematic of a developing pineal gland in week 6 of gestation]]

Pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammilian fetus, intrinsic circadian rhythms are already established prior to birth. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || pinealocytes; The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement.

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum
*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis
*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

[[File:Fetal pineal gland 01.jpg|300px|thumb|Image 5: shows a fetal pineal gland at the end of the first trimester of development.]]

===Abnormalities===

* '''Pineal tumors'''
Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>

[[File:Pineal-body.jpg|250px|thumb| Image 6: Shows the location of the pineal gland in the adult brain.]]
''

[[File:Congenital hydrocephalus MRI02.jpg|250px|thumb|Image 7: Infant with obstructive congenital hydrocephalus]]
''

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

===Abnormalities===

Complications in development of these nuclei regions lead to disorders characteristic to those regions affected.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==

<pubmed>10.1016/j.acthis.2014.04.003</pubmed>

<pubmed>10.1371/journal.pone.0004815</pubmed>

<pubmed>10.1371/journal.pone.0004513</pubmed>

[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]

=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || Example
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|-
| Example || Example || Example || Example
|}

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://ac.els-cdn.com/S030100820900046X/1-s2.0-S030100820900046X-main.pdf?_tid=42bc9e94-59ac-11e4-acd8-00000aacb361&acdnat=1413955891_77158b95d9eb4f3e4942d81440455daa></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Neurophysin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|left|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone !! Secreted by ||Function
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine.
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===

[[File:Ratio of alpha & beta cells at different phases of fetal development.png|400px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref>

<ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates. <ref name= PMID>17237341><pubmed>17237341</pubmed></ref>
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue. <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium. <ref name= PMID17237341><pubmed>17237341</pubmed></ref>
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups. <ref name= PMID>22106406<pubmed>22106406</pubmed></ref>
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium <ref name= PMID>17237341><pubmed>17237341</pubmed></ref>
**Primordial follicle formation is the result of active mitosis of oogonia <ref name= PMID>22106406<pubmed>22106406</pubmed></ref>

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone). <ref><pubmed>8292535</pubmed></ref>

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref> Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref>

M. Møller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland, 2014, BioMed Research International, http://www.hindawi.com/journals/bmri/2014/868567/

[[IMAGE 8 http://www.hindawi.com/journals/bmri/2014/868567/fig2/]]

=References=

<references/>

2014 Group Project 6

2014-10-22T12:17:48Z

Z3418702: /* Fetal development */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. however it also has a role in reproductive development. Recent findings have shown that the pineal gland does play an important role during fetal development through the production of it's primary hormone, melatonin.

[[File:Keith1902 fig167.jpg|300px|thumb| Image 1: schematic of a developing pineal gland in week 6 of gestation]]

Pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammilian fetus, intrinsic circadian rhythms are already established prior to birth. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || pinealocytes; The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement.

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum
*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis
*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

[[File:Fetal pineal gland 01.jpg|300px|thumb|Image 5: shows a fetal pineal gland at the end of the first trimester of development.]]

===Abnormalities===

* '''Pineal tumors'''
Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>

[[File:Pineal-body.jpg|250px|thumb| Image 6: Shows the location of the pineal gland in the adult brain.]]
''

[[File:Congenital hydrocephalus MRI02.jpg|250px|thumb|Image 7: Infant with obstructive congenital hydrocephalus]]
''

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

===Abnormalities===

Complications in development of these nuclei regions lead to disorders characteristic to those regions affected.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==

<pubmed>10.1016/j.acthis.2014.04.003</pubmed>

<pubmed>10.1371/journal.pone.0004815</pubmed>

<pubmed>10.1371/journal.pone.0004513</pubmed>

[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]

=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || Example
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|-
| Example || Example || Example || Example
|}

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://ac.els-cdn.com/S030100820900046X/1-s2.0-S030100820900046X-main.pdf?_tid=42bc9e94-59ac-11e4-acd8-00000aacb361&acdnat=1413955891_77158b95d9eb4f3e4942d81440455daa></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Neurophysin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|left|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone !! Secreted by ||Function
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine.
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===

[[File:Ratio of alpha & beta cells at different phases of fetal development.png|400px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref>

<ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

==Ovary==

===Fetal development===

'''Timeline'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates. <ref name= PMID17237341><pubmed>17237341</pubmed></ref>
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue. <ref name= PMID>7158813<pubmed>7158813</pubmed></ref>
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium. <ref name= PMID17237341><pubmed>17237341</pubmed></ref>
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups. <ref name= PMID>22106406<pubmed>22106406</pubmed></ref>
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium <ref name= PMID17237341><pubmed>17237341</pubmed></ref>
**Primordial follicle formation is the result of active mitosis of oogonia <ref name= PMID>22106406<pubmed>22106406</pubmed></ref>

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone). <ref><pubmed>8292535</pubmed></ref>

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref> Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref>

M. Møller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland, 2014, BioMed Research International, http://www.hindawi.com/journals/bmri/2014/868567/

[[IMAGE 8 http://www.hindawi.com/journals/bmri/2014/868567/fig2/]]

=References=

<references/>

2014 Group Project 6

2014-10-22T12:08:32Z

Z3418702: /* Abnormalities */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. however it also has a role in reproductive development. Recent findings have shown that the pineal gland does play an important role during fetal development through the production of it's primary hormone, melatonin.

[[File:Keith1902 fig167.jpg|300px|thumb| Image 1: schematic of a developing pineal gland in week 6 of gestation]]

Pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammilian fetus, intrinsic circadian rhythms are already established prior to birth. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || pinealocytes; The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement.

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum
*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis
*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

[[File:Fetal pineal gland 01.jpg|300px|thumb|Image 5: shows a fetal pineal gland at the end of the first trimester of development.]]

===Abnormalities===

* '''Pineal tumors'''
Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>

[[File:Pineal-body.jpg|250px|thumb| Image 6: Shows the location of the pineal gland in the adult brain.]]
''

[[File:Congenital hydrocephalus MRI02.jpg|250px|thumb|Image 7: Infant with obstructive congenital hydrocephalus]]
''

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

===Abnormalities===

Complications in development of these nuclei regions lead to disorders characteristic to those regions affected.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==

<pubmed>10.1016/j.acthis.2014.04.003</pubmed>

<pubmed>10.1371/journal.pone.0004815</pubmed>

<pubmed>10.1371/journal.pone.0004513</pubmed>

[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]

=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || Example
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|-
| Example || Example || Example || Example
|}

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://ac.els-cdn.com/S030100820900046X/1-s2.0-S030100820900046X-main.pdf?_tid=42bc9e94-59ac-11e4-acd8-00000aacb361&acdnat=1413955891_77158b95d9eb4f3e4942d81440455daa></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Neurophysin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|left|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone !! Secreted by ||Function
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine.
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===

[[File:Ratio of alpha & beta cells at different phases of fetal development.png|400px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref>

<ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

==Ovary==

===Fetal development===

'''Development overview:'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

'''References'''

<pubmed>17237341</pubmed>
<pubmed>7623307</pubmed>
<pubmed>7158813</pubmed>
<pubmed>22106406</pubmed>

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone). <ref><pubmed>8292535</pubmed></ref>

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref> There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Evain-Brion><Danielle Evain-Brion, Malassine Andre '’’Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#></ref>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref> Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref>

M. Møller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland, 2014, BioMed Research International, http://www.hindawi.com/journals/bmri/2014/868567/

[[IMAGE 8 http://www.hindawi.com/journals/bmri/2014/868567/fig2/]]

=References=

<references/>

2014 Group Project 6

2014-10-22T12:03:30Z

Z3418702: /* Abnormalities */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. however it also has a role in reproductive development. Recent findings have shown that the pineal gland does play an important role during fetal development through the production of it's primary hormone, melatonin.

[[File:Keith1902 fig167.jpg|300px|thumb| Image 1: schematic of a developing pineal gland in week 6 of gestation]]

Pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammilian fetus, intrinsic circadian rhythms are already established prior to birth. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || pinealocytes; The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement.

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum
*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis
*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

[[File:Fetal pineal gland 01.jpg|300px|thumb|Image 5: shows a fetal pineal gland at the end of the first trimester of development.]]

===Abnormalities===

* '''Pineal tumors'''
Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>

[[File:Pineal-body.jpg|250px|thumb| Image 6: Shows the location of the pineal gland in the adult brain.]]
''

[[File:Congenital hydrocephalus MRI02.jpg|250px|thumb|Image 7: Infant with obstructive congenital hydrocephalus]]
''

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

===Abnormalities===

Complications in development of these nuclei regions lead to disorders characteristic to those regions affected.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==

<pubmed>10.1016/j.acthis.2014.04.003</pubmed>

<pubmed>10.1371/journal.pone.0004815</pubmed>

<pubmed>10.1371/journal.pone.0004513</pubmed>

[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]

=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || Example
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|-
| Example || Example || Example || Example
|}

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://ac.els-cdn.com/S030100820900046X/1-s2.0-S030100820900046X-main.pdf?_tid=42bc9e94-59ac-11e4-acd8-00000aacb361&acdnat=1413955891_77158b95d9eb4f3e4942d81440455daa></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Neurophysin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|left|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone !! Secreted by ||Function
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine.
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===

[[File:Ratio of alpha & beta cells at different phases of fetal development.png|400px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref>

<ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

==Ovary==

===Fetal development===

'''Development overview:'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

'''References'''

<pubmed>17237341</pubmed>
<pubmed>7623307</pubmed>
<pubmed>7158813</pubmed>
<pubmed>22106406</pubmed>

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone). <ref><pubmed>8292535</pubmed></ref>

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. <ref><pubmed>25071761</pubmed></ref>. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. <ref name= Elosha Eiland>Elosha Eiland, Chike Nzerue, Marquetta Faulkner Pre-eclampsia 2012. Journal of Pregnancy: 2012, Volume 2012; 7 pages, http://www.hindawi.com/journals/jp/2012/586578/</ref>. There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref name= Elosha Eiland>Elosha Eiland, Chike Nzerue, Marquetta Faulkner Pre-eclampsia 2012. Journal of Pregnancy: 2012, Volume 2012; 7 pages, http://www.hindawi.com/journals/jp/2012/586578/</ref>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref> Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref>

M. Møller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland, 2014, BioMed Research International, http://www.hindawi.com/journals/bmri/2014/868567/

[[IMAGE 8 http://www.hindawi.com/journals/bmri/2014/868567/fig2/]]

=References=

<references/>

2014 Group Project 6

2014-10-22T11:51:16Z

Z3418702: /* Fetal development */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. however it also has a role in reproductive development. Recent findings have shown that the pineal gland does play an important role during fetal development through the production of it's primary hormone, melatonin.

[[File:Keith1902 fig167.jpg|300px|thumb| Image 1: schematic of a developing pineal gland in week 6 of gestation]]

Pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammilian fetus, intrinsic circadian rhythms are already established prior to birth. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || pinealocytes; The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement.

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum
*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis
*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

[[File:Fetal pineal gland 01.jpg|300px|thumb|Image 5: shows a fetal pineal gland at the end of the first trimester of development.]]

===Abnormalities===

* '''Pineal tumors'''
Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>

[[File:Pineal-body.jpg|250px|thumb| Image 6: Shows the location of the pineal gland in the adult brain.]]
''

[[File:Congenital hydrocephalus MRI02.jpg|250px|thumb|Image 7: Infant with obstructive congenital hydrocephalus]]
''

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

===Abnormalities===

Complications in development of these nuclei regions lead to disorders characteristic to those regions affected.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==

<pubmed>10.1016/j.acthis.2014.04.003</pubmed>

<pubmed>10.1371/journal.pone.0004815</pubmed>

<pubmed>10.1371/journal.pone.0004513</pubmed>

[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]

=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || Example
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|-
| Example || Example || Example || Example
|}

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://ac.els-cdn.com/S030100820900046X/1-s2.0-S030100820900046X-main.pdf?_tid=42bc9e94-59ac-11e4-acd8-00000aacb361&acdnat=1413955891_77158b95d9eb4f3e4942d81440455daa></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Neurophysin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|left|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone !! Secreted by ||Function
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine.
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===

[[File:Ratio of alpha & beta cells at different phases of fetal development.png|400px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref>

<ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

==Ovary==

===Fetal development===

'''Development overview:'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

'''References'''

<pubmed>17237341</pubmed>
<pubmed>7623307</pubmed>
<pubmed>7158813</pubmed>
<pubmed>22106406</pubmed>

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone). <ref><pubmed>8292535</pubmed></ref>

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1769902><pubmed>1260417</pubmed></ref>. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref>Elosha Eiland, Chike Nzerue, Marquetta Faulkner '''Pre-eclampsia 2012'''. Journal of Pregnancy: 2012, Volume 2012; 7 pages, http://www.hindawi.com/journals/jp/2012/586578/</ref>

<pubmed>10419690</pubmed>

<pubmed>7673080</pubmed>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref> Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref>

M. Møller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland, 2014, BioMed Research International, http://www.hindawi.com/journals/bmri/2014/868567/

[[IMAGE 8 http://www.hindawi.com/journals/bmri/2014/868567/fig2/]]

=References=

<references/>

2014 Group Project 6

2014-10-22T11:45:40Z

Z3418702: /* Fetal development */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. however it also has a role in reproductive development. Recent findings have shown that the pineal gland does play an important role during fetal development through the production of it's primary hormone, melatonin.

[[File:Keith1902 fig167.jpg|300px|thumb| Image 1: schematic of a developing pineal gland in week 6 of gestation]]

Pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammilian fetus, intrinsic circadian rhythms are already established prior to birth. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || pinealocytes; The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement.

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum
*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis
*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

[[File:Fetal pineal gland 01.jpg|300px|thumb|Image 5: shows a fetal pineal gland at the end of the first trimester of development.]]

===Abnormalities===

* '''Pineal tumors'''
Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>

[[File:Pineal-body.jpg|250px|thumb| Image 6: Shows the location of the pineal gland in the adult brain.]]
''

[[File:Congenital hydrocephalus MRI02.jpg|250px|thumb|Image 7: Infant with obstructive congenital hydrocephalus]]
''

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process<ref name= PMID7643957><pubmed>7643957</pubmed></ref>. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally<ref name= PMID11954031><pubmed>11954031</pubmed></ref>.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d)<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

* Week 28: Sexual differentiation of hypothalamus is complete

===Abnormalities===

Complications in development of these nuclei regions lead to disorders characteristic to those regions affected.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==

<pubmed>10.1016/j.acthis.2014.04.003</pubmed>

<pubmed>10.1371/journal.pone.0004815</pubmed>

<pubmed>10.1371/journal.pone.0004513</pubmed>

[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]

=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || Example
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|-
| Example || Example || Example || Example
|}

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://ac.els-cdn.com/S030100820900046X/1-s2.0-S030100820900046X-main.pdf?_tid=42bc9e94-59ac-11e4-acd8-00000aacb361&acdnat=1413955891_77158b95d9eb4f3e4942d81440455daa></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Neurophysin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|left|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone !! Secreted by ||Function
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine.
|}

<ref><pubmed>22808183</pubmed></ref> <ref><pubmed>21881196</pubmed></ref> <ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===

[[File:Ratio of alpha & beta cells at different phases of fetal development.png|400px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref>

<ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

==Ovary==

===Fetal development===

'''Development overview:'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

'''References'''

<pubmed>17237341</pubmed>
<pubmed>7623307</pubmed>
<pubmed>7158813</pubmed>
<pubmed>22106406</pubmed>

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemoral nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone).

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28- Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12. <ref name= PMID10510117><pubmed>10510117</pubmed></ref>

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the fallopian tubes and uterus in the developing male. <ref name= PMID1260417><pubmed>1260417</pubmed></ref>

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. <ref name= PMID1260417><pubmed>1260417</pubmed></ref> 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref>Elosha Eiland, Chike Nzerue, Marquetta Faulkner '''Pre-eclampsia 2012'''. Journal of Pregnancy: 2012, Volume 2012; 7 pages, http://www.hindawi.com/journals/jp/2012/586578/</ref>

<pubmed>10419690</pubmed>

<pubmed>7673080</pubmed>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref> Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref>

M. Møller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland, 2014, BioMed Research International, http://www.hindawi.com/journals/bmri/2014/868567/

[[IMAGE 8 http://www.hindawi.com/journals/bmri/2014/868567/fig2/]]

=References=

<references/>

2014 Group Project 6

2014-10-22T11:05:53Z

Z3418702:

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. however it also has a role in reproductive development. Recent findings have shown that the pineal gland does play an important role during fetal development through the production of it's primary hormone, melatonin.

[[File:Keith1902 fig167.jpg|300px|thumb| Image 1: schematic of a developing pineal gland in week 6 of gestation]]

Pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammilian fetus, intrinsic circadian rhythms are already established prior to birth. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || pinealocytes; The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement.

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum
*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis
*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

[[File:Fetal pineal gland 01.jpg|300px|thumb|Image 5: shows a fetal pineal gland at the end of the first trimester of development.]]

===Abnormalities===

* '''Pineal tumors'''
Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>

[[File:Pineal-body.jpg|250px|thumb| Image 6: Shows the location of the pineal gland in the adult brain.]]
''

[[File:Congenital hydrocephalus MRI02.jpg|250px|thumb|Image 7: Infant with obstructive congenital hydrocephalus]]
''

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<pubmed>7643957</pubmed>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex.<pubmed>11954031</pubmed>

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process.<pubmed>7643957</pubmed> Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally.<pubmed>11954031</pubmed>

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumen (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d).

* Week 28: Sexual differentiation of hypothalamus is complete [2]

===Abnormalities===

Complications in development of these nuclei regions lead to disorders characteristic to those regions affected.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==

<pubmed>10.1016/j.acthis.2014.04.003</pubmed>

<pubmed>10.1371/journal.pone.0004815</pubmed>

<pubmed>10.1371/journal.pone.0004513</pubmed>

[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]

=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || Example
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|-
| Example || Example || Example || Example
|}

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://ac.els-cdn.com/S030100820900046X/1-s2.0-S030100820900046X-main.pdf?_tid=42bc9e94-59ac-11e4-acd8-00000aacb361&acdnat=1413955891_77158b95d9eb4f3e4942d81440455daa></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Neurophysin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|left|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone !! Secreted by ||Function
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine.
|}

<ref><pubmed>22808183</pubmed></ref>

<ref><pubmed>21881196</pubmed></ref>

<ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===

[[File:Ratio of alpha & beta cells at different phases of fetal development.png|400px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref>

<ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

==Ovary==

===Fetal development===

'''Development overview:'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

'''References'''

<pubmed>17237341</pubmed>
<pubmed>7623307</pubmed>
<pubmed>7158813</pubmed>
<pubmed>22106406</pubmed>

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemroal nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone).

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28: Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally.

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks.

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12.

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the falltopian tubes and uterus in the developing male.

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

'''References'''

<pubmed>PMC1260417</pubmed>
<pubmed>6846859</pubmed>
<pubmed>8292535</pubmed>
<pubmed>10510117</pubmed>
[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466385578-2 Moore: The Developing Human, 9th ed. Chapter 12]

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref>Elosha Eiland, Chike Nzerue, Marquetta Faulkner '''Pre-eclampsia 2012'''. Journal of Pregnancy: 2012, Volume 2012; 7 pages, http://www.hindawi.com/journals/jp/2012/586578/</ref>

<pubmed>10419690</pubmed>

<pubmed>7673080</pubmed>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref> Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref>

M. Møller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland, 2014, BioMed Research International, http://www.hindawi.com/journals/bmri/2014/868567/

[[IMAGE 8 http://www.hindawi.com/journals/bmri/2014/868567/fig2/]]

=References=

<references/>

2014 Group Project 6

2014-10-22T11:01:25Z

Z3418702:

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. however it also has a role in reproductive development. Recent findings have shown that the pineal gland does play an important role during fetal development through the production of it's primary hormone, melatonin.

[[File:Keith1902 fig167.jpg|300px|thumb| Image 1: schematic of a developing pineal gland in week 6 of gestation]]

Pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammilian fetus, intrinsic circadian rhythms are already established prior to birth. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || pinealocytes; The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement.

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum
*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis
*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

[[File:Fetal pineal gland 01.jpg|300px|thumb|Image 5: shows a fetal pineal gland at the end of the first trimester of development.]]

===Abnormalities===

* '''Pineal tumors'''
Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>

[[File:Pineal-body.jpg|250px|thumb| Image 6: Shows the location of the pineal gland in the adult brain.]]
''

[[File:Congenital hydrocephalus MRI02.jpg|250px|thumb|Image 7: Infant with obstructive congenital hydrocephalus]]
''

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

'''Recent Findings'''

*'''Neuropeptide Y in the Adult and Fetal Human Pineal Gland'''


M. Møller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland, 2014, BioMed Research International, http://www.hindawi.com/journals/bmri/2014/868567/

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref> Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref>

[[IMAGE 8 http://www.hindawi.com/journals/bmri/2014/868567/fig2/]]

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour<pubmed>7643957</pubmed>. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex.<pubmed>11954031</pubmed>

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process.<pubmed>7643957</pubmed> Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally.<pubmed>11954031</pubmed>

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.<ref name=Rizzoti>K. Rizzoti, R. Lovell-Badge, ‘Regenerative Medicine: organ recital in a dish’, Nature:2011, http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumen (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d).

* Week 28: Sexual differentiation of hypothalamus is complete [2]

===Abnormalities===

Complications in development of these nuclei regions lead to disorders characteristic to those regions affected.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==

<pubmed>10.1016/j.acthis.2014.04.003</pubmed>

<pubmed>10.1371/journal.pone.0004815</pubmed>

<pubmed>10.1371/journal.pone.0004513</pubmed>

[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]

=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || Example
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|-
| Example || Example || Example || Example
|}

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://ac.els-cdn.com/S030100820900046X/1-s2.0-S030100820900046X-main.pdf?_tid=42bc9e94-59ac-11e4-acd8-00000aacb361&acdnat=1413955891_77158b95d9eb4f3e4942d81440455daa></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Neurophysin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|left|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

'''Table of hormones produced by the Parathyroid gland:'''

{| class="wikitable"
|-
! Hormone !! Secreted by ||Function
|-
| Parathyroid hormone || Chief cells || Regulates calcium levels in the blood by bone resorption releasing calcium in the blood when calcium levels are low. It also increases the ability to absorb calcium from food sources as well as aid the kidney in retaining calcium that would otherwise be lost in the urine.
|}

<ref><pubmed>22808183</pubmed></ref>

<ref><pubmed>21881196</pubmed></ref>

<ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic epithelial cell development and function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

'''Table of hormones produced by the thymus gland:'''

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===

[[File:Ratio of alpha & beta cells at different phases of fetal development.png|400px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

'''Table of hormones produced by the pancreas:'''

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref>

<ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

==Ovary==

===Fetal development===

'''Development overview:'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

'''References'''

<pubmed>17237341</pubmed>
<pubmed>7623307</pubmed>
<pubmed>7158813</pubmed>
<pubmed>22106406</pubmed>

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemroal nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone).

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28: Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally.

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks.

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12.

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the falltopian tubes and uterus in the developing male.

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

'''References'''

<pubmed>PMC1260417</pubmed>
<pubmed>6846859</pubmed>
<pubmed>8292535</pubmed>
<pubmed>10510117</pubmed>
[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466385578-2 Moore: The Developing Human, 9th ed. Chapter 12]

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref>Elosha Eiland, Chike Nzerue, Marquetta Faulkner '''Pre-eclampsia 2012'''. Journal of Pregnancy: 2012, Volume 2012; 7 pages, http://www.hindawi.com/journals/jp/2012/586578/</ref>

<pubmed>10419690</pubmed>

<pubmed>7673080</pubmed>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

''''Neuropeptide Y in the Adult and Fetal Human Pineal Gland''''

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref> Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref>

M. Møller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland, 2014, BioMed Research International, http://www.hindawi.com/journals/bmri/2014/868567/

=References=

<references/>

2014 Group Project 6

2014-10-22T10:51:55Z

Z3418702: /* Recent Findings */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

==Pineal gland==
===Fetal development===

The pineal gland is part of the epithalamus, located in the diencephalon. Like the other neurosecretory glands, it is formed by the neuroectoderm of the neural plate. Its primary function is to regulate circadian cycles postnatally through its secretion of melatonin. however it also has a role in reproductive development. Recent findings have shown that the pineal gland does play an important role during fetal development through the production of it's primary hormone, melatonin.

[[File:Keith1902 fig167.jpg|300px|thumb| Image 1: schematic of a developing pineal gland in week 6 of gestation]]

Pineal and placental melatonin have a regulatory effect on maintaining homeostasis in the uterus as well as fetal maturation and reproductive development. The suprachiasmatic nuclei in the hypothalamus acts as the central pacemaker for melatonin production. As the two circuits are already interconnected in the mammilian fetus, intrinsic circadian rhythms are already established prior to birth. However it is not until after birth that the infant produces significant levels of melatonin to sustain cyclic rhythms associated with day/night and light exposure. During early fetal development before the pineal gland is developed, it is the maternal melatonin that exerts its effect on development after crossing the placental barrier.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

In adults, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone (LH) and follicle-stimulating (FSH) hormone.

''Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and fetal development
''
{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Melatonin || pinealocytes; The synthesis of melatonin is regulated by a dense network of sympathetic nerve fibers located in the autonomic superior cervical ganglia. The activity of the pineal gland is inhibited by stimulation from the photoreceptors of the retina. This light sensitivity causes melatonin to be produced only in low light or darkness and thus the pineal gland is active most at night. || Contributes to the development of gametes and also helps in maintaining uterine homeostasis through its antioxidant properties.
Melatonin also inhibits the secretion of gonadotrophin releasing hormone (GnRH) until puberty. This mechanism is in place to protect premature initiation of pubertal pubertal activation of reproductive functions that are dependent on plasma gonadotropin levels. <ref name= PMID15119946
><pubmed>15119946
</pubmed></ref>
|}

'''Timeline''':

'''How far has the pineal gland developed by week 8 of gestation?'''

*Week 5 - The pineal gland primarily begins its development after the diencephalon is differentiated from the prosenecephalon and forms on the diencephalic roof of the third ventricle.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>
*Week 6 - A number of hollow diverticula begin formation in a clustered arrangement.

'''Fetal Stage of Pineal Development - from week 8 of gestation onwards:
'''
*Week 8 - Proliferation of cells begins and these cells form the walls of the diverticulum
*Week 9-11 - On the caudal roof of the hollow diverticulum, cells continue proliferation and begin to differentiate into pinealoctyes to form the solid epiphysis
*Week 15-17 - By the second trimester small amounts of melatonin production by the fetal pinealocytes has begun, however the pineal gland is not fully functional till post-natally.<ref name=Bruce>J.N. Bruce, E.M. Housepian, ‘Pineal Tumors’, Medscape:2013, http://emedicine.medscape.com/article/249945-overview</ref>

[[File:Fetal pineal gland 01.jpg|300px|thumb|Image 5: shows a fetal pineal gland at the end of the first trimester of development.]]

===Abnormalities===

* '''Pineal tumors'''
Tumors of the pineal region during fetal development are generally a result of displaced embryonic tissue or chromosomal abnormalities. Fetal pineal tumors are characterized by pigmented (melanin) epithelial cells, small undifferentiated cells, and a fibrovascular stroma. <ref name= PMID851944><pubmed>851944</pubmed></ref> Depending on the size and type of tumor the fetus may survive till birth however infants with pineal gland tumor experience abnormal puberty development and have a high probability of developing hydrocephalus. As the pineal gland sits just superior to the cerebral aqueduct (shown in image 7 below), pineal tumors can compress this aqueduct, resulting a build up of pressure of CSF in the brain, a condition known as obstructive congenital hydrocephalus.<ref name= PMID1652883><pubmed>1652883</pubmed></ref>

[[File:Pineal-body.jpg|250px|thumb| Image 6: Shows the location of the pineal gland in the adult brain.]]
''

[[File:Congenital hydrocephalus MRI02.jpg|250px|thumb|Image 7: Infant with obstructive congenital hydrocephalus]]
''

*'''Pineal hypoplasia'''

Pineal gland hypoplasia is the underdevelopment of the pineal gland resulting in the production of an insufficient level of melatonin. As discussed, fetal melatonin plays a crucial role in the growth and development of important organs and functions so a lack of melatonin particularly during the second and third trimesters of gestation may have detrimental results on the health of the fetus. Studies have suggested a possible link between neonatal pineal gland hypoplasia and sudden infant death syndrome (SIDS) with almost 95% of deaths occurring within 6 months of birth <ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>. Oxidative stress of the brain, as melatonin's hydroxyl radical reducing ability is lost is suggested as a possible cause of SIDS. Additionally, the loss of melatonin's antioxidant activity during the fetal period is proposed as another factor to consider in development of atherosclerotic vascular disease later on in adult life.<ref name=Maurizi>C.P. Maurizi, 'Could exogenous melatonin prevent sudden infant death syndrome?', Medical Hypotheses:1997, 49(5); 425-427, http://www.sciencedirect.com/science/article/pii/S0306987797900918</ref>

'''Recent Findings'''

*'''Neuropeptide Y in the Adult and Fetal Human Pineal Gland'''


M. Møller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland, 2014, BioMed Research International, http://www.hindawi.com/journals/bmri/2014/868567/

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be closely linked to noradrenaline in sympathetic nerve terminals. In a number of studies over the years the peptide has been detected in sympathetic nerve fibers innervating the pineal gland in many mammalian species. The investigation sets out to identify the presence of neuropeptide Y in the adult and fetal human pineal gland. Neuropeptide Y-containing nerve fibers were confirmed as being present in the adult pineal and could be also be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is markedly different from studies of rodents models, where the innervation starts postnatally which is an important factor to consider when applying animal models to research of the human pineal gland.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref> Another variation from rodent models were the numerous NPY-immunoreactive nerve fibers endowed with large boutons en passage (shown in image 8) that were present in a perifollicular position unlike in rodents where immunoreactive nerve fibers penetrate and densely innervate the follicle itself.<ref name =Moller>M. Moller, P. Phansuwan-Pujito & C. Badiu, Neuropeptide Y in the Adult and Fetal Human Pineal Gland.’ BioMed Research International:2014, http://www.hindawi.com/journals/bmri/2014/868567/</ref>

[[IMAGE 8 http://www.hindawi.com/journals/bmri/2014/868567/fig2/]]

==Hypothalamus==

===Fetal development===
The hypothalamus is part of the diencephalon and plays an important role in the maintenance of homeostasis and the driving of motivated behaviours. Distinct nuclei in the hypothalamus secrete specific hormones that function to regulate thirst, hunger, thermoregulation, circadian rhythms, reproduction and defensive behaviour. The hypothalamus is involved in two main signaling pathways or "axes":

[[File:Hypothalamus small.gif|thumb|location of hypothalamus in the adult brain]]

*HPA (Hyothalamus-Pituitary-Adrenal)

[[File: diagram

*HPG (Hypothalamus-Pituitary-Gonad).

[[File: diagram

''Table 1. Summarises the hormones released by the human hypothalamus and their role in embryonic and foetal development
''
{| class="wikitable"
|-
! Hormone !! Abbreviation !! Produced by !! Function
|-
| Vasopressin || ADH || Paraventricular and Magnocellullar neurosecretory neurons || Example
|-
| Oxytocin || || Magnocellular neurosecretory cells || Example
|-
| Thyrotropin-releasing hormone (Prolactin-releasing hormone) || TRH, TRF, or PRH || Parvocellular neurosecretory neurons || Example
|-
| Dopamine (Prolactin-inhibiting hormone) || DA or PIH || Dopamine neurons of the arcuate nucleus || Example
|-
| Growth hormone-releasing hormone || GHRH || Neuroendocrine neurons of the Arcuate nucleus || Example
|-
| Corticotropin-releasing hormone || CRH or CRF || Parvocellular neurosecretory neurons || Example
|-
| Gonadotropin-releasing hormone || GnRH or LHRH || Neuroendocrine cells of the Preoptic area || Example
|-
| Somatostatin (growth hormone-inhibiting hormone) || SS, GHIH, or SRIF || Neuroendocrine cells of the Periventricular nucleus || Example
|}

[[File:Adult human hypothalamus 04.jpg|250x|thumb|Figure 1. illustrates the location of nuclei in the hypothalamus]]

[[File:Stage 22 image 057.jpg|250x|thumb|Image 1. Histological cross-section of stage 22 embryo]]

The sexually dimorphic nucleus (SDN, intermediate nucleus) is twice as large in young male adults as in young females. Immediately after birth, only 20% of the SDN cell number is present. During the post-natal period up till two to four years of age cell numbers continue to increase rapidly and equally in both sexes. Past this age, cell numbers start to decrease in girls and this is the point of physiological differentiation in sex.

Neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. These hormones play an important role in foetal development up till and including the birth process. Foetal oxytocin may initiate or accelerate the course of labor whereas foetal vasopressin plays a role in the adaptation to stress caused by the birth process, by redistribution of the foetal blood flow.

[[File:Hypothalamus histology 001.jpg|250x|thumb|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]

'''Timeline'''

'''How far has the hypothalamus gland developed by week 8 of gestation?
'''

* Week 5: The development of the CNS has reached the five vesicle stage, where the prosencephalon divides into the diencephalon which is more caudal and in which the hypothalamus is formed, and the telencephalon located more rostrally.

* Week 6: During pre-foetal phase when the head folds begin to take shape, a thickening called the hypophyseal placode (shown in pink in Image 3.a) forms at the midline of the rostral ectoderm, adjacent to the area where the hypothalamus will form on the neural fold.

'''Fetal Stage of hypothalamus development - from week 8 of gestation onwards:
'''

* Week 9: The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch (shown in Image 3.b).

* Week 18: By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumean (shown in Image 3.c).

* Weeks 19-27 Subsequent cell proliferation and differentiation of the intermediate zone allows for the formation of the primordial hypothalamus. The posterior lobe and the pituitary stalk connects the gland to the hypothalamus (shown in Image 3.d).

* Week 28: Sexual differentiation of hypothalamus is complete [2]

===Abnormalities===

Complications in development of these nuclei regions lead to disorders characteristic to those regions affected.

'''Recent Findings'''

A. Peruffoa, M. Giacomellob, S. Montellia, M. Panina, B. Cozzia, 2013, Expression profile of the pore-forming subunits α1A and α1D in the foetal bovine hypothalamus: A mammal with a long gestation. ''Neuroscience Letters.'' Vol. 556, pp 124–128http://www.sciencedirect.com/science/article/pii/S0304394013009300

E. Muraa, M. Sumana, S. Montellia, A. Peruffoa, B. Cozzia, V. Farinab, 2013, Characterization of an established endothelial cell line from primary cultures of fetal sheep hypothalamus. ''Research in Veterinary Science''. Vol. 94:3, pp 388–393http://www.sciencedirect.com/science/article/pii/S0034528812003256

'''References'''

Rizzoti, K. & Lovell-Badge, R. Development of the pituitary and hypothalamus, Regenerative Medicine: Organ recital in a dish. ''Nature'' Vol. 480, pp 44–46http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

[2] http://www.nature.com/nature/journal/v480/n7375/box/480044a_BX1.html

<pubmed>11954031</pubmed>

<pubmed>7643957</pubmed>

Y. Koutcherov, J.K, Mai, G. Paxinos Hypothalamus of the human fetus, Journal of Chemical Neuroanatomy, 26:4, pp 253–270

==Pituitary gland==

<pubmed>10.1016/j.acthis.2014.04.003</pubmed>

<pubmed>10.1371/journal.pone.0004815</pubmed>

<pubmed>10.1371/journal.pone.0004513</pubmed>

[[File:Pituitary Development.jpg|300px|right|thumb|Anatomy of Human Pituitary Gland]]

=== Fetal development ===
Pre-fetal stage of pituitary gland development:
*Formation of Rathke's Pouch by week 4-5 of gestation
** At the point of the oropharynx in the primitive gut there is an invagination of the ectoderm and this is the origin of the anterior pituitary lobe
** Eventually Rathke's pouch is pinched off and separates from the oral cavity. All the Rathke cells need to migrate down to sit in the sphenoid bone of the skull. Any cells left behind can becomes tumours.
* The posterior pituitary is formed from the downward outgrowth of the third ventricle forming a median eminence
* Together with cells from the mammillary body, a neural stalk forms giving the neurohypophysis <ref name =Nussey S, Whitehead S>< Nussey S, Whitehead S, Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 7, The pituitary gland</ref>

The following table summarises the hormones secreted by particular cells of the anterior pituitary during the fetal period. The cell types that are present are somatotrophs and gonadotrophs which secrete hormones that cause cell proliferation and activation of gonadal cells respectively. <ref name =M A Japón, M Rubinstein and M J Low><M A Japón, M Rubinstein and M J Low, 1994, '''In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development''', Journal of Histochemistry and Cytochemistry; 8(42), 1117-1125, http://jhc.sagepub.com/content/42/8/1117.long></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Cell Type !! Function
|-
| Growth Hormone || GH || Somatotroph || Example
|-
| Luteinizing Hormone || LH || Gonadotroph ||
* Males: stimulates Leydig cells to produce testosterone
* Females: stimulates ovary to produce estrogen
|-
| Follicle Stimulating Hormone || FSH || Gonadotroph ||
* Males: stimulates Sertoli cells to produce androgen-binding protein --> in turn stimulating spermatogenesis
* Females: stimulates ovary to produce progesterone during luteal phase and estradiol during follicular phase
|-
| Example || Example || Example || Example
|}

The following table summarises the hormones secreted by cells of the posterior pituitary which is also known as the neurohypophysis. These hormones contribute to proper brain and central nervous system development. Their neuronal origin are from the hypothalamus and run into the pituitary gland where they are released to take action on various systems and organs. <ref name =Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd>Heon-Jin Lee, Abbe H. Macbeth, Jerome H. Pagani, W. Scott Young 3rd, 2009, '''Oxytocin: The great facilitator of life''', Progress in Neurobiology; 88, pp127-151, http://ac.els-cdn.com/S030100820900046X/1-s2.0-S030100820900046X-main.pdf?_tid=42bc9e94-59ac-11e4-acd8-00000aacb361&acdnat=1413955891_77158b95d9eb4f3e4942d81440455daa></ref>

{| class="wikitable"
|-
! Hormone !! Abbreviation !! Neuronal Origin !! Function
|-
| Neurophysin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Oxytocin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|-
| Vasopressin || Example || Hypothalamic paraventricular and supraoptic nuclei || Example
|}

===Abnormalities===

==Thyroid==

===Fetal development===

The functional unit of the thyroid gland is the follicle hence it is necessary to understand how the follicle develops in order to understand the important function of this gland. There are progenitor cells in the anterior endoderm that are specified thyroid progenitor cells and contribute to thyroid organogenesis. The proliferation of these cells results in the formation of a placode along the midline of the pharyngeal floor, just below the future tongue. The left and right lobes of the thyroid gland start off as single structures: buds of endoderm surrounded by mesoderm.

The mammalian thyroid gland is unique in the sense that there is a second endocrine cell called the parafollicular C cell. The progenitor cell for this enters the gland at the stage where there is a fusion between the thyroid progenitor proper and the ultimobranchial bodies. The ultimobranchial bodies arise bilaterally in the most inferior pharyngeal arches and are important in the final organ.

Eventually the midline primordium stretches laterally to reach the ultimobranchial bodies and there is a bilobation event resulting in the recognisable bilobed thyroid gland. <ref name="PMID24290349"><pubmed>24290349</pubmed></ref>

[[File:ThyroidDevelopment.png|300px|right|thumb|This image summarises the endodermal and mesodermal cellular contribution to the formation of the thyroid gland]]

How far has the thyroid gland developed by week 8 of gestation?
* Formation of medial anlage (foregut endoderm origin) and 2 lateral anlages (neuroectodermal origin and derivatives of the 4th pharyngeal pouch)
* Budding of ventral pharynx to form thryoid primoridum
* Fusion event of the median anlage with the lateral angales (ultimobranchial bodies) followed by migration of median anlage to it's final pretracheal location
* Sonic hedgehog plays a role in directing correct lobulation of the median anlage into two lobes connected by an isthmus

Fetal Stage of Thyroid Development - from week 8 of gestation onwards:
* Terminal differentiation of thyroid gland occurs from week 7 to 8 of embryo gestation and involves the onset of the gland function
* '''Pre-colloid''' stage is week 7-9 and is where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* '''The beginning colloid''' stage is week 10-11 and involves the polarisation of the TFC precursors.
**This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* '''Progressive follicular''' growth occurs in week 12
** At this point the fetal thyroid gland gains the ability to accumulate iodine and begin thyroid hormone synthesis <ref name="PMID10.1016/j.beem.2013.08.005"><pubmed>10.1016/j.beem.2013.08.005</pubmed></ref>

===Abnormalities===

==Parathyroid gland==

===Fetal development===

[[File:Parathyroid position in mouse embryo.jpg |420px|thumb|left|This image shows the position of the parathyroid in the embryo]]

The parathyroid gland is an important endocrine organ that plays an essential role in regulating extracellular calcium homeostasis and hence serves many physiological processes that involve muscle contraction, blood coagulation, and synaptic activity.<ref><pubmed>7835276</pubmed></ref> They detect changes fluctuations of calcium levels in blood which is detected by the calcium-sensing receptor (CasR). This process then stimulates the secretion of parathyroid hormone (PTH) which releases calcium from internal stores such as bone in order to counterbalance any extremities.<ref><pubmed>21904825</pubmed></ref>

'''Timeline'''

'''How far has the parathyroid gland developed by week 8 of gestation?'''

* Week 5 - the Parathyroid glands arise from the endodermal third and fourth pharyngeal pouches in cranial portions.
* Cranial third pharyngeal pouches form inferior parathyroids and cranial fourth pharyngeal pouches forms superior parathyroids.
* Pouches are bilateral and hence form four parathyroids
* Parathyroid gland development cannot occur without the transcription factor encoded by Gcm-2.
* Week 6 - diverticulum extends from the pouch which is hollow at first and then solidifies with dorsal cell proliferation

'''Fetal Stage of parathyroid Development - from week 8 of gestation onwards:'''

* Active transport regulates high fetal calcium concentrations levels (11-12 mg/dl) from maternal serum via an ATP-dependent calcium pump situated across the syncytiotrophoblast.
* The middle portion of the parathormone related peptide (PTHrP) is secreted via the fetal parathyroid and activates the placental calcium pump.
* Sections 1-34 of the Parathormone (PTH) or PTHrP stimulate PTH/PTHrP receptors causing a fetal skeletal calcium flux. This subsequently leads to the excretion of calcium via the fetal renal 1, 25 (OH) 2 D production also occurs which serves to increase the calcium transport occurring in carrying mothers. Calcium reabsorption from amniotic fluid also takes place through this action.

{| class="wikitable"
|-
! Hormone !! Secreted by ||Function
|-
| Parathyroid hormone || Chief cells || Regulate calcium levels in the blood.
|}

<ref><pubmed>22808183</pubmed></ref>

<ref><pubmed>21881196</pubmed></ref>

<ref><pubmed>7344740</pubmed></ref>

===Abnormalities===

==Thymus==
===Fetal development===

[[File:Thymic Epithelial Cell Development and Function.png|300px|thumb|right|This image shows thymic Epithelial Cell Development and Function]]

The thymus gland is an organ that belongs to two systems of the human body which are the endocrine and immune system. It consists of two distinct but identical lobes which are both encased by a tough and fibrous capsule. Within each lobe are two layers which is the cortex that is superficial to the deep medullary layer in the tissue. Epithelial tissues and lymphatic tissues including macrophages make up majority of the thymus.
In terms of its role in the endocrine system, it is responsible for the development of hormone called thymosin. This hormone is needed to tranform white blood cells (lymphocytes) that pass through the thymus gland into T cells, thereby forming the link to aid the immune system. This important gland is located in the upper anterior chest straight behind the sternum and in between the lungs. Other associated hormones of the thymus gland include thymopoietin hormones, thymic humoral factors , thymostimulin and factor thymic serum.

'''Timeline'''

'''How far has the thymus gland developed by week 8 of gestation?'''

* It originates primarily from the third pharyngeal pouch.
* The primordia is initially divided into the thymic and parathyroid domains which are both encased in a neural crest-derived mesenchymal capsule.
* Week 7 - mid week 8, the thymic part of the primordium migrates ventrally and attach at the pericardium

'''Fetal Stage of thymus Development - from week 8 of gestation onwards:'''

* Week 8 - the thymic primordium contains undifferentiated epithelial cells
* Week 8-9, intrathymic cell types such as mesenchymal, vascular and lymphoid cells begin to develop
* Weeks 8-16 - Medullary development occurs from week 8 and distinct cortical and medullary compartments are formed by week 16
*Weeks 14- 16, mature lymphocytes begin to migrate from the thymus to seed the peripheral immune system

{| class="wikitable"
|-
! Hormone !! Function
|-
| Thymosin || Transforms white blood cells (lymphocytes) that pass through the thymus gland into T cells.
|-
| Thymopoietin hormones || Belongs to the polypeptide hormone family and is secreted by thymic epithelial cells. These cause differentiation of precursor lymphocytes into thymocytes.
|-
| Thymic humoral factors || Increase the number of T-cells which enhances cell-mediated immunity.
|-
| Thymostimulin || Stimulates T cell proliferation and differentiation
|-
| Factor thymic serum || Involved in T-cell differentiation.
|}

<ref><pubmed>512270</pubmed></ref>

===Abnormalities===

==Pancreas==
===Fetal development===

[[File:Ratio of alpha & beta cells at different phases of fetal development.png|400px|thumb|right|This image shows the ratio of alpha & beta cells at different phases of fetal development]]

The pancreas is an endocrine organ situated well into the abdomen. It has a dual role and is responsible for digestion via its exocrine function and regulating blood sugar levels through its endocrine function.

'''Timeline'''

'''How far has the pancreas developed by week 8 of gestation?'''

* Week 4 – Pancreatic development begin at the septum transversum as dorsal and ventral endodermic buds forms. Dorsal and ventral mesentery are formed by splanchnic mesoderm.
* Dorsal buds normally develop first and form majority of the pancreas whereas the ventral bud only forms a portion of the head and uncinated process of the pancreas.
* Week 6-8 – These buds migrate and fuse from duodenum growth and rotation. In order to make space for the pancreas, the duodenum rotates in to C-shaped conformation. The ventral bud also situates itself dorsally behind the dorsal bud.
* Pancreatic bud endoderm in particularly the ventral bud duct and distal part of dorsal bud differentiates into islet cell clusters which form acini and exocrine ducts needed for exocrine function. At the periphery of these exocrine clusters form the pancreatic islets which serve endocrine function.

'''Fetal Stage of pancreas Development - from week 8 of gestation onwards:'''

* Week 7 to 20 – Maternal insulin increases exponentially as fetus grows.
* Week 10 – The first cells to differentiate are glucagon (alpha) cells followed by somatostatin (delta), and insulin (beta) cells. Fetus begins to secrete insulin
* Week 15 – Levels of glucagon become noticeable in fetal plasma

Hormones:

{| class="wikitable"
|-
! Hormone !! Produced by !! Function
|-
| Glucagon || Alpha cells of the islets of Langerhans || Elevates blood sugar levels when blood sugar levels are low.
|-
| Insulin || Beta cells of the islets of Langerhans || Reduces blood sugar levels when blood sugar levels are too high. It also converts glucose into glycogen to store in the liver for future source of energy.
|-
| Somatostatin || Delta cells of pancreas || Inhibits the secretion of other pancreatic hormones such as insulin and glucagon.
|-
| Pancreatic Polypeptide || Pancreatic polypeptide cells || Prevents secretion of somatostatin from the pancreas.
|}

<ref><pubmed>22761699</pubmed></ref>

<ref><pubmed>19893748</pubmed></ref>

===Abnormalities===

==Adrenal gland==
===Fetal development===
[[File:Fetal adrenal gland.png|300px|right|thumb|This image shows a transverse MRI and cross-sectional anatomy of the fetal adrenal gland at gestational weeks 24 (A) and 36 (B)]]

The characteristic zonation of the adult adrenal gland is absent in the fetal gland which is instead arranged in an inner fetal zone and an outer definitive (adult) zone. The inner zone atrophies following birth and contains steroid-secreting cell characteristics while the adult zone contains cells that resemble those present in the adult zona glomerulosa. The adrenal medulla is not a distinct, recogniseable zone during gestation, except for scattered chromaffin cells present throughout the cortex in small clusters. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>

'''Timeline'''

*Week 6: Adrenal gland is present at the cranial side of the mesonephric kidney as a condensed mass of coelomic epithelium, appearing as large cells like those of older fetus fetal zones <ref><pubmed>24116052</pubmed></ref>
*Week 8: The definitive or adult zone is formed by a second round of epithelial cell proliferation, where a cap is formed by a narrow rim of cells over the fetal zone. Around the central part of the gland can be seen clumps of medullary cells and neural elements infiltrate it through the vascular pole. <ref name= PMID7011178><pubmed>7011178</pubmed></ref>
*Weeks 10-20: Rapid growth of the adrenal gland by increased size of the fetal and definitive zones from about 100mg in week 10 to 2g at week 20. Appearance of vasculature and sinusoidal plexuses and increase of medullary cells.
*Weeks 20-30: Gland size doubles with adult-type zonation appearing in the definitive zone around week 30. The zona glomerulosa is delineated by connective tissue stroma and cells appear arranged in a columnar fashion in the developing zona fasciculata. <ref><pubmed>PMC3365797</pubmed></ref>
*Week 30-term: Weight of fetal adrenal gland doubles and 80% of the gland’s volume is made up of the fetal zone.

The zona reticularis develops post-natally in year 3 of development, unlike the two other cortical zones.

''Table of hormones produced by the adrenal gland:''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Aldosterone || Mineralocorticoid || Zona glomerulosa || Works on the kidneys, sweat and salivary glands to maintain normal extracellular concentrations of Na+ and K+ and so extracellular volume
|-
| Cortisol || Glucocorticoid || Zona fasciculata || Restoration of homeostasis following stress; suppresses immune system, increases blood sugar by gluconeogenesis, helps metabolise protein, carbohydrates and fat, activates the CNS. In the foetus/neonate, causes organ development and maturation e.g. lungs. There are high levels of cortisol at childbirth
|-
| Adrenaline and noradrenaline || Catecholamine || Adrenal medulla || Increase; heart rate contractility, vasoconstriction, ventilation, lipolysis, glycogenolysis and decrease gut motility. Work with the sympathetic nervous system to regulate 'flight or fight' response.
|-

|}

===Abnormalities===

*Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH) is the collective term for several autosomal recessive endocrine disorders caused by impaired adrenal steroidogenesis due to mutated steroidogenic enzymes. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>.These mutations inhibit proper synthesis of cortisol from cholesterol, which in turn leads to excess adrenal growth and hyperplasia due to adrenocorticotropic hormone (ACTH) hypersecretion by the pituitary gland. The most commonly affected enzyme (90% of cases) is a 21-hydroxylase deficiency (21-OHD) which clinically presents as cortisol and aldosterone production deficiency. <ref><pubmed>10748766</pubmed></ref> CAH has both a classic (severe) and non-classic (mild) forms with the classic form affecting 1 in 10 000 and non-classic form affecting many more. Females affected by the classic form undergo pre-natal virilisation and have genital ambiguity at birth, whereas virilisation does not occur in the mild form. <ref><pubmed>15838095</pubmed></ref> Males tend to appear asymptomatic but can exhibit oligozoospermia. <ref name= PMID25227725><pubmed>25227725</pubmed></ref>

==Ovary==

===Fetal development===

'''Development overview:'''

*Weeks 8 and 9:
**Week 8- Change to the gonad’s internal structure; it can be identified as an ovary now. Cortical differentiation occurs from the cranial pole to the lower pole. The dense central core spans the mesovarian into the mesonephric organ in a caudal direction, resembling the ‘rete blastema’ which differentiates.
**Inner ovary is composed of the indifferent gonad’s disintegrating blastema, surrounded by a thick blastemal layer, giving the ovary a non-uniform crenated surface
**Ovarian tissue has a cortical region and a central medullary region with an irregular demarcation. The cortex encloses primordial germ cells (PGCs) between somatic cells and medulla has a reticulum of somatic cells
*Weeks 10 to 12:
**Growth and lobulation of the cortex. Supporting cells grow peripherally and segment the cortex into irregular globules containing rapidly multiplying germ cells and light and dark somatic supporting cells, interspersed with connective tissue.
**Week 12- Cortex is penetrated by dark supporting cells, giving the superficial epithelium a ‘dark’ appearance, amongst the original ‘light’ cells of the coelomic epithelium.
**Oogonia appear in clusters, primordial cells still dominate and oocytes in the premeiotic period exist in small groups.
**Medulla contains less densely-packed globules, mainly oogonia
*Weeks 14 to 28:
**In mid-gestation- Depletion of the germ cells by apoptosis, highest from weeks 14-28 and decreasing closer to birth
**Week 16- Cortical cords break up into primordial follicles (cell clusters) housing an oogonium each from a PGC. Follicles enclosed by monolayer of flat follicular cells from surface epithelium
**Primordial follicle formation is the result of active mitosis of oogonia

'''References'''

<pubmed>17237341</pubmed>
<pubmed>7623307</pubmed>
<pubmed>7158813</pubmed>
<pubmed>22106406</pubmed>

===Abnormalities===

==Testis==
===Fetal development===

'''Testis migration'''

The human testes early in fetal development begins at the abdominal cavity and migrates progressively towards the scrotum. This migration is caused by both mechanical determinants (genitofemroal nerve development, cremasteric muscle and epipdydmis development and gubernaculum development) and hormonal regulators (influences of gonadotropin and androgens such as testosterone).

*Gestational week 17- Migration begins
*By Week 23- Approximately 90% of testes still remain in the abdomen, with migration accelerating in weeks 24-26.
*Weeks 26-28: Arrival of testes in the inguinal canal within a couple of days through the deep inguinal ring, helped by the gubernaculum
*Week 28- Passing of testes through superficial inguinal ring to scrotum. Is usually completed in 3-4 weeks but can occasionally take up to 12 weeks post-natally.

By 22 weeks, 10% of testes are descending and this changes to 50% by 25 weeks, 75% by 26 weeks and 80% by 32 weeks.

'''Testes development'''

By week 8, masculine differentiation is induced in the mesonephric duct and external genitalis. This is caused by the interstitial cells (Leydig cells) in the mesenchymal tissue surrounding seminiferous tubules beginning secretion of the androgens androstenedione and testosterone, which is stimulated by human chorionic gonadotropin, peaking in weeks 8-12.

Antimulleran hormone, AMH (or mullerian-inhibiting substance, MIS), a glycoprotein, is produced by sustentacular (Sertoli) cells. This causes mesonephric duct suppression to prevent formation of the falltopian tubes and uterus in the developing male.

The majority of the seminiferous epithelium of the fetal testes is composed of Sertoli cells and this epithelium later flattens forming external mesothelium. 15-20 mesonephric tubules are continuous with the rete testes later form efferent ductules, connected to the mesonephric duct to form the epididymis duct.

'''References'''

<pubmed>PMC1260417</pubmed>
<pubmed>6846859</pubmed>
<pubmed>8292535</pubmed>
<pubmed>10510117</pubmed>
[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466385578-2 Moore: The Developing Human, 9th ed. Chapter 12]

===Abnormalities===

==Placenta==
===Fetal development===

The placenta is a highly specialised, transient and autonomous organ of pregnancy that plays an essential role in normal fetal development. Its functions include; the transfer of nutrients and oxygen to the developing fetus, removal of carbon dioxide, release of hormones into the materno-fetal circulation, and exchange of metabolic products to protect the fetus from infection, maternal diseases and xenobiotic molecules <ref name= Evain-Brion>Danielle Evain-Brion, Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>

'''How far has the placenta developed by week 8 of gestation?'''

*Days 6-7- Placental development starts with invasion of the endometrium by the blastocyst. The outer cover of the blastocyst (trophectoderm) and vascular components are allantois-derived. The trophoblast differentiates into the syncytiotrophoblast following invasion of the uterine mucosa. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>
*Days 8-13- The chorionic villi are developed, arising in the syncytiotrophoblast and composed of trabeculae and lacunae. The primary chorionic plate surrounds this system
*From day 12- Establishment of the primitive maternal circulation from trophoblastic shell cels. Mesenchymal cells invade the primary villi to form secondary villi.
*By the end of week 5- The intra-placental fetal circulation is fully established. <ref name=PMID17624715><pubmed>17624715</pubmed></ref>

'''Fetal stage of placental development - from week 8 of gestation onwards:'''

*Until beginning of week 8- Chorionic villi cover the whole chorionic sac
*After week 8- Syncytiotrophoblast production of placental progesterone is enough to maintain pregnancy in spite of ovariectomy
*By about week 10- The fetal-placental maternal circulation is fully established. Exchange of blood to the embryo occurs via diffusion until week 10. Peak levels of hCG are produced in maternal serum. <ref name= Evain-Brion>Danielle Evain-Brion , Malassine Andre '''Human placenta as an endocrine organ'''. Proceedings of the 34th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism: 2003, 13;S37-S37, http://www.sciencedirect.com/science/article/pii/S1096637403000534#</ref>
*Until week 18- Rapid growth in the size and thickness of the placenta. Fully mature placenta comprises one sixth of the fetal weight.
*Week 22-24- Decidua capillaris degenerates due to lack of blood supply. There is fusion of the chorionic sac with the decidua parietalis <ref name=PMID17624715><pubmed>17624715</pubmed></ref>.

[[File:Placenta schematic.jpg|300px|right|thumb|This schematic shows the different components of the mature human placenta]]

Both fetal tissue from the chorionic sac and endometrium-derived maternal tissue contribute to form the utero-placental unit.The two parts of the mature placenta are; the chorionic plate (fetal part) containing chorionic blood vessels and the basal plate (maternal part) formed by the decidua basalis. In between these two parts is the intervillous space containing the villous structures of fetal blood vessels. Maternal-fetal exchange occurs at the terminal regions of these chorionic villi. <ref>Neil M Gude, Claire T Roberts, Bill Kalionis, Roger G King '''Growth and function of the normal human placenta'''. Thrombosis Research: 2004, 114(5-6); 397-407, http://www.sciencedirect.com/science/article/pii/S0049384804003421#</ref>

'''Table of hormones produced by the placenta:'''

{| class="wikitable"
|-
! Hormone !! Type !! Produced in !! Function
|-
| Human chorionic gonadotropin (hCG) || Glycoprotein || Trophectoderm || Maintenance of the corpus luteum in first 8 weeks of pregnancy, enhancement of spontaneous cytotrophoblast differentiation into syncytiotrophoblasts
|-
| Placental Growth Hormone (PGH) || Trophoblast hormone || Syncytiotrophoblast layer || Controls levels of maternal insulin-like growth factor I (IGF-I), prevents variations in maternal blood glucose and allows maternal pregnancy metabolic adaptation
|-
| Progesterone and estrogens || Steroid hormones || Syncytiotrophoblast || Maintenance of pregnancy even after ovary removal
|-

|}

===Abnormalities===

* '''Pre-eclampsia'''
Pre-eclampsia is a common abnormality of human pregnancy characterised by significant proteinuria (presence of protein in the urine) and systemic hypertension. There occurs significantly reduced uteroplacental blood flow due to; angiogenic and antiangiogenic factors, hypoxia and inflammation. Its incidence is about 2-8% of pregnancies, usually in women after gestational week 20 and it contributes to high maternal morbidity rates worldwide, with 50 000 deaths each year. There is evidence that the cause of pre-eclampsia is a combination of an abnormal inflammatory response cascade, damage to endothelial cells and impaired immune function of the maternal placenta. Soluble factors are released into the maternal placenta from the ischemic placenta, leading to significant endothelial dysfunction. It has also been suggested that abnormal differentiation and invasion of cytotrophoblasts into the uterus have an aetiological role, as does failure of arterial remodelling in the uterus. <ref>Elosha Eiland, Chike Nzerue, Marquetta Faulkner '''Pre-eclampsia 2012'''. Journal of Pregnancy: 2012, Volume 2012; 7 pages, http://www.hindawi.com/journals/jp/2012/586578/</ref>

<pubmed>10419690</pubmed>

<pubmed>7673080</pubmed>

==Recent Findings==

'''''Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis'''''

The third pharyngeal pouch endoderm is the origin of development for both the thymus and parathyroid glands. After the formation of the third pouch, there is are two noticeable domains by embryonic day 10.5 of mouse development. The parathyroid domain is located in the anterior-dorsal aspect of the pouch and is further recognised by lack of glial cells (Gcm2) expression needed for parathyroid organogenesis. On the posterior-ventral aspect of the pouch is the domain for the thymus where Bmp4 and Foxn1 expression characterise thymic differentiation and survival. Once these subdivisions are established, separation occurs between the two organs from the pharynx and migration towards to the anterior-ventral mediastinum occurs through apoptosis. Although, apoptotic signals Pax1, Pax9 and Hoxa3 have been shown to cause this separation, it is not fully understood how this separation actually occurs.

There has been research showing that fibroblast growth factor (FGF) signalling controls the organogenesis processes of the pharyngeal region. Mutations in FGF signalling are known to impact the thymus and parathyroid organs by causing aplasia or hypoplasia. FGF feedback antagonists of the sprouty gene family are key regulators in the formation of the mentioned organs. Localised inhibition of FGF signalling by sprouty proteins has shown a favourable result in the organogenesis of the thymus and parathyroid organs by inducing differentiating factors Gcm2, Bmp4 and Foxn1 expression in the third pouch as well as apoptosis.

In this study, mouse embryos are used to show how FGF feedback antagonists that inhibit FGF can result in proper organogenesis of the thymus and parathyroid organs. Mouse embryos that contained the two FGF feedback antagonists, Spry1 and Spry2 and those that lacked them were studied. Data revealed that there was increased FGF signalling when Spry1 and Spry2 were not present, thereby leading to lack of Gcm2 expression and hence parathyroid hypoplasia. Similarly, levels of Bmp4 expression was also decreased in the thymus domain when Spry1 and Spry2 were absent, leading to thymus hypoplasia. It was also found that FGF Ligands were upregulated in the third pouch which resulted in the deletion of the sprouty gene. Consequently, the markers needed for thymus and parathyroid organogenesis was altered and apoptosis was inhibited leaving the organs still attached to the pharynx. Therefore, it is established that localised inhibition of FGF signalling present in the third pharyngeal pouch is vital for the organogenesis of the thymus and parathyroid organs.

<ref><pubmed>22912418</pubmed></ref>

'''''Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life'''''

This article investigates the role of Follicle Stimulating Hormone (FSH) on Sertoli cell development in the fetal and post-natal period using a mouse model. Although the role of FSH is clear in the rat, there remains a lack of understanding in the mouse. They confirm the current understanding that Sertoli cell formation occurs during fetal life at 11.5-12.5 days post conception (dpc) in the mouse and proliferation is fully established at day 17. In Rathke’s pouch, detection of the alpha-gycoprotein subunit occurs 11.5dpc and the number of Sertoli cells reduces between 18.5dpc and birth in hypogonadal mice.

Through performing morphometric studies on FSH+/+, FSH+/- and FSH-/- mice, at days 0, 6, 8 and 10, the study found that FSH-/- mice contained 22% less fetal Sertoli cells than wild-type mice. Assessment of the transcription factor GATA-6 was performed to establish the expression of Sertoli cell specific markers and the study concluded that GATA-6 was expressed less than wild-type mice by 30% compared to FSH-R-/- mice. Also, a molecule involved in testis organogenesis, Claudin 11, was found to be expressed at significantly less levels in FSH-/- testes.The expression of testicular steroidogenesis genes such as P450scc and StAR revealed that these molecules had greater expression in FSH-/- mice than control ones.

The study thus provides light on the fact that Sertoli cells have a paracrine mechanism of action to regulate FSH-R function of Leydig cells in the fetal period and that FSH controls Sertoli cell development in both the mouse and rat.

<ref><pubmed>23300903</pubmed></ref>

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