Embryology - User contributions [en-gb]

User:Z3418837

2014-10-29T00:39:04Z

Z3418837: /* Lab Attendance */

==Lab Attendance==
*Lab 1 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 6 August 2014 (EST)
*Lab 2 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:11, 13 August 2014 (EST)
*Lab 3 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:12, 20 August 2014 (EST)
*Lab 4 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:55, 27 August 2014 (EST)
*Lab 5 -- Absent
*Lab 6 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:44, 10 September 2014 (EST)
*Lab 7 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:40, 17 September 2014 (EST)
*Lab 8 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:11, 24 September 2014 (EST)
*Lab 9 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:08, 8 October 2014 (EST)
*Lab 10 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 15 October 2014 (EST)
*Lab 11 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 22 October 2014 (EST)
*Lab 12 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:38, 29 October 2014 (EST)

==Individual Assessment==

==='''Lab 1'''===

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 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>

'''Your Lab assessment now requires you to find a 2 recent research references on fertilisation or in vitro fertilisation. Paste each reference on your page, as shown in the class. Write below each reference a brief summary of the research article methods and findings. The summary for each need not be more than 3-4 paragraphs in length. This will need to be completed before next weeks laboratory'''.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/25077107 PMID25077107]

<pubmed>25077107</pubmed>

This study was designed to investigate whether the levels of vitamin D is an imperative factor when it comes to the clinical success of implantation and pregnancy rates in infertile women via invitro fertilisation.

'''Method summary'''

A cohort of 173 women were evaluated and selected for this study based on their age, follicle-stimulating hormone levels and their consent to undergo invitro fertilisation. The following study was conducted at Mount Sinai Hospital where proper facilities were available. Blood tests were then conducted for each patient to determine their levels of Vitamin D via the serum 25-hydroxy-vitamin D (25[OH]D) levels. Following the results of the blood test, the cohort were then categorised into two groups which was either vitamin D sufficient (≥ 75 nmol/L) or insufficient ( < 75 nmol/L) based on serum levels of 25(OH)D.

Each patient then underwent IVF cycles whereby standard agonists that contained the active ingredient 0.5 mg/d of buserelin acetate in conjunction with cetrolix acetate as the standard antagonist were used to control the length of the luteal phase and estradiol levels. The length and dose of the treatment were varied for each individual based on their demographic data. Serial transvaginal ultrasonograpy and serum lutenizing hormone assays were then used to check ovarian response. When 3 or more dominant follicles (≥ 17 mm) were produced, 10 000 IU of human chorionic gonadotropin was added to enhance nuclear maturation. Oocyte retrieval was then conducted via transvaginal ultrasound whereby it was fertilised and the resulting embryo was transferred 3-5 days post-fertilisation. The rate of pregnancy per IVF cycle was then used as the primary outcome for this study whereby the visibility of the intrauterine sac of the embryo determined implantation.

'''Results summary'''

Out of the 182 patients that participated in this study, it was found that only 173 patients could continue on with this trial as they satisfied the criteria, however only 162 were fit for embryo transfer. Following the results from the blood test, it was noted that 53.8% of patients had insufficient levels of 25(OH)D and 45.1% had sufficient amounts. It was discovered that 71.8% of those with sufficient levels of 25(OH)D were more likely to proceed with embryo transfer on day 5 compared to 58.9% (p = 0.054) of those assigned to the ‘insufficient 25(OH)D’ category. Other factors such as oocyte retrieval and frequency of intracytoplasmic sperm injection were fairly similar in both groups. The study revealed that there was a higher clinical pregnancy rate per IVF cycle for those assigned to the sufficient 25(OH)D level category by 52.5% compared to those with insufficient amounts of 25(OH)D which was 34.7% (p < 0.001). Similarly, there was a significant clinical pregnancy rate per embryo transfer of 54.7% in comparison to 37.9% in woman belonging to the sufficient and insufficient category respectively. It was also noted that the implantation rate was greater in the sufficient category compared to the insufficient group, however the difference was only minimal (p= 0.6). Overall, the results suggest that serum 25(OH)D levels may be a predictor of clinical pregnancy.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/24672163 PMID24672163]

<pubmed>24672163</pubmed>

The process of achieving pregnancy via invitro fertilisation needs to be monitored and controlled with respect to the demographics of the individual in order to achieve a successful outcome. This study focuses on predicting the value of β-human chorionic gonadotrophin (β-HCG) that can lead to clinical success.

'''Method summary'''

Data analysis was taken from 171 female patients using the statistical package for social sciences program whereby all IVF cycles were monitored. The cycles that showed fresh multi-cell embryos (day 3) or blastocysts (day 5) were deemed fit for the trial and were the ones that were further used in this study. Serum β-HCG concentrations were then taken 14 days after the embryo was transferred whereby a second test was done on day 16 only if the first test revealed a positive β-HCG result. This was done to predict values that could enable doctors to evaluate a healthy intrauterine pregnancy or a problematic ectopic pregnancy. After 6-7 weeks of pregnancy, ultrasounds were conducted to check cardiac activity as well as the amount of gestational sacs. This was then repeated at 12 weeks of pregnancy to ensure there was no chance of abortion.

A continuing pregnancy was defined as one that continued for at least 12 weeks of gestation and showed signs of proper cardiac function. On the other hand, those pregnancies that were abnormal had dropped levels of β-HCG concentrations and led to empty gestational sacs that showed no embryonic cardiac function. As a measuring tool for detecting levels of β-HCG, Chemiluminescent microparticle immunoassays were used whereby the measuring range established was between 0.0-15,000 mIU/mL. HCG levels above 10 IU/L signified early pregnancy.

'''Results Summary'''

Out of the 171 patients that participated in this study, only 139 were included due to the missing data on the levels of β-HCG concentrations at day 14 and 16 post embryonic transfer. In total there were 39 abnormal pregnancies that involved ectopic pregnancy, abortions and biochemical pregnancies (sufficient HCG levels detected but no visible gestational sac). Overall the patients were categorised into two groups which were patients with ‘ongoing pregnancy’ (n=100) and ‘without ongoing pregnancy’ (n=39). The Mann-Whitney test (statistical testing) was then used to compare the levels of β-HCG levels in both groups. It was found that the group with ongoing pregnancy had a median serum β-HCG level of 600 mIU/ml, whereas the other group had a median serum β-HCG level of 178 mIU/ml. This indicated a significant difference of P < 0.05 when comparing the two groups. It was also found that when serum β-HCG levels reached 347 mIU/ml, there was a 73.6% chance that the pregnancy was ongoing. Furthermore, there was no definite correlation established between age and the rate of ongoing pregnancy as both categories had patients of similar age groups with a combined range of 23-41 year old patients. Overall, the study revealed that early serum β-HCG is a potential predictor of successful outcomes in invitro fertilisation.

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 19:11, 6 October 2014 (EST) These are relevant references and your descriptions/abstracts are good (5/5).

===Lab 2===

[[File:Phase-contrast images of embryos at different developmental stages via neogenin expression.png|300px]]

Phase-contrast images of embryos at different developmental stages via neogenin expression.<ref><pubmed>25013897</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0101989 PLos One]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:17, 21 August 2014 (EST) This is all correct. The image is very large (4.8 MB), perhaps a small version could have been uploaded. You can adjust the resolution and size in most image editing programs. (5/5)

<references/>

===Lab 3===

'''Parathyroid gland'''

<pubmed>22808183</pubmed>
<pubmed>22649358</pubmed>
<pubmed>21881196</pubmed>
<pubmed>21904825</pubmed>

'''Thymus'''

<pubmed>21733645</pubmed>
<pubmed>20836742</pubmed>
<pubmed>21263742</pubmed>
<pubmed>512270</pubmed>

'''Pancreas'''

<pubmed>22761699</pubmed>
<pubmed>22893718</pubmed>
<pubmed>24496309</pubmed>
<pubmed>24595965</pubmed>
<pubmed>23822675</pubmed>
<pubmed>22968764</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===

'''1. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

'''Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1'''

Glioblastoma multiforme (GBM) is known to belong to a very life threatening form of brain cancer. Research is currently focused on finding treatments regarding such abnormalities, such as the application of neuronal stem cells in reducing the population of tumours, however there were many problems that occurred with such treatment. Recently, Human umbilical cord blood derived stem cells (hUCBSC) has been extensively used as they are useful mesenchymal stem cells that are easy to isolate and are more available. GBM is caused by the overexpression of cyclin D1 and its subsequent binding to Cdk 4/Cdk 6 which defines the rate limiting step required for the cell to progress further on to the cell cycle from the G1 phase. In order to stop this over expression, scientists have used hUCBSC to inhibit the cell from progressing on with the cell cycle.

When (hUCBSC) were cultured with U251 and 5310 cells, flow cytometry technology revealed that the cells underwent G1 arrest showing an increase in the G0-G1/S phase ratio. There was also a 54% reduction in levels of cyclin D1 when hUCBSC was cultured with U251 in comparison to the control. Immunoprecipiation revealed that hUCBSC treated cells when immuno blotted with Cdk 4 and Cdk 6 antibodies, down regulated expression of both Cdk 4 and Cdk 6. Western blot also showed the same down regulating pattern of the individual expression and genes which confirmed that there was cell cycle arrest, thus preventing tumours from forming.

As such, this study helps researchers to grasp the foundation of using hUCBSC as a treatment for glioblastoma and to further build on such research. Since it is evident that hUCBSC is effective in reducing cyclin D1 expression; analysing glioblastomal hierarchy will aid in providing the missing links needed to create the clinical treatment.

<pubmed>21455311</pubmed>

'''2. There are a number of developmental vascular "shunts" present in the embryo, that are closed postnatally. Identify these shunts and their anatomical location.'''

Three major vascular shunts include:

• '''Ductus venosus''' - is a shunt of oxygenated blood from umbilical vein to IVC, bypassing the liver. The ductus venosus constricts and closes soon after birth and becomes the ligamentum venosum

• '''Foramen ovale''' - is a flap valve in the atrial septum between the right and left atrium that shunts highly oxygenated blood . The remnant of the foramen ovale is known as the fossa ovalis.

• '''Ductus arteriosus''' - is a shunt from the descending aorta to the left pulmonary artery near the bifurcation of the pulmonary trunk. Permanent closure takes 4-6 weeks by fibrosis, and the remnant is referred to as the ligamentum arteriosum.

===Lab 5===

'''Select an abnormality of either gastrointestinal or respiratory development and write a brief description of developmental causes(s) for this abnormality. Your answer should be added to your own student page, be brief (2-3 paragraphs) and referenced.'''

'''Midgut volvulus'''

The embryonic development of the midgut has a number of steps which ensures its proper formation. These include the viability of the superior mesenteric artery to divide the midgut into the cephalad (pre-arterial region) and caudad (post-arterial region). <ref><pubmed>15378215</pubmed></ref>During the fourth gestational week, the gastrointestinal system is composed of a centrally positioned linear tube in the abdomen. At approximately 6 weeks of gestational age, the midgut undergoes a process of U-shaped herniation causing the two portions of the midguts to face the opposite directions in relation to the superior mesenteric artery. From this moment, a number of rotation events occur to ensure the complete development of the gastrointestinal tract as it becomes set in the posterior abdominal wall.<ref><pubmed>7277164</pubmed></ref>

In some cases malrotations can occur during the developmental process of the midgut which involves the complete twisting of the midgut in relation to the axis of the superior mesenteric artery. In extreme cases this can lead to midgut volvulus which results in a narrowed mesenteric base that can obstruct the passage of blood and lead to tissue necrosis. Other complications resulting from midgut volvulus include intestinal ischaemia, peritonitis, mucosal necrosis and sepsis which can eventually lead to death if left untreated. <ref><pubmed>14655161</pubmed></ref>

Malrotation is known to occur within 1 in 500 live births and out of those who develop midgut volvusos, 68-71% are neonates. <ref><pubmed>22217896</pubmed></ref>Although the actual cause of malrotation is unknown, researchers have made links to congenital syndromes such as Down syndrome and the VACTERL. It is also hypothesized that any embryonic interference during the normal patterns of rotation and fetal development can lead to midgut volvulus. Treatment of midgut volvulus is dependent on when the disease is diagnosed. <ref><pubmed>18800265</pubmed></ref>Normally a sigmoidoscopy is carried out as well as the Ladd procedure to resect dead gastrointestinal tissues. Transduodenal bands of ladd may also be divided to widen the mesenteric pedicle and prevent obstruction of blood flow. <ref><pubmed>22208840</pubmed></ref>Overall, research is still being conducted on the specific causes of malrotation and other numerous treatments.

<references/>

===Lab 6===

Group work

===Lab 7===

'''1.Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

'''Novel genes upregulated when NOTCH signaling is disrupted during hypothalamic development.'''

It is known that the hypothalamus first develops from the ventral region of the diencephalon and signaling mechanisms such as the sonic hedgehog and bone morphogenic protein pathways are responsible for pattern arrangement. Neurogenesis is the key process required to ensure proper hypothalamus development which relies on many signaling pathways to produce neurons and glia. The Notch signaling pathway is currently known to inhibit neuronal differentiation and preserve neural progenitor identity. As a result of various studies and research, the combined theory has been implemented in this study to determine the effect of downregulating Notch signaling pathways in its effect on hypothalamic development.

Results show that when Notch signaling is inactivated, novel genes such as Dll1, Hes5, Hey1 and Ascl1 are upregulated in the rostral hypothalamus, subsequently leading to the early formation of hypothalamic neurons. This is also seen when embryos that are treated with DAPT (a chemical which inhibits cell differentiation mechanisms regulated by the Notch pathway) had an overexpression of cells differentiated into neurons in a clustered formation. This was compared to the control embryos which had differentiated cells in a scattered arrangement. As such, this research showed that Notch is a powerful signaling mechanism that is used to inhibit cell differentiation in order to control the number of cells differentiated into neurons or glia. This modulating ability of the Notch pathway is imperative in the early developing hypothalamus as it controls expression of cells and hence prevents any form of defects that can be harmful both prenatally and postnatally. Further research needs to be conducted on the Notch pathway to provide procedures where its mechanism can be used to resolve defects in the embryo and hence ensure proper hypothalamic development.

<pubmed>24360028</pubmed>

'''2.Identify the embryonic layers and tissues that contribute to the developing teeth.'''

'''Odontoblasts''' - neural crest-derived mesenchymal cells which establish the outer dental pulp. It differentiates via the enamel epithelium and releases dentin from dentinogenesis.

'''Ameloblasts''' - are derived from oral epithelium tissue of ectodermal origin and make up the inner enamel. They make pre-ameloblasts and produce enamel.

'''Periodontal ligament''' – is comprised of connective tissues which holds the tooth in place in the alveolar bone. It also encloses the cementum coating of the tooth root.

===Lab 8===

'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

'''Embryonic development of the ovary'''

The Gonads are known to be formed from the combination of primitive germ cells, adjacent mesenchyme and the mesothelium of the posterior abdominal wall. It isn’t until fifth week of embryonic development that the formation of Gonads occurs. The primordial germ cells first migrate from the embryonic yolk sac towards the hindgut along the dorsal mesentery. These cells then travel to the mesenchyme forming genital ridges positioned medially to the mesonephros by the sixth week of development. Coelomic epithelium and the mesonephros cells also proliferate at this stage. These cells then incorporate into the primary sex cords in which the process is driven by the genes stella, fragilis, and BMP-4 before the seventh week of embryonic development.<ref><pubmed>23409002</pubmed></ref>

The gonads are known to be indifferent until the sixth embryonic week as the gonads appear the same, however sex differentiation based on sex chromosomes determine the sex of the Gonad (XX for female and XY for males). The indifferent gonads are situated well inside the Wolffian body and are comprised of an inner medulla and outer cortex which contains precursors for ovarian stroma and parenchyma respectively.<ref><pubmed>3712511</pubmed></ref> In embryos consisting of XX sex chromosomes, the cortex of the indifferent gonad differentiates into an ovary meanwhile the medulla regresses by week eight of embryonic development. However, the sex cords leads to the formation of rete ovarii which is a complex of tubules and cords that arises from the mesonephros.

Another important event that occurs during the sixth week of development is the formation of the mullerian ducts which are responsible for female gonad formation and prevention of male gonad development. The established XX genotype of the female embryo prevents testosterone from being produced and hence causes the regression of the mesonephric duct since this form is only needed for male gonad expression. Also since there is no production of anti-mullarian hormone, the paramesonephric duct is able to be maintained driving female gonad expression. As of 10 weeks of development, ovaries first become recognizable and the growth of female external genitalia begins to occur.

[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]

<references/>

''' 2.Include an image from the historic genital embryology section of the online notes in your description.'''

[[File:Gray1112.jpg|400px]]

Figure 1. Longitudinal Section of Ovary of Cat Embryo of 9.4 cm long

===Lab 9===

'''Group project 1'''

The introduction was written quite well as it explains what the respiratory system is about and the origin of its development. It also briefly highlights the difference between the embryonic and fetal stage which is important in enabling the viewers to have an understanding on what the project will be focusing on. I also like how the group distinguished between the two zones of the respiratory tract and adequately described the features and function of each. The content in the lung development stages clearly relates to the topic and underlines fetal development. The group briefly mentioned the key features in each stage instead of pasting a whole lot of information; this makes it easier for viewers to understand. Overall the content relates to the learning objectives of embryology and the level of research is good as exemplified under ‘Current Research and Findings’ and ‘abnormalities’ (many forms of diseases described). The project however could benefit from having a ‘Glossary’ list so that viewers can understand some uncommon words.

The images under introduction and the image used for Meconium aspiration syndrome have not been referenced properly as there is missing information such as ((Template: Student Image)), description, copyright information and proper references for some. The image used under the ‘current research and findings’ subheading is a good example for the group to copy the referencing style. It is also vital that the group adds a brief description of what the image illustrates as a caption to help viewers understand the relation of the content and image (this is seen in the image under ‘surfactant’). More images could be added such as in the ‘lung development stage’ and under abnormalities. If images for lung development stages aren’t easily accessible, it is perhaps a good idea to draw them. The table format used for ‘lung development stages’ makes it easy for the viewers to navigate which is a good feature used in the project.

In terms of referencing, there are many in-cite references missing such as in the ‘introduction’ and in ‘lung development stages’. It is important to have these references formatted correctly under the one ‘references’ subheading. There seems to be many ‘references’ subheadings making it harder for viewers to navigate. Some references are shown as ‘ </li> which needs to be fixed right away. Overall, the content seems well written, formatted and concise making it easy to understand. However the problems related to referencing needs to be corrected as this is inconsistent throughout the project.

'''Group project 2'''

The introduction is well addressed as it sufficiently describes what the renal system is about and its function. Not to mention its anatomical structure as well as the difference between the embryonic and fetal stages of development. This differentiation enables viewers to understand what the content will be focused on, which is fetal development. Also, it helps focus the viewer’s attention on how the project will be divided as the group mentions abnormalities in the last paragraph. Overall the introduction has the right amount of information from each subheading and is very easy to comprehend.

There isn’t any information under ‘historic findings’. If there are any difficulties in finding some historic findings, members of the group can go to pubmed and on the side will be dates such as 1920 that could contain key historical events when renal is entered on search. The use of a development timeline was great as they outlined the major events that occur in a concise manner. Although, I believe a glossary is needed for words like ‘metanephros’ since the viewers would not know what that is. The content under current research models is interesting and correctly describes what the studies were about. Overall, the content used in the project was relating to the topic (fetal development of the kidney) and clearly showed extensive research. I really like how the group divided the different parts of the renal system as well as describing their anatomical positions. The abnormalities listed are also interesting and very easy to understand. I’m hoping to see information under the Horseshoe kidney disease.

In terms of images, there should be an image under introduction perhaps having all features of the renal system. Most images are missing the ‘student template’ aspect of the referencing and needs to be added right away. Other aspects such as description, copyright and referencing were correct. I also like the use of captions to describe what the images are about, however some are missing on the page such as the one under ‘anatomical position’ and ‘urethra’. The image used for the ‘development of the kidney’ should be removed from the page as it isn’t permissible. It should be replaced with an image relating to the content and have all the correct copyright and referencing information. Overall, I like the number of images used and its significance to the renal system. They accurately relate to the content of the project.

There is use of in-cite referencing which is good, however some references are just listed and should be placed under the proper ‘references’ subheading such as the ones under ‘ureter’ and ‘renal agenesis’. Some references in the ‘references’ list are used over again and can be fixed by combining it under one reference number. To make the project even more appealing, the group could format the information under ‘developmental timeline’ or even ’historic findings’ in a table. Overall, I think this project is great and by making edits based on the peer-reviews received could enhance their project.

'''Group project 3'''

The introduction is good as it accurately describes what the GIT system is about and the anatomical positions of the features in this system. It also briefly highlights the development stages at embryonic and fetal stages, however ‘embryonic development’ should be mentioned in a little more detail to understand how far in development the fetal stage begins. I also think the introduction should include a sentence or two describing how abnormalities in such organs can lead to these diseases. Basically a bit from each major subheading should be incorporated including current research as an introduction is a summary of the whole page. As for the ‘timeline’, it would’ve been more appropriate to place the timelines under each section, e.g foregut timeline under the ‘foregut’ subheading. This is because viewers would be confused on why there is so much difference in development in one section of the page. A glossary list should be incorporated in a separate subheading to define some of these words such as hematopoiesis so that viewers can fully grasp the information.

The information under recent findings is quite interesting and relatable to the content which is GIT fetal development. However, I believe more findings could be incorporated under this subheading. The information under each organ of the three ‘guts’ are quite detailed in fetal development which is good and shouldn’t be too difficult for the viewers to understand. However, I believe the group could include information on the function of these organs as well. The structure of the information under ‘guts’ does not flow in the sense that the midgut includes features and structure whereas the other ‘guts’ do not. The innvervation and bloody supply of the hindgut should be incorporated in a paragraph instead of being listed like that. All the deformities should be places under one subheading to make it easier for viewers to navigate. The abnormalities were also concise and related to the topic. Overall, the content is relating to the topic of the project and addresses key points. It also shows good amount of research, however there seems to be too much information in some parts which could be reduced a bit. The project needs a coherent flow of the structure.

As for images, there needs to be an image under introduction which includes all features of the GIT tract. There are a lot of potential images missing under each subheading except for the ‘midgut’ section. This shows that there has been one person working on this section or one section being focused on in comparison the others. The information used to reference the images is missing in some images such as the ‘Human- fetal week 10 sagittal plane D.jpg’ (although this is uploaded from a different user so this is understandable. However images such a ‘GIT 2.jpg’ need more information including ‘student template’ as well as the reference where the image idea may have come from. Also, if this is a hand-drawn image then please state this as one member did in ‘Week 11 midgut herniation.png’. Overall, I enjoy the use of self-drawn images as it makes it easier to show what the content is saying without going through the stress of looking for an image online that doesn’t relate to the content. However more images definitely need to be added. The use of captions is also good and indicates what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘Liver, Gallbladder and Bile Duct’ (the [6],[7] should be placed next to the text not above the text. The use of a ‘references’ subheading is good the same references have been combined into one number showing that the group knows how to make the references set out. The use of a table in formatting the ‘Percentage of Foetuses Herniated’ is great and shows more that the group has done research. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 4'''

The project doesn’t have an introduction yet; however information such as what the genital system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of genital development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. As for system development, I can see how there is dot-point description above the table which summarises the same thing. This structure is a bit confusing for me. I believe if the information was summarised into paragraphs and then tabulated it would make more sense. It’s best to format all that information into that table. The use of a table is a great way for the viewers to differentiate between the two sexes and understand the information more easily. I hope to see the table filled out completely soon. A glossary subheading should also be placed on the project page and have keywords defined to make viewers completely understand the content.

As for current findings, the information again is in dot points which should be paragraphed instead. However, the current findings are indeed interesting and the right amount of information is used to describe them in both sexes. The content under historic findings such as the ‘female genital development’ doesn’t show any historical events. There are no dates which show when something related was discovered. The ‘male genital development’ however shows dates and discoveries. In my opinion, if this information were tabulated rather than paragraphed, it’d be easier for viewers to navigate and understand. There is a good amount of detail under the abnormalities which relates to the key topic and is easy to understand. Overall, the content is relatable to the genital development of the fetus and underlines all the keys points. However, if this information were paragraphed in some areas and mentioned above, it would make the content easier to navigate and comprehend.

In terms of images, there are many places where images are missing such as introduction, system development and current models. I believe there needs to be more images on this page that relate to the content to make it more appealing and understandable to the viewers. The image called ‘File:Flow Diagram of Fetal Development of External Genitalia.pptx’ isn’t permissible and needs to be removed. The use of a hand drawn image on the testes is great, however there is information missing on referencing, student template and copyright laws. On the other hand, there are some images which correctly follow the uploading picture procedures such as the image on the ‘abnormalities of the vagina’; group members should follow this procedure. Captions should be added to each image to address what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘system development’. The use of a ‘references’ subheading is good, the same references have been combined into one number showing that the group knows how to make the references set out. However reference 20 and 21 are the same, please fix this. Also there are references under each subheading which should be placed all under one ‘references’ subheading. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 5'''

The introduction is a great summary of what the project page will discuss making sure to highlight every aspect. However, the introduction should also mention more about the integumentary system listing all the organs involved, their function, anatomical position and the difference between the embryonic and fetal stages of integumentary development. The content presented on the page is fantastic. All information under the subheadings looks complete and has key information related to the topic. I like how the timeline is divided into each organ making it easy to understand and navigate. The use of the table to format the information is a brilliant idea and has been presented beautifully with images in each textbox. Also the content under current research is relating to the topic and shows extensive research. The use of the purple background is appealing to the viewer highlighting its significance. I do however believe that the information under ‘historic findings’ should be formatted into a table to make it easier to navigate. The content under ‘abnormalities’ has the right amount of information and clearly relates to the key topic of the project.

In terms of images, I believe a satisfactory amount of images have been used which clearly describes the content. However, some images are missing the all the copyright information needed as well as the description, references and student template such as those in the ‘development overview’ table. This should be added right away to ensure these images do not get deleted. The use of captions on these pictures is important to highlight what the image is referring to and this is present in the page. Although, images could be added under current research as this section looks like it could use more images. Great job on the images under abnormalities, they accurately relate to the content mentioned.

There are some incite references missing such as in the development overview. I’m not sure if the references listed below are supposed to the references for it, however all references should be placed under one ‘references’ subheading. The same references have been combined into one number showing that the group knows how to make the references set out. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections. Overall, this is a great project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 7'''

The introduction is great as it mentions the features of the neural system, their anatomical positions and highlights the key events in the embryonic and fetal stages of development. The last paragraph of the introduction clearly addresses how the page will be divided and what the viewers are to expect which is good. The content under all subheadings are relating to the key topic and are formatted appropriately. I really like the image used under the subheading ‘Development during fetal period’ as it presents a diagrammatic representation of the content mentioned. The use of a table to briefly describe the events that occur at certain periods of fetal development is really helpful in grasping the main details. Some information is missing such as in ‘spinal cord development’, ‘Meninges development’, ‘future research’ and some ‘abnormalities’. This should be added right away. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the neural system and view dates on the side that may contain key findings. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

In terms of images, there are still many potential spaces for images such as under ‘introduction’, ‘current research’ and some ‘abnormalities’. The images used under ‘Development during fetal period’ are great and relate to the content. All images have correct description, referencing, copyright issues and ‘student template’, which shows that members of the group have followed correct ‘uploading image’ procedures. The images however need a caption to describe what the image is showing.

There needs to be more use of incite referencing such as in the ‘introduction’, ‘brain development’ and ‘abnormalities’. There is a huge list of references under ‘current research models and findings’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. References 7 and 8 are the same reference under the ‘references’ subheading and need to be combined into one number. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 8'''

The project doesn’t have an introduction yet; however information such as what the Musculoskeletal system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of musculoskeletal development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. I like the ‘making gains’ subheading as it adds humour to the page and engages the viewers. The general timeline needs information including what events take place at certain phases of fetal development. This could be present in a table to make the information more clear. It’s good that the project has information on the embryonic development so that the viewers can understand how the fetus arises to that point in development (fetal period).
All of the content seems to relate to the key topic and is appropriately paragraphed. However much of the content is still missing such as in ‘recent findings’ and ‘introduction’. More information could be added under the associated ‘trimesters’ and ‘abnormalities’. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the musculoskeletal system and view dates on the side that may contain key findings for historical events. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

There are no images on this page and definitely needs to be added with the appropriate information such as the description, referencing, copyright issues and ‘student template’. If images are not readily available, it is best to draw them. Also captions should be added on the page to state what the images are showing. As for referencing, there are some sections which shows incite referencing such as in the content under ‘Molecular and Cellular regulation of fetal myogenesis’ and some that don’t have any like in ‘tendon development’. There needs to be references in all sections. There is a huge list of references under ‘abnormalities’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. Number 15 of the reference list has an error in it and needs to be fixed right away. Overall, this is a working progress and if the group makes edits based on the peer-reviews received, this could enhance their project.

===Lab 10===

'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

'''''TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction.'''''

A major feature of the olfactory region is the olfactory bulb which contains mitral cells that serve to relay olfactory messages via sensory neurons of the olfactory epithelium to the piriform cortex of the brain. Within the granular cells and glomerular layers are interneurons which control the message output via synaptic linkages between mitral and tufted cell projection neurons. These interneurons continue to grow postnatally via neural stem cells located in the dorsolateral ganglionic eminence (dLGE) which consists of the subventricular zone and subependymal zone. When neuroblasts migrate to the dLGE, this stimulates dLGE-derived interneuron progenitors to migrate radially in the growing bulbs where they mature into the granular or glomerular cell layer. There has been research showing how teashirt zinc finger family member 1 (TSHZ1) is vital for the development of the olfactory bulb. In mice, it was found that olfactory bulb neuroblast differentiation required Tshz1 expression or else a large proportion of interneurons of the granular cell layer will not be present and radial migration of neuroblasts will be impaired. The basis of the previous studies was then replicated in humans suffering from congenital aural atresia that had TSHZ1 loss-of-function mutations.

Coronal sections 500-μm in size was obtained from the subjects which then underwent Nissl staining with cholineacetyl transferase histochemistry to observe the change in patterns of normal and abnormal olfactory development. In some parts of the experiment, mice were used as subjects to observe how congenital aural atresia may also affect them. In situ hybridization was used to investigate this effect on mice whereby Tshz1 positive and negative gene transcripts were obtained and amplified using polymerase chain reaction (PCR). Primers of the targeted gene and splicing enzymes were used to make sure the correct transcripts were produced.

Through immunoflourenscing and immunohistology, it was found that Tshz1 mutation lead to an abnormal distribution and differentiation of granule cell neurons of the developing olfactory bulb. Green fluoresce protein was integrated in the Tshz1 locus in both Tshz1+ and Tshz1- subjects. Through immunostaining of olfactory bulbs, it was shown that there was a consistent outer granule cell ring distribution of GFP+ cells in comparison to the unevenly distributed GFP+ cell located in the inner granule cell layer. DAPI staining revealed that the structure of the olfactory bulb in Tshz1 positive subjects were more layered and structure compared to deformed structure seen in Tshz1 mutants. The granule cell and external plexiform layers were indistinguishable and the glomerular layer had multilayers, thereby showing the abnormality in Tshz1 mutants.

Microarray hybridization was used to sort out gene expression in Tshz1 positive and negative subjects. Out of all the gene transcripts profiled, it was noted that the most significantly changed transcripts was Prokr2. Expression of PK2 was also downregulated in the rostral migratory stream of the subjects. Prokr2 expression was therefore examined in the developing olfactory bulb of Tshz1 positive and mutant mice using in situ hybridization. It was found that Tshz1 mRNA expression was seen in both the outer granule cell layer and the inner layers of the olfactory bulb mainly consisting of immature cells. Prokr2 expression was observed only in the inner layers of the OB in Tshz1 positive subjects and in mutants, Prokr2 expression was greatly downregulated. Overall, it was established that Tshz1 is needed to control the expression of Prokr2 which radially migrates neuroblasts. In addition, the PK2 family and its associated receptor are imperative factors required for normal olfactory bulb development.

<pubmed>24487590</pubmed>

'''Wiki link: https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Smell_Development'''

===Lab 11===

'''Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

'''Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration.'''

As cardiovascular disease continues to be the number one cause of death in the older population, there is significant research based on using stem cells as a tool to regenerate functional and healthy cardiomyctes in patients who’ve suffered from myocardial infarction. In particular, human induced pluripotent stem cells (hiPSCs) are used in this study to observe how these cells can generate cardiovascular cell sheets that may be used to treat infarcted heart tissue. Not to mention how hiPSCs may overcome obstacles such as poor engraftment of the cells injected in the heat and immunorejection, thereby placing the research more towards clinical practice.

'''Main findings'''

Data obtained from the study showed that there was simultaneous induction of cardiomyocytes and vascular cells using human IPSCs. It was shown that the levels of gene expression of cardiac mesoderm/progenitor genes (KDR/ISL1) were heightened on the day they were due to differentiate and when Dkk1 (a canonical Wnt antagonist) was added, the rate of differentiation of cardiomyocytes from mesoderm cells was increased. However when VEGF was added, this stimulated the induction of cardiomyocytes and vascular cells at the same time.

Furthermore, it was discovered that hiPSCs could generate cardiovascular cell sheets by placing hiPSC-derived cardiovascular cells into 12-multiwell temperature-responsive culture plates. After reducing the temperature, it was found that self-pulsating cell sheets (hiPSC-CTSs) was comprised of 3-4 cell layers with complete stratified structure of collagen positioned adjacent to the cell constituents. Immunostaining revealed that cardiomyocytes were expressed in large numbers out of all the three cells (myocytes and vascular endothelial cells), suggesting that non-myocytes are needed in cell sheet formation by remodelling cardiac cell distribution.

hiPSc-CTs were also shown to improve cardiac function after acute myocardial infarction in rats. The hiPSc-CTs were lined up in a 3-sheet structure where they were transplanted into a rat with acute myocardial infarction. After 8 weeks, an echocardiogram was performed and showed that anterior wall contraction was restored and parameters for left ventricle (LV) systolic function, fractional shortening (FS) and fractional area change (FAC) were improved. Sirius red staining also indicated that hiPSC-CTS transplantation greatly prevented fibrosis, thereby leaving more cardiac tissues to function properly.

Overall, this study shows evidence that HiPSC-CTSs are showing promising results in the generation of cardiomyocytes and in restoring cardiac function of those that suffered from myocardial infarction.

<ref><pubmed>25336194</pubmed></ref>

<references/>

User:Z3418837

2014-10-27T12:53:07Z

Z3418837: /* Lab 11 */

==Lab Attendance==
*Lab 1 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 6 August 2014 (EST)
*Lab 2 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:11, 13 August 2014 (EST)
*Lab 3 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:12, 20 August 2014 (EST)
*Lab 4 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:55, 27 August 2014 (EST)
*Lab 5 -- Absent
*Lab 6 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:44, 10 September 2014 (EST)
*Lab 7 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:40, 17 September 2014 (EST)
*Lab 8 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:11, 24 September 2014 (EST)
*Lab 9 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:08, 8 October 2014 (EST)
*Lab 10 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 15 October 2014 (EST)
*Lab 11 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 22 October 2014 (EST)
*Lab 12

==Individual Assessment==

==='''Lab 1'''===

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 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>

'''Your Lab assessment now requires you to find a 2 recent research references on fertilisation or in vitro fertilisation. Paste each reference on your page, as shown in the class. Write below each reference a brief summary of the research article methods and findings. The summary for each need not be more than 3-4 paragraphs in length. This will need to be completed before next weeks laboratory'''.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/25077107 PMID25077107]

<pubmed>25077107</pubmed>

This study was designed to investigate whether the levels of vitamin D is an imperative factor when it comes to the clinical success of implantation and pregnancy rates in infertile women via invitro fertilisation.

'''Method summary'''

A cohort of 173 women were evaluated and selected for this study based on their age, follicle-stimulating hormone levels and their consent to undergo invitro fertilisation. The following study was conducted at Mount Sinai Hospital where proper facilities were available. Blood tests were then conducted for each patient to determine their levels of Vitamin D via the serum 25-hydroxy-vitamin D (25[OH]D) levels. Following the results of the blood test, the cohort were then categorised into two groups which was either vitamin D sufficient (≥ 75 nmol/L) or insufficient ( < 75 nmol/L) based on serum levels of 25(OH)D.

Each patient then underwent IVF cycles whereby standard agonists that contained the active ingredient 0.5 mg/d of buserelin acetate in conjunction with cetrolix acetate as the standard antagonist were used to control the length of the luteal phase and estradiol levels. The length and dose of the treatment were varied for each individual based on their demographic data. Serial transvaginal ultrasonograpy and serum lutenizing hormone assays were then used to check ovarian response. When 3 or more dominant follicles (≥ 17 mm) were produced, 10 000 IU of human chorionic gonadotropin was added to enhance nuclear maturation. Oocyte retrieval was then conducted via transvaginal ultrasound whereby it was fertilised and the resulting embryo was transferred 3-5 days post-fertilisation. The rate of pregnancy per IVF cycle was then used as the primary outcome for this study whereby the visibility of the intrauterine sac of the embryo determined implantation.

'''Results summary'''

Out of the 182 patients that participated in this study, it was found that only 173 patients could continue on with this trial as they satisfied the criteria, however only 162 were fit for embryo transfer. Following the results from the blood test, it was noted that 53.8% of patients had insufficient levels of 25(OH)D and 45.1% had sufficient amounts. It was discovered that 71.8% of those with sufficient levels of 25(OH)D were more likely to proceed with embryo transfer on day 5 compared to 58.9% (p = 0.054) of those assigned to the ‘insufficient 25(OH)D’ category. Other factors such as oocyte retrieval and frequency of intracytoplasmic sperm injection were fairly similar in both groups. The study revealed that there was a higher clinical pregnancy rate per IVF cycle for those assigned to the sufficient 25(OH)D level category by 52.5% compared to those with insufficient amounts of 25(OH)D which was 34.7% (p < 0.001). Similarly, there was a significant clinical pregnancy rate per embryo transfer of 54.7% in comparison to 37.9% in woman belonging to the sufficient and insufficient category respectively. It was also noted that the implantation rate was greater in the sufficient category compared to the insufficient group, however the difference was only minimal (p= 0.6). Overall, the results suggest that serum 25(OH)D levels may be a predictor of clinical pregnancy.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/24672163 PMID24672163]

<pubmed>24672163</pubmed>

The process of achieving pregnancy via invitro fertilisation needs to be monitored and controlled with respect to the demographics of the individual in order to achieve a successful outcome. This study focuses on predicting the value of β-human chorionic gonadotrophin (β-HCG) that can lead to clinical success.

'''Method summary'''

Data analysis was taken from 171 female patients using the statistical package for social sciences program whereby all IVF cycles were monitored. The cycles that showed fresh multi-cell embryos (day 3) or blastocysts (day 5) were deemed fit for the trial and were the ones that were further used in this study. Serum β-HCG concentrations were then taken 14 days after the embryo was transferred whereby a second test was done on day 16 only if the first test revealed a positive β-HCG result. This was done to predict values that could enable doctors to evaluate a healthy intrauterine pregnancy or a problematic ectopic pregnancy. After 6-7 weeks of pregnancy, ultrasounds were conducted to check cardiac activity as well as the amount of gestational sacs. This was then repeated at 12 weeks of pregnancy to ensure there was no chance of abortion.

A continuing pregnancy was defined as one that continued for at least 12 weeks of gestation and showed signs of proper cardiac function. On the other hand, those pregnancies that were abnormal had dropped levels of β-HCG concentrations and led to empty gestational sacs that showed no embryonic cardiac function. As a measuring tool for detecting levels of β-HCG, Chemiluminescent microparticle immunoassays were used whereby the measuring range established was between 0.0-15,000 mIU/mL. HCG levels above 10 IU/L signified early pregnancy.

'''Results Summary'''

Out of the 171 patients that participated in this study, only 139 were included due to the missing data on the levels of β-HCG concentrations at day 14 and 16 post embryonic transfer. In total there were 39 abnormal pregnancies that involved ectopic pregnancy, abortions and biochemical pregnancies (sufficient HCG levels detected but no visible gestational sac). Overall the patients were categorised into two groups which were patients with ‘ongoing pregnancy’ (n=100) and ‘without ongoing pregnancy’ (n=39). The Mann-Whitney test (statistical testing) was then used to compare the levels of β-HCG levels in both groups. It was found that the group with ongoing pregnancy had a median serum β-HCG level of 600 mIU/ml, whereas the other group had a median serum β-HCG level of 178 mIU/ml. This indicated a significant difference of P < 0.05 when comparing the two groups. It was also found that when serum β-HCG levels reached 347 mIU/ml, there was a 73.6% chance that the pregnancy was ongoing. Furthermore, there was no definite correlation established between age and the rate of ongoing pregnancy as both categories had patients of similar age groups with a combined range of 23-41 year old patients. Overall, the study revealed that early serum β-HCG is a potential predictor of successful outcomes in invitro fertilisation.

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 19:11, 6 October 2014 (EST) These are relevant references and your descriptions/abstracts are good (5/5).

===Lab 2===

[[File:Phase-contrast images of embryos at different developmental stages via neogenin expression.png|300px]]

Phase-contrast images of embryos at different developmental stages via neogenin expression.<ref><pubmed>25013897</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0101989 PLos One]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:17, 21 August 2014 (EST) This is all correct. The image is very large (4.8 MB), perhaps a small version could have been uploaded. You can adjust the resolution and size in most image editing programs. (5/5)

<references/>

===Lab 3===

'''Parathyroid gland'''

<pubmed>22808183</pubmed>
<pubmed>22649358</pubmed>
<pubmed>21881196</pubmed>
<pubmed>21904825</pubmed>

'''Thymus'''

<pubmed>21733645</pubmed>
<pubmed>20836742</pubmed>
<pubmed>21263742</pubmed>
<pubmed>512270</pubmed>

'''Pancreas'''

<pubmed>22761699</pubmed>
<pubmed>22893718</pubmed>
<pubmed>24496309</pubmed>
<pubmed>24595965</pubmed>
<pubmed>23822675</pubmed>
<pubmed>22968764</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===

'''1. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

'''Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1'''

Glioblastoma multiforme (GBM) is known to belong to a very life threatening form of brain cancer. Research is currently focused on finding treatments regarding such abnormalities, such as the application of neuronal stem cells in reducing the population of tumours, however there were many problems that occurred with such treatment. Recently, Human umbilical cord blood derived stem cells (hUCBSC) has been extensively used as they are useful mesenchymal stem cells that are easy to isolate and are more available. GBM is caused by the overexpression of cyclin D1 and its subsequent binding to Cdk 4/Cdk 6 which defines the rate limiting step required for the cell to progress further on to the cell cycle from the G1 phase. In order to stop this over expression, scientists have used hUCBSC to inhibit the cell from progressing on with the cell cycle.

When (hUCBSC) were cultured with U251 and 5310 cells, flow cytometry technology revealed that the cells underwent G1 arrest showing an increase in the G0-G1/S phase ratio. There was also a 54% reduction in levels of cyclin D1 when hUCBSC was cultured with U251 in comparison to the control. Immunoprecipiation revealed that hUCBSC treated cells when immuno blotted with Cdk 4 and Cdk 6 antibodies, down regulated expression of both Cdk 4 and Cdk 6. Western blot also showed the same down regulating pattern of the individual expression and genes which confirmed that there was cell cycle arrest, thus preventing tumours from forming.

As such, this study helps researchers to grasp the foundation of using hUCBSC as a treatment for glioblastoma and to further build on such research. Since it is evident that hUCBSC is effective in reducing cyclin D1 expression; analysing glioblastomal hierarchy will aid in providing the missing links needed to create the clinical treatment.

<pubmed>21455311</pubmed>

'''2. There are a number of developmental vascular "shunts" present in the embryo, that are closed postnatally. Identify these shunts and their anatomical location.'''

Three major vascular shunts include:

• '''Ductus venosus''' - is a shunt of oxygenated blood from umbilical vein to IVC, bypassing the liver. The ductus venosus constricts and closes soon after birth and becomes the ligamentum venosum

• '''Foramen ovale''' - is a flap valve in the atrial septum between the right and left atrium that shunts highly oxygenated blood . The remnant of the foramen ovale is known as the fossa ovalis.

• '''Ductus arteriosus''' - is a shunt from the descending aorta to the left pulmonary artery near the bifurcation of the pulmonary trunk. Permanent closure takes 4-6 weeks by fibrosis, and the remnant is referred to as the ligamentum arteriosum.

===Lab 5===

'''Select an abnormality of either gastrointestinal or respiratory development and write a brief description of developmental causes(s) for this abnormality. Your answer should be added to your own student page, be brief (2-3 paragraphs) and referenced.'''

'''Midgut volvulus'''

The embryonic development of the midgut has a number of steps which ensures its proper formation. These include the viability of the superior mesenteric artery to divide the midgut into the cephalad (pre-arterial region) and caudad (post-arterial region). <ref><pubmed>15378215</pubmed></ref>During the fourth gestational week, the gastrointestinal system is composed of a centrally positioned linear tube in the abdomen. At approximately 6 weeks of gestational age, the midgut undergoes a process of U-shaped herniation causing the two portions of the midguts to face the opposite directions in relation to the superior mesenteric artery. From this moment, a number of rotation events occur to ensure the complete development of the gastrointestinal tract as it becomes set in the posterior abdominal wall.<ref><pubmed>7277164</pubmed></ref>

In some cases malrotations can occur during the developmental process of the midgut which involves the complete twisting of the midgut in relation to the axis of the superior mesenteric artery. In extreme cases this can lead to midgut volvulus which results in a narrowed mesenteric base that can obstruct the passage of blood and lead to tissue necrosis. Other complications resulting from midgut volvulus include intestinal ischaemia, peritonitis, mucosal necrosis and sepsis which can eventually lead to death if left untreated. <ref><pubmed>14655161</pubmed></ref>

Malrotation is known to occur within 1 in 500 live births and out of those who develop midgut volvusos, 68-71% are neonates. <ref><pubmed>22217896</pubmed></ref>Although the actual cause of malrotation is unknown, researchers have made links to congenital syndromes such as Down syndrome and the VACTERL. It is also hypothesized that any embryonic interference during the normal patterns of rotation and fetal development can lead to midgut volvulus. Treatment of midgut volvulus is dependent on when the disease is diagnosed. <ref><pubmed>18800265</pubmed></ref>Normally a sigmoidoscopy is carried out as well as the Ladd procedure to resect dead gastrointestinal tissues. Transduodenal bands of ladd may also be divided to widen the mesenteric pedicle and prevent obstruction of blood flow. <ref><pubmed>22208840</pubmed></ref>Overall, research is still being conducted on the specific causes of malrotation and other numerous treatments.

<references/>

===Lab 6===

Group work

===Lab 7===

'''1.Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

'''Novel genes upregulated when NOTCH signaling is disrupted during hypothalamic development.'''

It is known that the hypothalamus first develops from the ventral region of the diencephalon and signaling mechanisms such as the sonic hedgehog and bone morphogenic protein pathways are responsible for pattern arrangement. Neurogenesis is the key process required to ensure proper hypothalamus development which relies on many signaling pathways to produce neurons and glia. The Notch signaling pathway is currently known to inhibit neuronal differentiation and preserve neural progenitor identity. As a result of various studies and research, the combined theory has been implemented in this study to determine the effect of downregulating Notch signaling pathways in its effect on hypothalamic development.

Results show that when Notch signaling is inactivated, novel genes such as Dll1, Hes5, Hey1 and Ascl1 are upregulated in the rostral hypothalamus, subsequently leading to the early formation of hypothalamic neurons. This is also seen when embryos that are treated with DAPT (a chemical which inhibits cell differentiation mechanisms regulated by the Notch pathway) had an overexpression of cells differentiated into neurons in a clustered formation. This was compared to the control embryos which had differentiated cells in a scattered arrangement. As such, this research showed that Notch is a powerful signaling mechanism that is used to inhibit cell differentiation in order to control the number of cells differentiated into neurons or glia. This modulating ability of the Notch pathway is imperative in the early developing hypothalamus as it controls expression of cells and hence prevents any form of defects that can be harmful both prenatally and postnatally. Further research needs to be conducted on the Notch pathway to provide procedures where its mechanism can be used to resolve defects in the embryo and hence ensure proper hypothalamic development.

<pubmed>24360028</pubmed>

'''2.Identify the embryonic layers and tissues that contribute to the developing teeth.'''

'''Odontoblasts''' - neural crest-derived mesenchymal cells which establish the outer dental pulp. It differentiates via the enamel epithelium and releases dentin from dentinogenesis.

'''Ameloblasts''' - are derived from oral epithelium tissue of ectodermal origin and make up the inner enamel. They make pre-ameloblasts and produce enamel.

'''Periodontal ligament''' – is comprised of connective tissues which holds the tooth in place in the alveolar bone. It also encloses the cementum coating of the tooth root.

===Lab 8===

'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

'''Embryonic development of the ovary'''

The Gonads are known to be formed from the combination of primitive germ cells, adjacent mesenchyme and the mesothelium of the posterior abdominal wall. It isn’t until fifth week of embryonic development that the formation of Gonads occurs. The primordial germ cells first migrate from the embryonic yolk sac towards the hindgut along the dorsal mesentery. These cells then travel to the mesenchyme forming genital ridges positioned medially to the mesonephros by the sixth week of development. Coelomic epithelium and the mesonephros cells also proliferate at this stage. These cells then incorporate into the primary sex cords in which the process is driven by the genes stella, fragilis, and BMP-4 before the seventh week of embryonic development.<ref><pubmed>23409002</pubmed></ref>

The gonads are known to be indifferent until the sixth embryonic week as the gonads appear the same, however sex differentiation based on sex chromosomes determine the sex of the Gonad (XX for female and XY for males). The indifferent gonads are situated well inside the Wolffian body and are comprised of an inner medulla and outer cortex which contains precursors for ovarian stroma and parenchyma respectively.<ref><pubmed>3712511</pubmed></ref> In embryos consisting of XX sex chromosomes, the cortex of the indifferent gonad differentiates into an ovary meanwhile the medulla regresses by week eight of embryonic development. However, the sex cords leads to the formation of rete ovarii which is a complex of tubules and cords that arises from the mesonephros.

Another important event that occurs during the sixth week of development is the formation of the mullerian ducts which are responsible for female gonad formation and prevention of male gonad development. The established XX genotype of the female embryo prevents testosterone from being produced and hence causes the regression of the mesonephric duct since this form is only needed for male gonad expression. Also since there is no production of anti-mullarian hormone, the paramesonephric duct is able to be maintained driving female gonad expression. As of 10 weeks of development, ovaries first become recognizable and the growth of female external genitalia begins to occur.

[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]

<references/>

''' 2.Include an image from the historic genital embryology section of the online notes in your description.'''

[[File:Gray1112.jpg|400px]]

Figure 1. Longitudinal Section of Ovary of Cat Embryo of 9.4 cm long

===Lab 9===

'''Group project 1'''

The introduction was written quite well as it explains what the respiratory system is about and the origin of its development. It also briefly highlights the difference between the embryonic and fetal stage which is important in enabling the viewers to have an understanding on what the project will be focusing on. I also like how the group distinguished between the two zones of the respiratory tract and adequately described the features and function of each. The content in the lung development stages clearly relates to the topic and underlines fetal development. The group briefly mentioned the key features in each stage instead of pasting a whole lot of information; this makes it easier for viewers to understand. Overall the content relates to the learning objectives of embryology and the level of research is good as exemplified under ‘Current Research and Findings’ and ‘abnormalities’ (many forms of diseases described). The project however could benefit from having a ‘Glossary’ list so that viewers can understand some uncommon words.

The images under introduction and the image used for Meconium aspiration syndrome have not been referenced properly as there is missing information such as ((Template: Student Image)), description, copyright information and proper references for some. The image used under the ‘current research and findings’ subheading is a good example for the group to copy the referencing style. It is also vital that the group adds a brief description of what the image illustrates as a caption to help viewers understand the relation of the content and image (this is seen in the image under ‘surfactant’). More images could be added such as in the ‘lung development stage’ and under abnormalities. If images for lung development stages aren’t easily accessible, it is perhaps a good idea to draw them. The table format used for ‘lung development stages’ makes it easy for the viewers to navigate which is a good feature used in the project.

In terms of referencing, there are many in-cite references missing such as in the ‘introduction’ and in ‘lung development stages’. It is important to have these references formatted correctly under the one ‘references’ subheading. There seems to be many ‘references’ subheadings making it harder for viewers to navigate. Some references are shown as ‘ </li> which needs to be fixed right away. Overall, the content seems well written, formatted and concise making it easy to understand. However the problems related to referencing needs to be corrected as this is inconsistent throughout the project.

'''Group project 2'''

The introduction is well addressed as it sufficiently describes what the renal system is about and its function. Not to mention its anatomical structure as well as the difference between the embryonic and fetal stages of development. This differentiation enables viewers to understand what the content will be focused on, which is fetal development. Also, it helps focus the viewer’s attention on how the project will be divided as the group mentions abnormalities in the last paragraph. Overall the introduction has the right amount of information from each subheading and is very easy to comprehend.

There isn’t any information under ‘historic findings’. If there are any difficulties in finding some historic findings, members of the group can go to pubmed and on the side will be dates such as 1920 that could contain key historical events when renal is entered on search. The use of a development timeline was great as they outlined the major events that occur in a concise manner. Although, I believe a glossary is needed for words like ‘metanephros’ since the viewers would not know what that is. The content under current research models is interesting and correctly describes what the studies were about. Overall, the content used in the project was relating to the topic (fetal development of the kidney) and clearly showed extensive research. I really like how the group divided the different parts of the renal system as well as describing their anatomical positions. The abnormalities listed are also interesting and very easy to understand. I’m hoping to see information under the Horseshoe kidney disease.

In terms of images, there should be an image under introduction perhaps having all features of the renal system. Most images are missing the ‘student template’ aspect of the referencing and needs to be added right away. Other aspects such as description, copyright and referencing were correct. I also like the use of captions to describe what the images are about, however some are missing on the page such as the one under ‘anatomical position’ and ‘urethra’. The image used for the ‘development of the kidney’ should be removed from the page as it isn’t permissible. It should be replaced with an image relating to the content and have all the correct copyright and referencing information. Overall, I like the number of images used and its significance to the renal system. They accurately relate to the content of the project.

There is use of in-cite referencing which is good, however some references are just listed and should be placed under the proper ‘references’ subheading such as the ones under ‘ureter’ and ‘renal agenesis’. Some references in the ‘references’ list are used over again and can be fixed by combining it under one reference number. To make the project even more appealing, the group could format the information under ‘developmental timeline’ or even ’historic findings’ in a table. Overall, I think this project is great and by making edits based on the peer-reviews received could enhance their project.

'''Group project 3'''

The introduction is good as it accurately describes what the GIT system is about and the anatomical positions of the features in this system. It also briefly highlights the development stages at embryonic and fetal stages, however ‘embryonic development’ should be mentioned in a little more detail to understand how far in development the fetal stage begins. I also think the introduction should include a sentence or two describing how abnormalities in such organs can lead to these diseases. Basically a bit from each major subheading should be incorporated including current research as an introduction is a summary of the whole page. As for the ‘timeline’, it would’ve been more appropriate to place the timelines under each section, e.g foregut timeline under the ‘foregut’ subheading. This is because viewers would be confused on why there is so much difference in development in one section of the page. A glossary list should be incorporated in a separate subheading to define some of these words such as hematopoiesis so that viewers can fully grasp the information.

The information under recent findings is quite interesting and relatable to the content which is GIT fetal development. However, I believe more findings could be incorporated under this subheading. The information under each organ of the three ‘guts’ are quite detailed in fetal development which is good and shouldn’t be too difficult for the viewers to understand. However, I believe the group could include information on the function of these organs as well. The structure of the information under ‘guts’ does not flow in the sense that the midgut includes features and structure whereas the other ‘guts’ do not. The innvervation and bloody supply of the hindgut should be incorporated in a paragraph instead of being listed like that. All the deformities should be places under one subheading to make it easier for viewers to navigate. The abnormalities were also concise and related to the topic. Overall, the content is relating to the topic of the project and addresses key points. It also shows good amount of research, however there seems to be too much information in some parts which could be reduced a bit. The project needs a coherent flow of the structure.

As for images, there needs to be an image under introduction which includes all features of the GIT tract. There are a lot of potential images missing under each subheading except for the ‘midgut’ section. This shows that there has been one person working on this section or one section being focused on in comparison the others. The information used to reference the images is missing in some images such as the ‘Human- fetal week 10 sagittal plane D.jpg’ (although this is uploaded from a different user so this is understandable. However images such a ‘GIT 2.jpg’ need more information including ‘student template’ as well as the reference where the image idea may have come from. Also, if this is a hand-drawn image then please state this as one member did in ‘Week 11 midgut herniation.png’. Overall, I enjoy the use of self-drawn images as it makes it easier to show what the content is saying without going through the stress of looking for an image online that doesn’t relate to the content. However more images definitely need to be added. The use of captions is also good and indicates what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘Liver, Gallbladder and Bile Duct’ (the [6],[7] should be placed next to the text not above the text. The use of a ‘references’ subheading is good the same references have been combined into one number showing that the group knows how to make the references set out. The use of a table in formatting the ‘Percentage of Foetuses Herniated’ is great and shows more that the group has done research. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 4'''

The project doesn’t have an introduction yet; however information such as what the genital system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of genital development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. As for system development, I can see how there is dot-point description above the table which summarises the same thing. This structure is a bit confusing for me. I believe if the information was summarised into paragraphs and then tabulated it would make more sense. It’s best to format all that information into that table. The use of a table is a great way for the viewers to differentiate between the two sexes and understand the information more easily. I hope to see the table filled out completely soon. A glossary subheading should also be placed on the project page and have keywords defined to make viewers completely understand the content.

As for current findings, the information again is in dot points which should be paragraphed instead. However, the current findings are indeed interesting and the right amount of information is used to describe them in both sexes. The content under historic findings such as the ‘female genital development’ doesn’t show any historical events. There are no dates which show when something related was discovered. The ‘male genital development’ however shows dates and discoveries. In my opinion, if this information were tabulated rather than paragraphed, it’d be easier for viewers to navigate and understand. There is a good amount of detail under the abnormalities which relates to the key topic and is easy to understand. Overall, the content is relatable to the genital development of the fetus and underlines all the keys points. However, if this information were paragraphed in some areas and mentioned above, it would make the content easier to navigate and comprehend.

In terms of images, there are many places where images are missing such as introduction, system development and current models. I believe there needs to be more images on this page that relate to the content to make it more appealing and understandable to the viewers. The image called ‘File:Flow Diagram of Fetal Development of External Genitalia.pptx’ isn’t permissible and needs to be removed. The use of a hand drawn image on the testes is great, however there is information missing on referencing, student template and copyright laws. On the other hand, there are some images which correctly follow the uploading picture procedures such as the image on the ‘abnormalities of the vagina’; group members should follow this procedure. Captions should be added to each image to address what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘system development’. The use of a ‘references’ subheading is good, the same references have been combined into one number showing that the group knows how to make the references set out. However reference 20 and 21 are the same, please fix this. Also there are references under each subheading which should be placed all under one ‘references’ subheading. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 5'''

The introduction is a great summary of what the project page will discuss making sure to highlight every aspect. However, the introduction should also mention more about the integumentary system listing all the organs involved, their function, anatomical position and the difference between the embryonic and fetal stages of integumentary development. The content presented on the page is fantastic. All information under the subheadings looks complete and has key information related to the topic. I like how the timeline is divided into each organ making it easy to understand and navigate. The use of the table to format the information is a brilliant idea and has been presented beautifully with images in each textbox. Also the content under current research is relating to the topic and shows extensive research. The use of the purple background is appealing to the viewer highlighting its significance. I do however believe that the information under ‘historic findings’ should be formatted into a table to make it easier to navigate. The content under ‘abnormalities’ has the right amount of information and clearly relates to the key topic of the project.

In terms of images, I believe a satisfactory amount of images have been used which clearly describes the content. However, some images are missing the all the copyright information needed as well as the description, references and student template such as those in the ‘development overview’ table. This should be added right away to ensure these images do not get deleted. The use of captions on these pictures is important to highlight what the image is referring to and this is present in the page. Although, images could be added under current research as this section looks like it could use more images. Great job on the images under abnormalities, they accurately relate to the content mentioned.

There are some incite references missing such as in the development overview. I’m not sure if the references listed below are supposed to the references for it, however all references should be placed under one ‘references’ subheading. The same references have been combined into one number showing that the group knows how to make the references set out. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections. Overall, this is a great project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 7'''

The introduction is great as it mentions the features of the neural system, their anatomical positions and highlights the key events in the embryonic and fetal stages of development. The last paragraph of the introduction clearly addresses how the page will be divided and what the viewers are to expect which is good. The content under all subheadings are relating to the key topic and are formatted appropriately. I really like the image used under the subheading ‘Development during fetal period’ as it presents a diagrammatic representation of the content mentioned. The use of a table to briefly describe the events that occur at certain periods of fetal development is really helpful in grasping the main details. Some information is missing such as in ‘spinal cord development’, ‘Meninges development’, ‘future research’ and some ‘abnormalities’. This should be added right away. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the neural system and view dates on the side that may contain key findings. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

In terms of images, there are still many potential spaces for images such as under ‘introduction’, ‘current research’ and some ‘abnormalities’. The images used under ‘Development during fetal period’ are great and relate to the content. All images have correct description, referencing, copyright issues and ‘student template’, which shows that members of the group have followed correct ‘uploading image’ procedures. The images however need a caption to describe what the image is showing.

There needs to be more use of incite referencing such as in the ‘introduction’, ‘brain development’ and ‘abnormalities’. There is a huge list of references under ‘current research models and findings’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. References 7 and 8 are the same reference under the ‘references’ subheading and need to be combined into one number. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 8'''

The project doesn’t have an introduction yet; however information such as what the Musculoskeletal system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of musculoskeletal development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. I like the ‘making gains’ subheading as it adds humour to the page and engages the viewers. The general timeline needs information including what events take place at certain phases of fetal development. This could be present in a table to make the information more clear. It’s good that the project has information on the embryonic development so that the viewers can understand how the fetus arises to that point in development (fetal period).
All of the content seems to relate to the key topic and is appropriately paragraphed. However much of the content is still missing such as in ‘recent findings’ and ‘introduction’. More information could be added under the associated ‘trimesters’ and ‘abnormalities’. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the musculoskeletal system and view dates on the side that may contain key findings for historical events. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

There are no images on this page and definitely needs to be added with the appropriate information such as the description, referencing, copyright issues and ‘student template’. If images are not readily available, it is best to draw them. Also captions should be added on the page to state what the images are showing. As for referencing, there are some sections which shows incite referencing such as in the content under ‘Molecular and Cellular regulation of fetal myogenesis’ and some that don’t have any like in ‘tendon development’. There needs to be references in all sections. There is a huge list of references under ‘abnormalities’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. Number 15 of the reference list has an error in it and needs to be fixed right away. Overall, this is a working progress and if the group makes edits based on the peer-reviews received, this could enhance their project.

===Lab 10===

'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

'''''TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction.'''''

A major feature of the olfactory region is the olfactory bulb which contains mitral cells that serve to relay olfactory messages via sensory neurons of the olfactory epithelium to the piriform cortex of the brain. Within the granular cells and glomerular layers are interneurons which control the message output via synaptic linkages between mitral and tufted cell projection neurons. These interneurons continue to grow postnatally via neural stem cells located in the dorsolateral ganglionic eminence (dLGE) which consists of the subventricular zone and subependymal zone. When neuroblasts migrate to the dLGE, this stimulates dLGE-derived interneuron progenitors to migrate radially in the growing bulbs where they mature into the granular or glomerular cell layer. There has been research showing how teashirt zinc finger family member 1 (TSHZ1) is vital for the development of the olfactory bulb. In mice, it was found that olfactory bulb neuroblast differentiation required Tshz1 expression or else a large proportion of interneurons of the granular cell layer will not be present and radial migration of neuroblasts will be impaired. The basis of the previous studies was then replicated in humans suffering from congenital aural atresia that had TSHZ1 loss-of-function mutations.

Coronal sections 500-μm in size was obtained from the subjects which then underwent Nissl staining with cholineacetyl transferase histochemistry to observe the change in patterns of normal and abnormal olfactory development. In some parts of the experiment, mice were used as subjects to observe how congenital aural atresia may also affect them. In situ hybridization was used to investigate this effect on mice whereby Tshz1 positive and negative gene transcripts were obtained and amplified using polymerase chain reaction (PCR). Primers of the targeted gene and splicing enzymes were used to make sure the correct transcripts were produced.

Through immunoflourenscing and immunohistology, it was found that Tshz1 mutation lead to an abnormal distribution and differentiation of granule cell neurons of the developing olfactory bulb. Green fluoresce protein was integrated in the Tshz1 locus in both Tshz1+ and Tshz1- subjects. Through immunostaining of olfactory bulbs, it was shown that there was a consistent outer granule cell ring distribution of GFP+ cells in comparison to the unevenly distributed GFP+ cell located in the inner granule cell layer. DAPI staining revealed that the structure of the olfactory bulb in Tshz1 positive subjects were more layered and structure compared to deformed structure seen in Tshz1 mutants. The granule cell and external plexiform layers were indistinguishable and the glomerular layer had multilayers, thereby showing the abnormality in Tshz1 mutants.

Microarray hybridization was used to sort out gene expression in Tshz1 positive and negative subjects. Out of all the gene transcripts profiled, it was noted that the most significantly changed transcripts was Prokr2. Expression of PK2 was also downregulated in the rostral migratory stream of the subjects. Prokr2 expression was therefore examined in the developing olfactory bulb of Tshz1 positive and mutant mice using in situ hybridization. It was found that Tshz1 mRNA expression was seen in both the outer granule cell layer and the inner layers of the olfactory bulb mainly consisting of immature cells. Prokr2 expression was observed only in the inner layers of the OB in Tshz1 positive subjects and in mutants, Prokr2 expression was greatly downregulated. Overall, it was established that Tshz1 is needed to control the expression of Prokr2 which radially migrates neuroblasts. In addition, the PK2 family and its associated receptor are imperative factors required for normal olfactory bulb development.

<pubmed>24487590</pubmed>

'''Wiki link: https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Smell_Development'''

===Lab 11===

'''Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

'''Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration.'''

As cardiovascular disease continues to be the number one cause of death in the older population, there is significant research based on using stem cells as a tool to regenerate functional and healthy cardiomyctes in patients who’ve suffered from myocardial infarction. In particular, human induced pluripotent stem cells (hiPSCs) are used in this study to observe how these cells can generate cardiovascular cell sheets that may be used to treat infarcted heart tissue. Not to mention how hiPSCs may overcome obstacles such as poor engraftment of the cells injected in the heat and immunorejection, thereby placing the research more towards clinical practice.

'''Main findings'''

Data obtained from the study showed that there was simultaneous induction of cardiomyocytes and vascular cells using human IPSCs. It was shown that the levels of gene expression of cardiac mesoderm/progenitor genes (KDR/ISL1) were heightened on the day they were due to differentiate and when Dkk1 (a canonical Wnt antagonist) was added, the rate of differentiation of cardiomyocytes from mesoderm cells was increased. However when VEGF was added, this stimulated the induction of cardiomyocytes and vascular cells at the same time.

Furthermore, it was discovered that hiPSCs could generate cardiovascular cell sheets by placing hiPSC-derived cardiovascular cells into 12-multiwell temperature-responsive culture plates. After reducing the temperature, it was found that self-pulsating cell sheets (hiPSC-CTSs) was comprised of 3-4 cell layers with complete stratified structure of collagen positioned adjacent to the cell constituents. Immunostaining revealed that cardiomyocytes were expressed in large numbers out of all the three cells (myocytes and vascular endothelial cells), suggesting that non-myocytes are needed in cell sheet formation by remodelling cardiac cell distribution.

hiPSc-CTs were also shown to improve cardiac function after acute myocardial infarction in rats. The hiPSc-CTs were lined up in a 3-sheet structure where they were transplanted into a rat with acute myocardial infarction. After 8 weeks, an echocardiogram was performed and showed that anterior wall contraction was restored and parameters for left ventricle (LV) systolic function, fractional shortening (FS) and fractional area change (FAC) were improved. Sirius red staining also indicated that hiPSC-CTS transplantation greatly prevented fibrosis, thereby leaving more cardiac tissues to function properly.

Overall, this study shows evidence that HiPSC-CTSs are showing promising results in the generation of cardiomyocytes and in restoring cardiac function of those that suffered from myocardial infarction.

<ref><pubmed>25336194</pubmed></ref>

<references/>

User:Z3418837

2014-10-27T12:50:31Z

Z3418837: /* Lab 11 */

==Lab Attendance==
*Lab 1 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 6 August 2014 (EST)
*Lab 2 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:11, 13 August 2014 (EST)
*Lab 3 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:12, 20 August 2014 (EST)
*Lab 4 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:55, 27 August 2014 (EST)
*Lab 5 -- Absent
*Lab 6 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:44, 10 September 2014 (EST)
*Lab 7 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:40, 17 September 2014 (EST)
*Lab 8 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:11, 24 September 2014 (EST)
*Lab 9 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:08, 8 October 2014 (EST)
*Lab 10 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 15 October 2014 (EST)
*Lab 11 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 22 October 2014 (EST)
*Lab 12

==Individual Assessment==

==='''Lab 1'''===

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 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>

'''Your Lab assessment now requires you to find a 2 recent research references on fertilisation or in vitro fertilisation. Paste each reference on your page, as shown in the class. Write below each reference a brief summary of the research article methods and findings. The summary for each need not be more than 3-4 paragraphs in length. This will need to be completed before next weeks laboratory'''.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/25077107 PMID25077107]

<pubmed>25077107</pubmed>

This study was designed to investigate whether the levels of vitamin D is an imperative factor when it comes to the clinical success of implantation and pregnancy rates in infertile women via invitro fertilisation.

'''Method summary'''

A cohort of 173 women were evaluated and selected for this study based on their age, follicle-stimulating hormone levels and their consent to undergo invitro fertilisation. The following study was conducted at Mount Sinai Hospital where proper facilities were available. Blood tests were then conducted for each patient to determine their levels of Vitamin D via the serum 25-hydroxy-vitamin D (25[OH]D) levels. Following the results of the blood test, the cohort were then categorised into two groups which was either vitamin D sufficient (≥ 75 nmol/L) or insufficient ( < 75 nmol/L) based on serum levels of 25(OH)D.

Each patient then underwent IVF cycles whereby standard agonists that contained the active ingredient 0.5 mg/d of buserelin acetate in conjunction with cetrolix acetate as the standard antagonist were used to control the length of the luteal phase and estradiol levels. The length and dose of the treatment were varied for each individual based on their demographic data. Serial transvaginal ultrasonograpy and serum lutenizing hormone assays were then used to check ovarian response. When 3 or more dominant follicles (≥ 17 mm) were produced, 10 000 IU of human chorionic gonadotropin was added to enhance nuclear maturation. Oocyte retrieval was then conducted via transvaginal ultrasound whereby it was fertilised and the resulting embryo was transferred 3-5 days post-fertilisation. The rate of pregnancy per IVF cycle was then used as the primary outcome for this study whereby the visibility of the intrauterine sac of the embryo determined implantation.

'''Results summary'''

Out of the 182 patients that participated in this study, it was found that only 173 patients could continue on with this trial as they satisfied the criteria, however only 162 were fit for embryo transfer. Following the results from the blood test, it was noted that 53.8% of patients had insufficient levels of 25(OH)D and 45.1% had sufficient amounts. It was discovered that 71.8% of those with sufficient levels of 25(OH)D were more likely to proceed with embryo transfer on day 5 compared to 58.9% (p = 0.054) of those assigned to the ‘insufficient 25(OH)D’ category. Other factors such as oocyte retrieval and frequency of intracytoplasmic sperm injection were fairly similar in both groups. The study revealed that there was a higher clinical pregnancy rate per IVF cycle for those assigned to the sufficient 25(OH)D level category by 52.5% compared to those with insufficient amounts of 25(OH)D which was 34.7% (p < 0.001). Similarly, there was a significant clinical pregnancy rate per embryo transfer of 54.7% in comparison to 37.9% in woman belonging to the sufficient and insufficient category respectively. It was also noted that the implantation rate was greater in the sufficient category compared to the insufficient group, however the difference was only minimal (p= 0.6). Overall, the results suggest that serum 25(OH)D levels may be a predictor of clinical pregnancy.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/24672163 PMID24672163]

<pubmed>24672163</pubmed>

The process of achieving pregnancy via invitro fertilisation needs to be monitored and controlled with respect to the demographics of the individual in order to achieve a successful outcome. This study focuses on predicting the value of β-human chorionic gonadotrophin (β-HCG) that can lead to clinical success.

'''Method summary'''

Data analysis was taken from 171 female patients using the statistical package for social sciences program whereby all IVF cycles were monitored. The cycles that showed fresh multi-cell embryos (day 3) or blastocysts (day 5) were deemed fit for the trial and were the ones that were further used in this study. Serum β-HCG concentrations were then taken 14 days after the embryo was transferred whereby a second test was done on day 16 only if the first test revealed a positive β-HCG result. This was done to predict values that could enable doctors to evaluate a healthy intrauterine pregnancy or a problematic ectopic pregnancy. After 6-7 weeks of pregnancy, ultrasounds were conducted to check cardiac activity as well as the amount of gestational sacs. This was then repeated at 12 weeks of pregnancy to ensure there was no chance of abortion.

A continuing pregnancy was defined as one that continued for at least 12 weeks of gestation and showed signs of proper cardiac function. On the other hand, those pregnancies that were abnormal had dropped levels of β-HCG concentrations and led to empty gestational sacs that showed no embryonic cardiac function. As a measuring tool for detecting levels of β-HCG, Chemiluminescent microparticle immunoassays were used whereby the measuring range established was between 0.0-15,000 mIU/mL. HCG levels above 10 IU/L signified early pregnancy.

'''Results Summary'''

Out of the 171 patients that participated in this study, only 139 were included due to the missing data on the levels of β-HCG concentrations at day 14 and 16 post embryonic transfer. In total there were 39 abnormal pregnancies that involved ectopic pregnancy, abortions and biochemical pregnancies (sufficient HCG levels detected but no visible gestational sac). Overall the patients were categorised into two groups which were patients with ‘ongoing pregnancy’ (n=100) and ‘without ongoing pregnancy’ (n=39). The Mann-Whitney test (statistical testing) was then used to compare the levels of β-HCG levels in both groups. It was found that the group with ongoing pregnancy had a median serum β-HCG level of 600 mIU/ml, whereas the other group had a median serum β-HCG level of 178 mIU/ml. This indicated a significant difference of P < 0.05 when comparing the two groups. It was also found that when serum β-HCG levels reached 347 mIU/ml, there was a 73.6% chance that the pregnancy was ongoing. Furthermore, there was no definite correlation established between age and the rate of ongoing pregnancy as both categories had patients of similar age groups with a combined range of 23-41 year old patients. Overall, the study revealed that early serum β-HCG is a potential predictor of successful outcomes in invitro fertilisation.

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 19:11, 6 October 2014 (EST) These are relevant references and your descriptions/abstracts are good (5/5).

===Lab 2===

[[File:Phase-contrast images of embryos at different developmental stages via neogenin expression.png|300px]]

Phase-contrast images of embryos at different developmental stages via neogenin expression.<ref><pubmed>25013897</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0101989 PLos One]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:17, 21 August 2014 (EST) This is all correct. The image is very large (4.8 MB), perhaps a small version could have been uploaded. You can adjust the resolution and size in most image editing programs. (5/5)

<references/>

===Lab 3===

'''Parathyroid gland'''

<pubmed>22808183</pubmed>
<pubmed>22649358</pubmed>
<pubmed>21881196</pubmed>
<pubmed>21904825</pubmed>

'''Thymus'''

<pubmed>21733645</pubmed>
<pubmed>20836742</pubmed>
<pubmed>21263742</pubmed>
<pubmed>512270</pubmed>

'''Pancreas'''

<pubmed>22761699</pubmed>
<pubmed>22893718</pubmed>
<pubmed>24496309</pubmed>
<pubmed>24595965</pubmed>
<pubmed>23822675</pubmed>
<pubmed>22968764</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===

'''1. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

'''Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1'''

Glioblastoma multiforme (GBM) is known to belong to a very life threatening form of brain cancer. Research is currently focused on finding treatments regarding such abnormalities, such as the application of neuronal stem cells in reducing the population of tumours, however there were many problems that occurred with such treatment. Recently, Human umbilical cord blood derived stem cells (hUCBSC) has been extensively used as they are useful mesenchymal stem cells that are easy to isolate and are more available. GBM is caused by the overexpression of cyclin D1 and its subsequent binding to Cdk 4/Cdk 6 which defines the rate limiting step required for the cell to progress further on to the cell cycle from the G1 phase. In order to stop this over expression, scientists have used hUCBSC to inhibit the cell from progressing on with the cell cycle.

When (hUCBSC) were cultured with U251 and 5310 cells, flow cytometry technology revealed that the cells underwent G1 arrest showing an increase in the G0-G1/S phase ratio. There was also a 54% reduction in levels of cyclin D1 when hUCBSC was cultured with U251 in comparison to the control. Immunoprecipiation revealed that hUCBSC treated cells when immuno blotted with Cdk 4 and Cdk 6 antibodies, down regulated expression of both Cdk 4 and Cdk 6. Western blot also showed the same down regulating pattern of the individual expression and genes which confirmed that there was cell cycle arrest, thus preventing tumours from forming.

As such, this study helps researchers to grasp the foundation of using hUCBSC as a treatment for glioblastoma and to further build on such research. Since it is evident that hUCBSC is effective in reducing cyclin D1 expression; analysing glioblastomal hierarchy will aid in providing the missing links needed to create the clinical treatment.

<pubmed>21455311</pubmed>

'''2. There are a number of developmental vascular "shunts" present in the embryo, that are closed postnatally. Identify these shunts and their anatomical location.'''

Three major vascular shunts include:

• '''Ductus venosus''' - is a shunt of oxygenated blood from umbilical vein to IVC, bypassing the liver. The ductus venosus constricts and closes soon after birth and becomes the ligamentum venosum

• '''Foramen ovale''' - is a flap valve in the atrial septum between the right and left atrium that shunts highly oxygenated blood . The remnant of the foramen ovale is known as the fossa ovalis.

• '''Ductus arteriosus''' - is a shunt from the descending aorta to the left pulmonary artery near the bifurcation of the pulmonary trunk. Permanent closure takes 4-6 weeks by fibrosis, and the remnant is referred to as the ligamentum arteriosum.

===Lab 5===

'''Select an abnormality of either gastrointestinal or respiratory development and write a brief description of developmental causes(s) for this abnormality. Your answer should be added to your own student page, be brief (2-3 paragraphs) and referenced.'''

'''Midgut volvulus'''

The embryonic development of the midgut has a number of steps which ensures its proper formation. These include the viability of the superior mesenteric artery to divide the midgut into the cephalad (pre-arterial region) and caudad (post-arterial region). <ref><pubmed>15378215</pubmed></ref>During the fourth gestational week, the gastrointestinal system is composed of a centrally positioned linear tube in the abdomen. At approximately 6 weeks of gestational age, the midgut undergoes a process of U-shaped herniation causing the two portions of the midguts to face the opposite directions in relation to the superior mesenteric artery. From this moment, a number of rotation events occur to ensure the complete development of the gastrointestinal tract as it becomes set in the posterior abdominal wall.<ref><pubmed>7277164</pubmed></ref>

In some cases malrotations can occur during the developmental process of the midgut which involves the complete twisting of the midgut in relation to the axis of the superior mesenteric artery. In extreme cases this can lead to midgut volvulus which results in a narrowed mesenteric base that can obstruct the passage of blood and lead to tissue necrosis. Other complications resulting from midgut volvulus include intestinal ischaemia, peritonitis, mucosal necrosis and sepsis which can eventually lead to death if left untreated. <ref><pubmed>14655161</pubmed></ref>

Malrotation is known to occur within 1 in 500 live births and out of those who develop midgut volvusos, 68-71% are neonates. <ref><pubmed>22217896</pubmed></ref>Although the actual cause of malrotation is unknown, researchers have made links to congenital syndromes such as Down syndrome and the VACTERL. It is also hypothesized that any embryonic interference during the normal patterns of rotation and fetal development can lead to midgut volvulus. Treatment of midgut volvulus is dependent on when the disease is diagnosed. <ref><pubmed>18800265</pubmed></ref>Normally a sigmoidoscopy is carried out as well as the Ladd procedure to resect dead gastrointestinal tissues. Transduodenal bands of ladd may also be divided to widen the mesenteric pedicle and prevent obstruction of blood flow. <ref><pubmed>22208840</pubmed></ref>Overall, research is still being conducted on the specific causes of malrotation and other numerous treatments.

<references/>

===Lab 6===

Group work

===Lab 7===

'''1.Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

'''Novel genes upregulated when NOTCH signaling is disrupted during hypothalamic development.'''

It is known that the hypothalamus first develops from the ventral region of the diencephalon and signaling mechanisms such as the sonic hedgehog and bone morphogenic protein pathways are responsible for pattern arrangement. Neurogenesis is the key process required to ensure proper hypothalamus development which relies on many signaling pathways to produce neurons and glia. The Notch signaling pathway is currently known to inhibit neuronal differentiation and preserve neural progenitor identity. As a result of various studies and research, the combined theory has been implemented in this study to determine the effect of downregulating Notch signaling pathways in its effect on hypothalamic development.

Results show that when Notch signaling is inactivated, novel genes such as Dll1, Hes5, Hey1 and Ascl1 are upregulated in the rostral hypothalamus, subsequently leading to the early formation of hypothalamic neurons. This is also seen when embryos that are treated with DAPT (a chemical which inhibits cell differentiation mechanisms regulated by the Notch pathway) had an overexpression of cells differentiated into neurons in a clustered formation. This was compared to the control embryos which had differentiated cells in a scattered arrangement. As such, this research showed that Notch is a powerful signaling mechanism that is used to inhibit cell differentiation in order to control the number of cells differentiated into neurons or glia. This modulating ability of the Notch pathway is imperative in the early developing hypothalamus as it controls expression of cells and hence prevents any form of defects that can be harmful both prenatally and postnatally. Further research needs to be conducted on the Notch pathway to provide procedures where its mechanism can be used to resolve defects in the embryo and hence ensure proper hypothalamic development.

<pubmed>24360028</pubmed>

'''2.Identify the embryonic layers and tissues that contribute to the developing teeth.'''

'''Odontoblasts''' - neural crest-derived mesenchymal cells which establish the outer dental pulp. It differentiates via the enamel epithelium and releases dentin from dentinogenesis.

'''Ameloblasts''' - are derived from oral epithelium tissue of ectodermal origin and make up the inner enamel. They make pre-ameloblasts and produce enamel.

'''Periodontal ligament''' – is comprised of connective tissues which holds the tooth in place in the alveolar bone. It also encloses the cementum coating of the tooth root.

===Lab 8===

'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

'''Embryonic development of the ovary'''

The Gonads are known to be formed from the combination of primitive germ cells, adjacent mesenchyme and the mesothelium of the posterior abdominal wall. It isn’t until fifth week of embryonic development that the formation of Gonads occurs. The primordial germ cells first migrate from the embryonic yolk sac towards the hindgut along the dorsal mesentery. These cells then travel to the mesenchyme forming genital ridges positioned medially to the mesonephros by the sixth week of development. Coelomic epithelium and the mesonephros cells also proliferate at this stage. These cells then incorporate into the primary sex cords in which the process is driven by the genes stella, fragilis, and BMP-4 before the seventh week of embryonic development.<ref><pubmed>23409002</pubmed></ref>

The gonads are known to be indifferent until the sixth embryonic week as the gonads appear the same, however sex differentiation based on sex chromosomes determine the sex of the Gonad (XX for female and XY for males). The indifferent gonads are situated well inside the Wolffian body and are comprised of an inner medulla and outer cortex which contains precursors for ovarian stroma and parenchyma respectively.<ref><pubmed>3712511</pubmed></ref> In embryos consisting of XX sex chromosomes, the cortex of the indifferent gonad differentiates into an ovary meanwhile the medulla regresses by week eight of embryonic development. However, the sex cords leads to the formation of rete ovarii which is a complex of tubules and cords that arises from the mesonephros.

Another important event that occurs during the sixth week of development is the formation of the mullerian ducts which are responsible for female gonad formation and prevention of male gonad development. The established XX genotype of the female embryo prevents testosterone from being produced and hence causes the regression of the mesonephric duct since this form is only needed for male gonad expression. Also since there is no production of anti-mullarian hormone, the paramesonephric duct is able to be maintained driving female gonad expression. As of 10 weeks of development, ovaries first become recognizable and the growth of female external genitalia begins to occur.

[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]

<references/>

''' 2.Include an image from the historic genital embryology section of the online notes in your description.'''

[[File:Gray1112.jpg|400px]]

Figure 1. Longitudinal Section of Ovary of Cat Embryo of 9.4 cm long

===Lab 9===

'''Group project 1'''

The introduction was written quite well as it explains what the respiratory system is about and the origin of its development. It also briefly highlights the difference between the embryonic and fetal stage which is important in enabling the viewers to have an understanding on what the project will be focusing on. I also like how the group distinguished between the two zones of the respiratory tract and adequately described the features and function of each. The content in the lung development stages clearly relates to the topic and underlines fetal development. The group briefly mentioned the key features in each stage instead of pasting a whole lot of information; this makes it easier for viewers to understand. Overall the content relates to the learning objectives of embryology and the level of research is good as exemplified under ‘Current Research and Findings’ and ‘abnormalities’ (many forms of diseases described). The project however could benefit from having a ‘Glossary’ list so that viewers can understand some uncommon words.

The images under introduction and the image used for Meconium aspiration syndrome have not been referenced properly as there is missing information such as ((Template: Student Image)), description, copyright information and proper references for some. The image used under the ‘current research and findings’ subheading is a good example for the group to copy the referencing style. It is also vital that the group adds a brief description of what the image illustrates as a caption to help viewers understand the relation of the content and image (this is seen in the image under ‘surfactant’). More images could be added such as in the ‘lung development stage’ and under abnormalities. If images for lung development stages aren’t easily accessible, it is perhaps a good idea to draw them. The table format used for ‘lung development stages’ makes it easy for the viewers to navigate which is a good feature used in the project.

In terms of referencing, there are many in-cite references missing such as in the ‘introduction’ and in ‘lung development stages’. It is important to have these references formatted correctly under the one ‘references’ subheading. There seems to be many ‘references’ subheadings making it harder for viewers to navigate. Some references are shown as ‘ </li> which needs to be fixed right away. Overall, the content seems well written, formatted and concise making it easy to understand. However the problems related to referencing needs to be corrected as this is inconsistent throughout the project.

'''Group project 2'''

The introduction is well addressed as it sufficiently describes what the renal system is about and its function. Not to mention its anatomical structure as well as the difference between the embryonic and fetal stages of development. This differentiation enables viewers to understand what the content will be focused on, which is fetal development. Also, it helps focus the viewer’s attention on how the project will be divided as the group mentions abnormalities in the last paragraph. Overall the introduction has the right amount of information from each subheading and is very easy to comprehend.

There isn’t any information under ‘historic findings’. If there are any difficulties in finding some historic findings, members of the group can go to pubmed and on the side will be dates such as 1920 that could contain key historical events when renal is entered on search. The use of a development timeline was great as they outlined the major events that occur in a concise manner. Although, I believe a glossary is needed for words like ‘metanephros’ since the viewers would not know what that is. The content under current research models is interesting and correctly describes what the studies were about. Overall, the content used in the project was relating to the topic (fetal development of the kidney) and clearly showed extensive research. I really like how the group divided the different parts of the renal system as well as describing their anatomical positions. The abnormalities listed are also interesting and very easy to understand. I’m hoping to see information under the Horseshoe kidney disease.

In terms of images, there should be an image under introduction perhaps having all features of the renal system. Most images are missing the ‘student template’ aspect of the referencing and needs to be added right away. Other aspects such as description, copyright and referencing were correct. I also like the use of captions to describe what the images are about, however some are missing on the page such as the one under ‘anatomical position’ and ‘urethra’. The image used for the ‘development of the kidney’ should be removed from the page as it isn’t permissible. It should be replaced with an image relating to the content and have all the correct copyright and referencing information. Overall, I like the number of images used and its significance to the renal system. They accurately relate to the content of the project.

There is use of in-cite referencing which is good, however some references are just listed and should be placed under the proper ‘references’ subheading such as the ones under ‘ureter’ and ‘renal agenesis’. Some references in the ‘references’ list are used over again and can be fixed by combining it under one reference number. To make the project even more appealing, the group could format the information under ‘developmental timeline’ or even ’historic findings’ in a table. Overall, I think this project is great and by making edits based on the peer-reviews received could enhance their project.

'''Group project 3'''

The introduction is good as it accurately describes what the GIT system is about and the anatomical positions of the features in this system. It also briefly highlights the development stages at embryonic and fetal stages, however ‘embryonic development’ should be mentioned in a little more detail to understand how far in development the fetal stage begins. I also think the introduction should include a sentence or two describing how abnormalities in such organs can lead to these diseases. Basically a bit from each major subheading should be incorporated including current research as an introduction is a summary of the whole page. As for the ‘timeline’, it would’ve been more appropriate to place the timelines under each section, e.g foregut timeline under the ‘foregut’ subheading. This is because viewers would be confused on why there is so much difference in development in one section of the page. A glossary list should be incorporated in a separate subheading to define some of these words such as hematopoiesis so that viewers can fully grasp the information.

The information under recent findings is quite interesting and relatable to the content which is GIT fetal development. However, I believe more findings could be incorporated under this subheading. The information under each organ of the three ‘guts’ are quite detailed in fetal development which is good and shouldn’t be too difficult for the viewers to understand. However, I believe the group could include information on the function of these organs as well. The structure of the information under ‘guts’ does not flow in the sense that the midgut includes features and structure whereas the other ‘guts’ do not. The innvervation and bloody supply of the hindgut should be incorporated in a paragraph instead of being listed like that. All the deformities should be places under one subheading to make it easier for viewers to navigate. The abnormalities were also concise and related to the topic. Overall, the content is relating to the topic of the project and addresses key points. It also shows good amount of research, however there seems to be too much information in some parts which could be reduced a bit. The project needs a coherent flow of the structure.

As for images, there needs to be an image under introduction which includes all features of the GIT tract. There are a lot of potential images missing under each subheading except for the ‘midgut’ section. This shows that there has been one person working on this section or one section being focused on in comparison the others. The information used to reference the images is missing in some images such as the ‘Human- fetal week 10 sagittal plane D.jpg’ (although this is uploaded from a different user so this is understandable. However images such a ‘GIT 2.jpg’ need more information including ‘student template’ as well as the reference where the image idea may have come from. Also, if this is a hand-drawn image then please state this as one member did in ‘Week 11 midgut herniation.png’. Overall, I enjoy the use of self-drawn images as it makes it easier to show what the content is saying without going through the stress of looking for an image online that doesn’t relate to the content. However more images definitely need to be added. The use of captions is also good and indicates what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘Liver, Gallbladder and Bile Duct’ (the [6],[7] should be placed next to the text not above the text. The use of a ‘references’ subheading is good the same references have been combined into one number showing that the group knows how to make the references set out. The use of a table in formatting the ‘Percentage of Foetuses Herniated’ is great and shows more that the group has done research. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 4'''

The project doesn’t have an introduction yet; however information such as what the genital system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of genital development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. As for system development, I can see how there is dot-point description above the table which summarises the same thing. This structure is a bit confusing for me. I believe if the information was summarised into paragraphs and then tabulated it would make more sense. It’s best to format all that information into that table. The use of a table is a great way for the viewers to differentiate between the two sexes and understand the information more easily. I hope to see the table filled out completely soon. A glossary subheading should also be placed on the project page and have keywords defined to make viewers completely understand the content.

As for current findings, the information again is in dot points which should be paragraphed instead. However, the current findings are indeed interesting and the right amount of information is used to describe them in both sexes. The content under historic findings such as the ‘female genital development’ doesn’t show any historical events. There are no dates which show when something related was discovered. The ‘male genital development’ however shows dates and discoveries. In my opinion, if this information were tabulated rather than paragraphed, it’d be easier for viewers to navigate and understand. There is a good amount of detail under the abnormalities which relates to the key topic and is easy to understand. Overall, the content is relatable to the genital development of the fetus and underlines all the keys points. However, if this information were paragraphed in some areas and mentioned above, it would make the content easier to navigate and comprehend.

In terms of images, there are many places where images are missing such as introduction, system development and current models. I believe there needs to be more images on this page that relate to the content to make it more appealing and understandable to the viewers. The image called ‘File:Flow Diagram of Fetal Development of External Genitalia.pptx’ isn’t permissible and needs to be removed. The use of a hand drawn image on the testes is great, however there is information missing on referencing, student template and copyright laws. On the other hand, there are some images which correctly follow the uploading picture procedures such as the image on the ‘abnormalities of the vagina’; group members should follow this procedure. Captions should be added to each image to address what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘system development’. The use of a ‘references’ subheading is good, the same references have been combined into one number showing that the group knows how to make the references set out. However reference 20 and 21 are the same, please fix this. Also there are references under each subheading which should be placed all under one ‘references’ subheading. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 5'''

The introduction is a great summary of what the project page will discuss making sure to highlight every aspect. However, the introduction should also mention more about the integumentary system listing all the organs involved, their function, anatomical position and the difference between the embryonic and fetal stages of integumentary development. The content presented on the page is fantastic. All information under the subheadings looks complete and has key information related to the topic. I like how the timeline is divided into each organ making it easy to understand and navigate. The use of the table to format the information is a brilliant idea and has been presented beautifully with images in each textbox. Also the content under current research is relating to the topic and shows extensive research. The use of the purple background is appealing to the viewer highlighting its significance. I do however believe that the information under ‘historic findings’ should be formatted into a table to make it easier to navigate. The content under ‘abnormalities’ has the right amount of information and clearly relates to the key topic of the project.

In terms of images, I believe a satisfactory amount of images have been used which clearly describes the content. However, some images are missing the all the copyright information needed as well as the description, references and student template such as those in the ‘development overview’ table. This should be added right away to ensure these images do not get deleted. The use of captions on these pictures is important to highlight what the image is referring to and this is present in the page. Although, images could be added under current research as this section looks like it could use more images. Great job on the images under abnormalities, they accurately relate to the content mentioned.

There are some incite references missing such as in the development overview. I’m not sure if the references listed below are supposed to the references for it, however all references should be placed under one ‘references’ subheading. The same references have been combined into one number showing that the group knows how to make the references set out. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections. Overall, this is a great project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 7'''

The introduction is great as it mentions the features of the neural system, their anatomical positions and highlights the key events in the embryonic and fetal stages of development. The last paragraph of the introduction clearly addresses how the page will be divided and what the viewers are to expect which is good. The content under all subheadings are relating to the key topic and are formatted appropriately. I really like the image used under the subheading ‘Development during fetal period’ as it presents a diagrammatic representation of the content mentioned. The use of a table to briefly describe the events that occur at certain periods of fetal development is really helpful in grasping the main details. Some information is missing such as in ‘spinal cord development’, ‘Meninges development’, ‘future research’ and some ‘abnormalities’. This should be added right away. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the neural system and view dates on the side that may contain key findings. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

In terms of images, there are still many potential spaces for images such as under ‘introduction’, ‘current research’ and some ‘abnormalities’. The images used under ‘Development during fetal period’ are great and relate to the content. All images have correct description, referencing, copyright issues and ‘student template’, which shows that members of the group have followed correct ‘uploading image’ procedures. The images however need a caption to describe what the image is showing.

There needs to be more use of incite referencing such as in the ‘introduction’, ‘brain development’ and ‘abnormalities’. There is a huge list of references under ‘current research models and findings’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. References 7 and 8 are the same reference under the ‘references’ subheading and need to be combined into one number. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 8'''

The project doesn’t have an introduction yet; however information such as what the Musculoskeletal system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of musculoskeletal development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. I like the ‘making gains’ subheading as it adds humour to the page and engages the viewers. The general timeline needs information including what events take place at certain phases of fetal development. This could be present in a table to make the information more clear. It’s good that the project has information on the embryonic development so that the viewers can understand how the fetus arises to that point in development (fetal period).
All of the content seems to relate to the key topic and is appropriately paragraphed. However much of the content is still missing such as in ‘recent findings’ and ‘introduction’. More information could be added under the associated ‘trimesters’ and ‘abnormalities’. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the musculoskeletal system and view dates on the side that may contain key findings for historical events. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

There are no images on this page and definitely needs to be added with the appropriate information such as the description, referencing, copyright issues and ‘student template’. If images are not readily available, it is best to draw them. Also captions should be added on the page to state what the images are showing. As for referencing, there are some sections which shows incite referencing such as in the content under ‘Molecular and Cellular regulation of fetal myogenesis’ and some that don’t have any like in ‘tendon development’. There needs to be references in all sections. There is a huge list of references under ‘abnormalities’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. Number 15 of the reference list has an error in it and needs to be fixed right away. Overall, this is a working progress and if the group makes edits based on the peer-reviews received, this could enhance their project.

===Lab 10===

'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

'''''TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction.'''''

A major feature of the olfactory region is the olfactory bulb which contains mitral cells that serve to relay olfactory messages via sensory neurons of the olfactory epithelium to the piriform cortex of the brain. Within the granular cells and glomerular layers are interneurons which control the message output via synaptic linkages between mitral and tufted cell projection neurons. These interneurons continue to grow postnatally via neural stem cells located in the dorsolateral ganglionic eminence (dLGE) which consists of the subventricular zone and subependymal zone. When neuroblasts migrate to the dLGE, this stimulates dLGE-derived interneuron progenitors to migrate radially in the growing bulbs where they mature into the granular or glomerular cell layer. There has been research showing how teashirt zinc finger family member 1 (TSHZ1) is vital for the development of the olfactory bulb. In mice, it was found that olfactory bulb neuroblast differentiation required Tshz1 expression or else a large proportion of interneurons of the granular cell layer will not be present and radial migration of neuroblasts will be impaired. The basis of the previous studies was then replicated in humans suffering from congenital aural atresia that had TSHZ1 loss-of-function mutations.

Coronal sections 500-μm in size was obtained from the subjects which then underwent Nissl staining with cholineacetyl transferase histochemistry to observe the change in patterns of normal and abnormal olfactory development. In some parts of the experiment, mice were used as subjects to observe how congenital aural atresia may also affect them. In situ hybridization was used to investigate this effect on mice whereby Tshz1 positive and negative gene transcripts were obtained and amplified using polymerase chain reaction (PCR). Primers of the targeted gene and splicing enzymes were used to make sure the correct transcripts were produced.

Through immunoflourenscing and immunohistology, it was found that Tshz1 mutation lead to an abnormal distribution and differentiation of granule cell neurons of the developing olfactory bulb. Green fluoresce protein was integrated in the Tshz1 locus in both Tshz1+ and Tshz1- subjects. Through immunostaining of olfactory bulbs, it was shown that there was a consistent outer granule cell ring distribution of GFP+ cells in comparison to the unevenly distributed GFP+ cell located in the inner granule cell layer. DAPI staining revealed that the structure of the olfactory bulb in Tshz1 positive subjects were more layered and structure compared to deformed structure seen in Tshz1 mutants. The granule cell and external plexiform layers were indistinguishable and the glomerular layer had multilayers, thereby showing the abnormality in Tshz1 mutants.

Microarray hybridization was used to sort out gene expression in Tshz1 positive and negative subjects. Out of all the gene transcripts profiled, it was noted that the most significantly changed transcripts was Prokr2. Expression of PK2 was also downregulated in the rostral migratory stream of the subjects. Prokr2 expression was therefore examined in the developing olfactory bulb of Tshz1 positive and mutant mice using in situ hybridization. It was found that Tshz1 mRNA expression was seen in both the outer granule cell layer and the inner layers of the olfactory bulb mainly consisting of immature cells. Prokr2 expression was observed only in the inner layers of the OB in Tshz1 positive subjects and in mutants, Prokr2 expression was greatly downregulated. Overall, it was established that Tshz1 is needed to control the expression of Prokr2 which radially migrates neuroblasts. In addition, the PK2 family and its associated receptor are imperative factors required for normal olfactory bulb development.

<pubmed>24487590</pubmed>

'''Wiki link: https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Smell_Development'''

===Lab 11===

'''Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

'''Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration.'''

As cardiovascular disease continues to be the number one cause of death in the older population, there is significant research based on using stem cells as a tool to regenerate functional and healthy cardiomyctes in patients who’ve suffered from myocardial infarction. In particular, human induced pluripotent stem cells (hiPSCs) are used in this study to observe how these cells can generate cardiovascular cell sheets that may be used to treat infarcted heart tissue. Not to mention how hiPSCs may overcome obstacles such as poor engraftment of the cells injected in the heat and immunorejection, thereby placing the research more towards clinical practice.

'''Main findings'''

Data obtained from the study showed that there was simultaneous induction of cardiomyocytes and vascular cells using human IPSCs. It was shown that the levels of gene expression of cardiac mesoderm/progenitor genes (KDR/ISL1) were heightened on the day they were due to differentiate and when Dkk1 (a canonical Wnt antagonist) was added, the rate of differentiation of cardiomyocytes from mesoderm cells was increased. However when VEGF was added, this stimulated the induction of cardiomyocytes and vascular cells at the same time.

Furthermore, it was discovered that hiPSCs could generate cardiovascular cell sheets by placing hiPSC-derived cardiovascular cells into 12-multiwell temperature-responsive culture plates. After reducing the temperature, it was found that self-pulsating cell sheets (hiPSC-CTSs) was comprised of 3-4 cell layers with complete stratified structure of collagen positioned adjacent to the cell constituents. Immunostaining revealed that cardiomyocytes were expressed in large numbers out of all the three cells (myocytes and vascular endothelial cells), suggesting that non-myocytes are needed in cell sheet formation by remodelling cardiac cell distribution.

hiPSc-CTs were also shown to improve cardiac function after acute myocardial infarction in rats. The hiPSc-CTs were lined up in a 3-sheet structure where they were transplanted into a rat with acute myocardial infartction. After 8 weeks, an echocardiogram was performed and showed that anterior wall contraction was restored and parameters for left ventricle (LV) systolic function, fractional shortening (FS) and fractional area change (FAC) were improved. Sirius red staining also indicated that hiPSC-CTS transplantation greatly prevented fibrosis, thereby leaving more cardiac tissues to function properly.

Overall, this study shows evidence that HiPSC-CTSs are showing promising results in the generation of cardiomyocytes and in restoring cardiac function of those that suffered from myocardial infarction.

<ref><pubmed>25336194</pubmed></ref>

<references/>

User:Z3418837

2014-10-27T12:40:41Z

Z3418837: /* Lab 11 */

==Lab Attendance==
*Lab 1 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 6 August 2014 (EST)
*Lab 2 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:11, 13 August 2014 (EST)
*Lab 3 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:12, 20 August 2014 (EST)
*Lab 4 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:55, 27 August 2014 (EST)
*Lab 5 -- Absent
*Lab 6 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:44, 10 September 2014 (EST)
*Lab 7 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:40, 17 September 2014 (EST)
*Lab 8 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:11, 24 September 2014 (EST)
*Lab 9 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:08, 8 October 2014 (EST)
*Lab 10 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 15 October 2014 (EST)
*Lab 11 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 22 October 2014 (EST)
*Lab 12

==Individual Assessment==

==='''Lab 1'''===

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 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>

'''Your Lab assessment now requires you to find a 2 recent research references on fertilisation or in vitro fertilisation. Paste each reference on your page, as shown in the class. Write below each reference a brief summary of the research article methods and findings. The summary for each need not be more than 3-4 paragraphs in length. This will need to be completed before next weeks laboratory'''.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/25077107 PMID25077107]

<pubmed>25077107</pubmed>

This study was designed to investigate whether the levels of vitamin D is an imperative factor when it comes to the clinical success of implantation and pregnancy rates in infertile women via invitro fertilisation.

'''Method summary'''

A cohort of 173 women were evaluated and selected for this study based on their age, follicle-stimulating hormone levels and their consent to undergo invitro fertilisation. The following study was conducted at Mount Sinai Hospital where proper facilities were available. Blood tests were then conducted for each patient to determine their levels of Vitamin D via the serum 25-hydroxy-vitamin D (25[OH]D) levels. Following the results of the blood test, the cohort were then categorised into two groups which was either vitamin D sufficient (≥ 75 nmol/L) or insufficient ( < 75 nmol/L) based on serum levels of 25(OH)D.

Each patient then underwent IVF cycles whereby standard agonists that contained the active ingredient 0.5 mg/d of buserelin acetate in conjunction with cetrolix acetate as the standard antagonist were used to control the length of the luteal phase and estradiol levels. The length and dose of the treatment were varied for each individual based on their demographic data. Serial transvaginal ultrasonograpy and serum lutenizing hormone assays were then used to check ovarian response. When 3 or more dominant follicles (≥ 17 mm) were produced, 10 000 IU of human chorionic gonadotropin was added to enhance nuclear maturation. Oocyte retrieval was then conducted via transvaginal ultrasound whereby it was fertilised and the resulting embryo was transferred 3-5 days post-fertilisation. The rate of pregnancy per IVF cycle was then used as the primary outcome for this study whereby the visibility of the intrauterine sac of the embryo determined implantation.

'''Results summary'''

Out of the 182 patients that participated in this study, it was found that only 173 patients could continue on with this trial as they satisfied the criteria, however only 162 were fit for embryo transfer. Following the results from the blood test, it was noted that 53.8% of patients had insufficient levels of 25(OH)D and 45.1% had sufficient amounts. It was discovered that 71.8% of those with sufficient levels of 25(OH)D were more likely to proceed with embryo transfer on day 5 compared to 58.9% (p = 0.054) of those assigned to the ‘insufficient 25(OH)D’ category. Other factors such as oocyte retrieval and frequency of intracytoplasmic sperm injection were fairly similar in both groups. The study revealed that there was a higher clinical pregnancy rate per IVF cycle for those assigned to the sufficient 25(OH)D level category by 52.5% compared to those with insufficient amounts of 25(OH)D which was 34.7% (p < 0.001). Similarly, there was a significant clinical pregnancy rate per embryo transfer of 54.7% in comparison to 37.9% in woman belonging to the sufficient and insufficient category respectively. It was also noted that the implantation rate was greater in the sufficient category compared to the insufficient group, however the difference was only minimal (p= 0.6). Overall, the results suggest that serum 25(OH)D levels may be a predictor of clinical pregnancy.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/24672163 PMID24672163]

<pubmed>24672163</pubmed>

The process of achieving pregnancy via invitro fertilisation needs to be monitored and controlled with respect to the demographics of the individual in order to achieve a successful outcome. This study focuses on predicting the value of β-human chorionic gonadotrophin (β-HCG) that can lead to clinical success.

'''Method summary'''

Data analysis was taken from 171 female patients using the statistical package for social sciences program whereby all IVF cycles were monitored. The cycles that showed fresh multi-cell embryos (day 3) or blastocysts (day 5) were deemed fit for the trial and were the ones that were further used in this study. Serum β-HCG concentrations were then taken 14 days after the embryo was transferred whereby a second test was done on day 16 only if the first test revealed a positive β-HCG result. This was done to predict values that could enable doctors to evaluate a healthy intrauterine pregnancy or a problematic ectopic pregnancy. After 6-7 weeks of pregnancy, ultrasounds were conducted to check cardiac activity as well as the amount of gestational sacs. This was then repeated at 12 weeks of pregnancy to ensure there was no chance of abortion.

A continuing pregnancy was defined as one that continued for at least 12 weeks of gestation and showed signs of proper cardiac function. On the other hand, those pregnancies that were abnormal had dropped levels of β-HCG concentrations and led to empty gestational sacs that showed no embryonic cardiac function. As a measuring tool for detecting levels of β-HCG, Chemiluminescent microparticle immunoassays were used whereby the measuring range established was between 0.0-15,000 mIU/mL. HCG levels above 10 IU/L signified early pregnancy.

'''Results Summary'''

Out of the 171 patients that participated in this study, only 139 were included due to the missing data on the levels of β-HCG concentrations at day 14 and 16 post embryonic transfer. In total there were 39 abnormal pregnancies that involved ectopic pregnancy, abortions and biochemical pregnancies (sufficient HCG levels detected but no visible gestational sac). Overall the patients were categorised into two groups which were patients with ‘ongoing pregnancy’ (n=100) and ‘without ongoing pregnancy’ (n=39). The Mann-Whitney test (statistical testing) was then used to compare the levels of β-HCG levels in both groups. It was found that the group with ongoing pregnancy had a median serum β-HCG level of 600 mIU/ml, whereas the other group had a median serum β-HCG level of 178 mIU/ml. This indicated a significant difference of P < 0.05 when comparing the two groups. It was also found that when serum β-HCG levels reached 347 mIU/ml, there was a 73.6% chance that the pregnancy was ongoing. Furthermore, there was no definite correlation established between age and the rate of ongoing pregnancy as both categories had patients of similar age groups with a combined range of 23-41 year old patients. Overall, the study revealed that early serum β-HCG is a potential predictor of successful outcomes in invitro fertilisation.

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 19:11, 6 October 2014 (EST) These are relevant references and your descriptions/abstracts are good (5/5).

===Lab 2===

[[File:Phase-contrast images of embryos at different developmental stages via neogenin expression.png|300px]]

Phase-contrast images of embryos at different developmental stages via neogenin expression.<ref><pubmed>25013897</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0101989 PLos One]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:17, 21 August 2014 (EST) This is all correct. The image is very large (4.8 MB), perhaps a small version could have been uploaded. You can adjust the resolution and size in most image editing programs. (5/5)

<references/>

===Lab 3===

'''Parathyroid gland'''

<pubmed>22808183</pubmed>
<pubmed>22649358</pubmed>
<pubmed>21881196</pubmed>
<pubmed>21904825</pubmed>

'''Thymus'''

<pubmed>21733645</pubmed>
<pubmed>20836742</pubmed>
<pubmed>21263742</pubmed>
<pubmed>512270</pubmed>

'''Pancreas'''

<pubmed>22761699</pubmed>
<pubmed>22893718</pubmed>
<pubmed>24496309</pubmed>
<pubmed>24595965</pubmed>
<pubmed>23822675</pubmed>
<pubmed>22968764</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===

'''1. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

'''Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1'''

Glioblastoma multiforme (GBM) is known to belong to a very life threatening form of brain cancer. Research is currently focused on finding treatments regarding such abnormalities, such as the application of neuronal stem cells in reducing the population of tumours, however there were many problems that occurred with such treatment. Recently, Human umbilical cord blood derived stem cells (hUCBSC) has been extensively used as they are useful mesenchymal stem cells that are easy to isolate and are more available. GBM is caused by the overexpression of cyclin D1 and its subsequent binding to Cdk 4/Cdk 6 which defines the rate limiting step required for the cell to progress further on to the cell cycle from the G1 phase. In order to stop this over expression, scientists have used hUCBSC to inhibit the cell from progressing on with the cell cycle.

When (hUCBSC) were cultured with U251 and 5310 cells, flow cytometry technology revealed that the cells underwent G1 arrest showing an increase in the G0-G1/S phase ratio. There was also a 54% reduction in levels of cyclin D1 when hUCBSC was cultured with U251 in comparison to the control. Immunoprecipiation revealed that hUCBSC treated cells when immuno blotted with Cdk 4 and Cdk 6 antibodies, down regulated expression of both Cdk 4 and Cdk 6. Western blot also showed the same down regulating pattern of the individual expression and genes which confirmed that there was cell cycle arrest, thus preventing tumours from forming.

As such, this study helps researchers to grasp the foundation of using hUCBSC as a treatment for glioblastoma and to further build on such research. Since it is evident that hUCBSC is effective in reducing cyclin D1 expression; analysing glioblastomal hierarchy will aid in providing the missing links needed to create the clinical treatment.

<pubmed>21455311</pubmed>

'''2. There are a number of developmental vascular "shunts" present in the embryo, that are closed postnatally. Identify these shunts and their anatomical location.'''

Three major vascular shunts include:

• '''Ductus venosus''' - is a shunt of oxygenated blood from umbilical vein to IVC, bypassing the liver. The ductus venosus constricts and closes soon after birth and becomes the ligamentum venosum

• '''Foramen ovale''' - is a flap valve in the atrial septum between the right and left atrium that shunts highly oxygenated blood . The remnant of the foramen ovale is known as the fossa ovalis.

• '''Ductus arteriosus''' - is a shunt from the descending aorta to the left pulmonary artery near the bifurcation of the pulmonary trunk. Permanent closure takes 4-6 weeks by fibrosis, and the remnant is referred to as the ligamentum arteriosum.

===Lab 5===

'''Select an abnormality of either gastrointestinal or respiratory development and write a brief description of developmental causes(s) for this abnormality. Your answer should be added to your own student page, be brief (2-3 paragraphs) and referenced.'''

'''Midgut volvulus'''

The embryonic development of the midgut has a number of steps which ensures its proper formation. These include the viability of the superior mesenteric artery to divide the midgut into the cephalad (pre-arterial region) and caudad (post-arterial region). <ref><pubmed>15378215</pubmed></ref>During the fourth gestational week, the gastrointestinal system is composed of a centrally positioned linear tube in the abdomen. At approximately 6 weeks of gestational age, the midgut undergoes a process of U-shaped herniation causing the two portions of the midguts to face the opposite directions in relation to the superior mesenteric artery. From this moment, a number of rotation events occur to ensure the complete development of the gastrointestinal tract as it becomes set in the posterior abdominal wall.<ref><pubmed>7277164</pubmed></ref>

In some cases malrotations can occur during the developmental process of the midgut which involves the complete twisting of the midgut in relation to the axis of the superior mesenteric artery. In extreme cases this can lead to midgut volvulus which results in a narrowed mesenteric base that can obstruct the passage of blood and lead to tissue necrosis. Other complications resulting from midgut volvulus include intestinal ischaemia, peritonitis, mucosal necrosis and sepsis which can eventually lead to death if left untreated. <ref><pubmed>14655161</pubmed></ref>

Malrotation is known to occur within 1 in 500 live births and out of those who develop midgut volvusos, 68-71% are neonates. <ref><pubmed>22217896</pubmed></ref>Although the actual cause of malrotation is unknown, researchers have made links to congenital syndromes such as Down syndrome and the VACTERL. It is also hypothesized that any embryonic interference during the normal patterns of rotation and fetal development can lead to midgut volvulus. Treatment of midgut volvulus is dependent on when the disease is diagnosed. <ref><pubmed>18800265</pubmed></ref>Normally a sigmoidoscopy is carried out as well as the Ladd procedure to resect dead gastrointestinal tissues. Transduodenal bands of ladd may also be divided to widen the mesenteric pedicle and prevent obstruction of blood flow. <ref><pubmed>22208840</pubmed></ref>Overall, research is still being conducted on the specific causes of malrotation and other numerous treatments.

<references/>

===Lab 6===

Group work

===Lab 7===

'''1.Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

'''Novel genes upregulated when NOTCH signaling is disrupted during hypothalamic development.'''

It is known that the hypothalamus first develops from the ventral region of the diencephalon and signaling mechanisms such as the sonic hedgehog and bone morphogenic protein pathways are responsible for pattern arrangement. Neurogenesis is the key process required to ensure proper hypothalamus development which relies on many signaling pathways to produce neurons and glia. The Notch signaling pathway is currently known to inhibit neuronal differentiation and preserve neural progenitor identity. As a result of various studies and research, the combined theory has been implemented in this study to determine the effect of downregulating Notch signaling pathways in its effect on hypothalamic development.

Results show that when Notch signaling is inactivated, novel genes such as Dll1, Hes5, Hey1 and Ascl1 are upregulated in the rostral hypothalamus, subsequently leading to the early formation of hypothalamic neurons. This is also seen when embryos that are treated with DAPT (a chemical which inhibits cell differentiation mechanisms regulated by the Notch pathway) had an overexpression of cells differentiated into neurons in a clustered formation. This was compared to the control embryos which had differentiated cells in a scattered arrangement. As such, this research showed that Notch is a powerful signaling mechanism that is used to inhibit cell differentiation in order to control the number of cells differentiated into neurons or glia. This modulating ability of the Notch pathway is imperative in the early developing hypothalamus as it controls expression of cells and hence prevents any form of defects that can be harmful both prenatally and postnatally. Further research needs to be conducted on the Notch pathway to provide procedures where its mechanism can be used to resolve defects in the embryo and hence ensure proper hypothalamic development.

<pubmed>24360028</pubmed>

'''2.Identify the embryonic layers and tissues that contribute to the developing teeth.'''

'''Odontoblasts''' - neural crest-derived mesenchymal cells which establish the outer dental pulp. It differentiates via the enamel epithelium and releases dentin from dentinogenesis.

'''Ameloblasts''' - are derived from oral epithelium tissue of ectodermal origin and make up the inner enamel. They make pre-ameloblasts and produce enamel.

'''Periodontal ligament''' – is comprised of connective tissues which holds the tooth in place in the alveolar bone. It also encloses the cementum coating of the tooth root.

===Lab 8===

'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

'''Embryonic development of the ovary'''

The Gonads are known to be formed from the combination of primitive germ cells, adjacent mesenchyme and the mesothelium of the posterior abdominal wall. It isn’t until fifth week of embryonic development that the formation of Gonads occurs. The primordial germ cells first migrate from the embryonic yolk sac towards the hindgut along the dorsal mesentery. These cells then travel to the mesenchyme forming genital ridges positioned medially to the mesonephros by the sixth week of development. Coelomic epithelium and the mesonephros cells also proliferate at this stage. These cells then incorporate into the primary sex cords in which the process is driven by the genes stella, fragilis, and BMP-4 before the seventh week of embryonic development.<ref><pubmed>23409002</pubmed></ref>

The gonads are known to be indifferent until the sixth embryonic week as the gonads appear the same, however sex differentiation based on sex chromosomes determine the sex of the Gonad (XX for female and XY for males). The indifferent gonads are situated well inside the Wolffian body and are comprised of an inner medulla and outer cortex which contains precursors for ovarian stroma and parenchyma respectively.<ref><pubmed>3712511</pubmed></ref> In embryos consisting of XX sex chromosomes, the cortex of the indifferent gonad differentiates into an ovary meanwhile the medulla regresses by week eight of embryonic development. However, the sex cords leads to the formation of rete ovarii which is a complex of tubules and cords that arises from the mesonephros.

Another important event that occurs during the sixth week of development is the formation of the mullerian ducts which are responsible for female gonad formation and prevention of male gonad development. The established XX genotype of the female embryo prevents testosterone from being produced and hence causes the regression of the mesonephric duct since this form is only needed for male gonad expression. Also since there is no production of anti-mullarian hormone, the paramesonephric duct is able to be maintained driving female gonad expression. As of 10 weeks of development, ovaries first become recognizable and the growth of female external genitalia begins to occur.

[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]

<references/>

''' 2.Include an image from the historic genital embryology section of the online notes in your description.'''

[[File:Gray1112.jpg|400px]]

Figure 1. Longitudinal Section of Ovary of Cat Embryo of 9.4 cm long

===Lab 9===

'''Group project 1'''

The introduction was written quite well as it explains what the respiratory system is about and the origin of its development. It also briefly highlights the difference between the embryonic and fetal stage which is important in enabling the viewers to have an understanding on what the project will be focusing on. I also like how the group distinguished between the two zones of the respiratory tract and adequately described the features and function of each. The content in the lung development stages clearly relates to the topic and underlines fetal development. The group briefly mentioned the key features in each stage instead of pasting a whole lot of information; this makes it easier for viewers to understand. Overall the content relates to the learning objectives of embryology and the level of research is good as exemplified under ‘Current Research and Findings’ and ‘abnormalities’ (many forms of diseases described). The project however could benefit from having a ‘Glossary’ list so that viewers can understand some uncommon words.

The images under introduction and the image used for Meconium aspiration syndrome have not been referenced properly as there is missing information such as ((Template: Student Image)), description, copyright information and proper references for some. The image used under the ‘current research and findings’ subheading is a good example for the group to copy the referencing style. It is also vital that the group adds a brief description of what the image illustrates as a caption to help viewers understand the relation of the content and image (this is seen in the image under ‘surfactant’). More images could be added such as in the ‘lung development stage’ and under abnormalities. If images for lung development stages aren’t easily accessible, it is perhaps a good idea to draw them. The table format used for ‘lung development stages’ makes it easy for the viewers to navigate which is a good feature used in the project.

In terms of referencing, there are many in-cite references missing such as in the ‘introduction’ and in ‘lung development stages’. It is important to have these references formatted correctly under the one ‘references’ subheading. There seems to be many ‘references’ subheadings making it harder for viewers to navigate. Some references are shown as ‘ </li> which needs to be fixed right away. Overall, the content seems well written, formatted and concise making it easy to understand. However the problems related to referencing needs to be corrected as this is inconsistent throughout the project.

'''Group project 2'''

The introduction is well addressed as it sufficiently describes what the renal system is about and its function. Not to mention its anatomical structure as well as the difference between the embryonic and fetal stages of development. This differentiation enables viewers to understand what the content will be focused on, which is fetal development. Also, it helps focus the viewer’s attention on how the project will be divided as the group mentions abnormalities in the last paragraph. Overall the introduction has the right amount of information from each subheading and is very easy to comprehend.

There isn’t any information under ‘historic findings’. If there are any difficulties in finding some historic findings, members of the group can go to pubmed and on the side will be dates such as 1920 that could contain key historical events when renal is entered on search. The use of a development timeline was great as they outlined the major events that occur in a concise manner. Although, I believe a glossary is needed for words like ‘metanephros’ since the viewers would not know what that is. The content under current research models is interesting and correctly describes what the studies were about. Overall, the content used in the project was relating to the topic (fetal development of the kidney) and clearly showed extensive research. I really like how the group divided the different parts of the renal system as well as describing their anatomical positions. The abnormalities listed are also interesting and very easy to understand. I’m hoping to see information under the Horseshoe kidney disease.

In terms of images, there should be an image under introduction perhaps having all features of the renal system. Most images are missing the ‘student template’ aspect of the referencing and needs to be added right away. Other aspects such as description, copyright and referencing were correct. I also like the use of captions to describe what the images are about, however some are missing on the page such as the one under ‘anatomical position’ and ‘urethra’. The image used for the ‘development of the kidney’ should be removed from the page as it isn’t permissible. It should be replaced with an image relating to the content and have all the correct copyright and referencing information. Overall, I like the number of images used and its significance to the renal system. They accurately relate to the content of the project.

There is use of in-cite referencing which is good, however some references are just listed and should be placed under the proper ‘references’ subheading such as the ones under ‘ureter’ and ‘renal agenesis’. Some references in the ‘references’ list are used over again and can be fixed by combining it under one reference number. To make the project even more appealing, the group could format the information under ‘developmental timeline’ or even ’historic findings’ in a table. Overall, I think this project is great and by making edits based on the peer-reviews received could enhance their project.

'''Group project 3'''

The introduction is good as it accurately describes what the GIT system is about and the anatomical positions of the features in this system. It also briefly highlights the development stages at embryonic and fetal stages, however ‘embryonic development’ should be mentioned in a little more detail to understand how far in development the fetal stage begins. I also think the introduction should include a sentence or two describing how abnormalities in such organs can lead to these diseases. Basically a bit from each major subheading should be incorporated including current research as an introduction is a summary of the whole page. As for the ‘timeline’, it would’ve been more appropriate to place the timelines under each section, e.g foregut timeline under the ‘foregut’ subheading. This is because viewers would be confused on why there is so much difference in development in one section of the page. A glossary list should be incorporated in a separate subheading to define some of these words such as hematopoiesis so that viewers can fully grasp the information.

The information under recent findings is quite interesting and relatable to the content which is GIT fetal development. However, I believe more findings could be incorporated under this subheading. The information under each organ of the three ‘guts’ are quite detailed in fetal development which is good and shouldn’t be too difficult for the viewers to understand. However, I believe the group could include information on the function of these organs as well. The structure of the information under ‘guts’ does not flow in the sense that the midgut includes features and structure whereas the other ‘guts’ do not. The innvervation and bloody supply of the hindgut should be incorporated in a paragraph instead of being listed like that. All the deformities should be places under one subheading to make it easier for viewers to navigate. The abnormalities were also concise and related to the topic. Overall, the content is relating to the topic of the project and addresses key points. It also shows good amount of research, however there seems to be too much information in some parts which could be reduced a bit. The project needs a coherent flow of the structure.

As for images, there needs to be an image under introduction which includes all features of the GIT tract. There are a lot of potential images missing under each subheading except for the ‘midgut’ section. This shows that there has been one person working on this section or one section being focused on in comparison the others. The information used to reference the images is missing in some images such as the ‘Human- fetal week 10 sagittal plane D.jpg’ (although this is uploaded from a different user so this is understandable. However images such a ‘GIT 2.jpg’ need more information including ‘student template’ as well as the reference where the image idea may have come from. Also, if this is a hand-drawn image then please state this as one member did in ‘Week 11 midgut herniation.png’. Overall, I enjoy the use of self-drawn images as it makes it easier to show what the content is saying without going through the stress of looking for an image online that doesn’t relate to the content. However more images definitely need to be added. The use of captions is also good and indicates what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘Liver, Gallbladder and Bile Duct’ (the [6],[7] should be placed next to the text not above the text. The use of a ‘references’ subheading is good the same references have been combined into one number showing that the group knows how to make the references set out. The use of a table in formatting the ‘Percentage of Foetuses Herniated’ is great and shows more that the group has done research. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 4'''

The project doesn’t have an introduction yet; however information such as what the genital system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of genital development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. As for system development, I can see how there is dot-point description above the table which summarises the same thing. This structure is a bit confusing for me. I believe if the information was summarised into paragraphs and then tabulated it would make more sense. It’s best to format all that information into that table. The use of a table is a great way for the viewers to differentiate between the two sexes and understand the information more easily. I hope to see the table filled out completely soon. A glossary subheading should also be placed on the project page and have keywords defined to make viewers completely understand the content.

As for current findings, the information again is in dot points which should be paragraphed instead. However, the current findings are indeed interesting and the right amount of information is used to describe them in both sexes. The content under historic findings such as the ‘female genital development’ doesn’t show any historical events. There are no dates which show when something related was discovered. The ‘male genital development’ however shows dates and discoveries. In my opinion, if this information were tabulated rather than paragraphed, it’d be easier for viewers to navigate and understand. There is a good amount of detail under the abnormalities which relates to the key topic and is easy to understand. Overall, the content is relatable to the genital development of the fetus and underlines all the keys points. However, if this information were paragraphed in some areas and mentioned above, it would make the content easier to navigate and comprehend.

In terms of images, there are many places where images are missing such as introduction, system development and current models. I believe there needs to be more images on this page that relate to the content to make it more appealing and understandable to the viewers. The image called ‘File:Flow Diagram of Fetal Development of External Genitalia.pptx’ isn’t permissible and needs to be removed. The use of a hand drawn image on the testes is great, however there is information missing on referencing, student template and copyright laws. On the other hand, there are some images which correctly follow the uploading picture procedures such as the image on the ‘abnormalities of the vagina’; group members should follow this procedure. Captions should be added to each image to address what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘system development’. The use of a ‘references’ subheading is good, the same references have been combined into one number showing that the group knows how to make the references set out. However reference 20 and 21 are the same, please fix this. Also there are references under each subheading which should be placed all under one ‘references’ subheading. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 5'''

The introduction is a great summary of what the project page will discuss making sure to highlight every aspect. However, the introduction should also mention more about the integumentary system listing all the organs involved, their function, anatomical position and the difference between the embryonic and fetal stages of integumentary development. The content presented on the page is fantastic. All information under the subheadings looks complete and has key information related to the topic. I like how the timeline is divided into each organ making it easy to understand and navigate. The use of the table to format the information is a brilliant idea and has been presented beautifully with images in each textbox. Also the content under current research is relating to the topic and shows extensive research. The use of the purple background is appealing to the viewer highlighting its significance. I do however believe that the information under ‘historic findings’ should be formatted into a table to make it easier to navigate. The content under ‘abnormalities’ has the right amount of information and clearly relates to the key topic of the project.

In terms of images, I believe a satisfactory amount of images have been used which clearly describes the content. However, some images are missing the all the copyright information needed as well as the description, references and student template such as those in the ‘development overview’ table. This should be added right away to ensure these images do not get deleted. The use of captions on these pictures is important to highlight what the image is referring to and this is present in the page. Although, images could be added under current research as this section looks like it could use more images. Great job on the images under abnormalities, they accurately relate to the content mentioned.

There are some incite references missing such as in the development overview. I’m not sure if the references listed below are supposed to the references for it, however all references should be placed under one ‘references’ subheading. The same references have been combined into one number showing that the group knows how to make the references set out. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections. Overall, this is a great project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 7'''

The introduction is great as it mentions the features of the neural system, their anatomical positions and highlights the key events in the embryonic and fetal stages of development. The last paragraph of the introduction clearly addresses how the page will be divided and what the viewers are to expect which is good. The content under all subheadings are relating to the key topic and are formatted appropriately. I really like the image used under the subheading ‘Development during fetal period’ as it presents a diagrammatic representation of the content mentioned. The use of a table to briefly describe the events that occur at certain periods of fetal development is really helpful in grasping the main details. Some information is missing such as in ‘spinal cord development’, ‘Meninges development’, ‘future research’ and some ‘abnormalities’. This should be added right away. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the neural system and view dates on the side that may contain key findings. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

In terms of images, there are still many potential spaces for images such as under ‘introduction’, ‘current research’ and some ‘abnormalities’. The images used under ‘Development during fetal period’ are great and relate to the content. All images have correct description, referencing, copyright issues and ‘student template’, which shows that members of the group have followed correct ‘uploading image’ procedures. The images however need a caption to describe what the image is showing.

There needs to be more use of incite referencing such as in the ‘introduction’, ‘brain development’ and ‘abnormalities’. There is a huge list of references under ‘current research models and findings’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. References 7 and 8 are the same reference under the ‘references’ subheading and need to be combined into one number. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 8'''

The project doesn’t have an introduction yet; however information such as what the Musculoskeletal system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of musculoskeletal development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. I like the ‘making gains’ subheading as it adds humour to the page and engages the viewers. The general timeline needs information including what events take place at certain phases of fetal development. This could be present in a table to make the information more clear. It’s good that the project has information on the embryonic development so that the viewers can understand how the fetus arises to that point in development (fetal period).
All of the content seems to relate to the key topic and is appropriately paragraphed. However much of the content is still missing such as in ‘recent findings’ and ‘introduction’. More information could be added under the associated ‘trimesters’ and ‘abnormalities’. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the musculoskeletal system and view dates on the side that may contain key findings for historical events. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

There are no images on this page and definitely needs to be added with the appropriate information such as the description, referencing, copyright issues and ‘student template’. If images are not readily available, it is best to draw them. Also captions should be added on the page to state what the images are showing. As for referencing, there are some sections which shows incite referencing such as in the content under ‘Molecular and Cellular regulation of fetal myogenesis’ and some that don’t have any like in ‘tendon development’. There needs to be references in all sections. There is a huge list of references under ‘abnormalities’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. Number 15 of the reference list has an error in it and needs to be fixed right away. Overall, this is a working progress and if the group makes edits based on the peer-reviews received, this could enhance their project.

===Lab 10===

'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

'''''TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction.'''''

A major feature of the olfactory region is the olfactory bulb which contains mitral cells that serve to relay olfactory messages via sensory neurons of the olfactory epithelium to the piriform cortex of the brain. Within the granular cells and glomerular layers are interneurons which control the message output via synaptic linkages between mitral and tufted cell projection neurons. These interneurons continue to grow postnatally via neural stem cells located in the dorsolateral ganglionic eminence (dLGE) which consists of the subventricular zone and subependymal zone. When neuroblasts migrate to the dLGE, this stimulates dLGE-derived interneuron progenitors to migrate radially in the growing bulbs where they mature into the granular or glomerular cell layer. There has been research showing how teashirt zinc finger family member 1 (TSHZ1) is vital for the development of the olfactory bulb. In mice, it was found that olfactory bulb neuroblast differentiation required Tshz1 expression or else a large proportion of interneurons of the granular cell layer will not be present and radial migration of neuroblasts will be impaired. The basis of the previous studies was then replicated in humans suffering from congenital aural atresia that had TSHZ1 loss-of-function mutations.

Coronal sections 500-μm in size was obtained from the subjects which then underwent Nissl staining with cholineacetyl transferase histochemistry to observe the change in patterns of normal and abnormal olfactory development. In some parts of the experiment, mice were used as subjects to observe how congenital aural atresia may also affect them. In situ hybridization was used to investigate this effect on mice whereby Tshz1 positive and negative gene transcripts were obtained and amplified using polymerase chain reaction (PCR). Primers of the targeted gene and splicing enzymes were used to make sure the correct transcripts were produced.

Through immunoflourenscing and immunohistology, it was found that Tshz1 mutation lead to an abnormal distribution and differentiation of granule cell neurons of the developing olfactory bulb. Green fluoresce protein was integrated in the Tshz1 locus in both Tshz1+ and Tshz1- subjects. Through immunostaining of olfactory bulbs, it was shown that there was a consistent outer granule cell ring distribution of GFP+ cells in comparison to the unevenly distributed GFP+ cell located in the inner granule cell layer. DAPI staining revealed that the structure of the olfactory bulb in Tshz1 positive subjects were more layered and structure compared to deformed structure seen in Tshz1 mutants. The granule cell and external plexiform layers were indistinguishable and the glomerular layer had multilayers, thereby showing the abnormality in Tshz1 mutants.

Microarray hybridization was used to sort out gene expression in Tshz1 positive and negative subjects. Out of all the gene transcripts profiled, it was noted that the most significantly changed transcripts was Prokr2. Expression of PK2 was also downregulated in the rostral migratory stream of the subjects. Prokr2 expression was therefore examined in the developing olfactory bulb of Tshz1 positive and mutant mice using in situ hybridization. It was found that Tshz1 mRNA expression was seen in both the outer granule cell layer and the inner layers of the olfactory bulb mainly consisting of immature cells. Prokr2 expression was observed only in the inner layers of the OB in Tshz1 positive subjects and in mutants, Prokr2 expression was greatly downregulated. Overall, it was established that Tshz1 is needed to control the expression of Prokr2 which radially migrates neuroblasts. In addition, the PK2 family and its associated receptor are imperative factors required for normal olfactory bulb development.

<pubmed>24487590</pubmed>

'''Wiki link: https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Smell_Development'''

===Lab 11===

'''Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

'''Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration.'''

As cardiovascular disease continues to be the number one cause of death in the older population, there is significant research based on using stem cells as a tool to regenerate functional and healthy cardiomyctes in patients who’ve suffered from myocardial infarction. In particular, human induced pluripotent stem cells (hiPSCs) are used in this study to observe how these cells can generate cardiovascular cell sheets that may be used to treat infarcted heart tissue. Not to mention how hiPSCs may overcome obstacles such as poor engraftment of the cells injected in the heat and immunorejection, thereby placing the research more towards clinical practice.

'''Main findings'''

Data obtained from the study showed that there was simultaneous induction of cardiomyocytes and vascular cells using human IPSCs. It was shown that the levels of gene expression of cardiac mesoderm/progenitor genes (KDR/ISL1) were heightened on the day they were due to differentiate and when Dkk1 (a canonical Wnt antagonist) was added, the rate of differentiation of cardiomyocytes from mesoderm cells was increased. However when VEGF was added, this stimulated the induction of cardiomyocytes and vascular cells at the same time.

Furthermore, it was discovered that hiPSCs could generate cardiovascular cell sheets by placing hiPSC-derived cardiovascular cells into 12-multiwell temperature-responsive culture plates. After reducing the temperature, it was found that self-pulsating cell sheets (hiPSC-CTSs) was comprised of 3-4 cell layers with complete stratified structure of collagen positioned adjacent to the cell constituents. Immunostaining revealed that cardiomyocytes were expressed in large numbers out of all the three cells (myocytes and vascular endothelial cells), suggesting that non-myocytes are needed in cell sheet formation by remodelling cardiac cell distribution.

hiPSc-CTs were also shown to improve cardiac function after acute myocardial infarction in rats. The hiPSc-CTs were lined up in a 3-sheet structure where there were transplanted into a rat with acute myocardial infartction. After 8 weeks, an echocardiogram was performed and showed that anterior wall contraction was restored and parameters for left ventricle (LV) systolic function, fractional shortening (FS) and fractional area change (FAC) were improved. Sirius red staining also indicated that hiPSC-CTS transplantation greatly prevented fibrosis thereby leaving more cardiac tissues to function properly.

Overall, this study shows evidence that HiPSC-CTSs are showing promising results in the generation of cardiomyocytes and in restoring cardiac function of those that suffered from myocardial infarction.

<ref><pubmed>25336194</pubmed></ref>

<references/>

User:Z3418837

2014-10-27T11:49:38Z

Z3418837: /* Lab 11 */

==Lab Attendance==
*Lab 1 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 6 August 2014 (EST)
*Lab 2 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:11, 13 August 2014 (EST)
*Lab 3 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:12, 20 August 2014 (EST)
*Lab 4 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:55, 27 August 2014 (EST)
*Lab 5 -- Absent
*Lab 6 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:44, 10 September 2014 (EST)
*Lab 7 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:40, 17 September 2014 (EST)
*Lab 8 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:11, 24 September 2014 (EST)
*Lab 9 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:08, 8 October 2014 (EST)
*Lab 10 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 15 October 2014 (EST)
*Lab 11 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 22 October 2014 (EST)
*Lab 12

==Individual Assessment==

==='''Lab 1'''===

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 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>

'''Your Lab assessment now requires you to find a 2 recent research references on fertilisation or in vitro fertilisation. Paste each reference on your page, as shown in the class. Write below each reference a brief summary of the research article methods and findings. The summary for each need not be more than 3-4 paragraphs in length. This will need to be completed before next weeks laboratory'''.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/25077107 PMID25077107]

<pubmed>25077107</pubmed>

This study was designed to investigate whether the levels of vitamin D is an imperative factor when it comes to the clinical success of implantation and pregnancy rates in infertile women via invitro fertilisation.

'''Method summary'''

A cohort of 173 women were evaluated and selected for this study based on their age, follicle-stimulating hormone levels and their consent to undergo invitro fertilisation. The following study was conducted at Mount Sinai Hospital where proper facilities were available. Blood tests were then conducted for each patient to determine their levels of Vitamin D via the serum 25-hydroxy-vitamin D (25[OH]D) levels. Following the results of the blood test, the cohort were then categorised into two groups which was either vitamin D sufficient (≥ 75 nmol/L) or insufficient ( < 75 nmol/L) based on serum levels of 25(OH)D.

Each patient then underwent IVF cycles whereby standard agonists that contained the active ingredient 0.5 mg/d of buserelin acetate in conjunction with cetrolix acetate as the standard antagonist were used to control the length of the luteal phase and estradiol levels. The length and dose of the treatment were varied for each individual based on their demographic data. Serial transvaginal ultrasonograpy and serum lutenizing hormone assays were then used to check ovarian response. When 3 or more dominant follicles (≥ 17 mm) were produced, 10 000 IU of human chorionic gonadotropin was added to enhance nuclear maturation. Oocyte retrieval was then conducted via transvaginal ultrasound whereby it was fertilised and the resulting embryo was transferred 3-5 days post-fertilisation. The rate of pregnancy per IVF cycle was then used as the primary outcome for this study whereby the visibility of the intrauterine sac of the embryo determined implantation.

'''Results summary'''

Out of the 182 patients that participated in this study, it was found that only 173 patients could continue on with this trial as they satisfied the criteria, however only 162 were fit for embryo transfer. Following the results from the blood test, it was noted that 53.8% of patients had insufficient levels of 25(OH)D and 45.1% had sufficient amounts. It was discovered that 71.8% of those with sufficient levels of 25(OH)D were more likely to proceed with embryo transfer on day 5 compared to 58.9% (p = 0.054) of those assigned to the ‘insufficient 25(OH)D’ category. Other factors such as oocyte retrieval and frequency of intracytoplasmic sperm injection were fairly similar in both groups. The study revealed that there was a higher clinical pregnancy rate per IVF cycle for those assigned to the sufficient 25(OH)D level category by 52.5% compared to those with insufficient amounts of 25(OH)D which was 34.7% (p < 0.001). Similarly, there was a significant clinical pregnancy rate per embryo transfer of 54.7% in comparison to 37.9% in woman belonging to the sufficient and insufficient category respectively. It was also noted that the implantation rate was greater in the sufficient category compared to the insufficient group, however the difference was only minimal (p= 0.6). Overall, the results suggest that serum 25(OH)D levels may be a predictor of clinical pregnancy.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/24672163 PMID24672163]

<pubmed>24672163</pubmed>

The process of achieving pregnancy via invitro fertilisation needs to be monitored and controlled with respect to the demographics of the individual in order to achieve a successful outcome. This study focuses on predicting the value of β-human chorionic gonadotrophin (β-HCG) that can lead to clinical success.

'''Method summary'''

Data analysis was taken from 171 female patients using the statistical package for social sciences program whereby all IVF cycles were monitored. The cycles that showed fresh multi-cell embryos (day 3) or blastocysts (day 5) were deemed fit for the trial and were the ones that were further used in this study. Serum β-HCG concentrations were then taken 14 days after the embryo was transferred whereby a second test was done on day 16 only if the first test revealed a positive β-HCG result. This was done to predict values that could enable doctors to evaluate a healthy intrauterine pregnancy or a problematic ectopic pregnancy. After 6-7 weeks of pregnancy, ultrasounds were conducted to check cardiac activity as well as the amount of gestational sacs. This was then repeated at 12 weeks of pregnancy to ensure there was no chance of abortion.

A continuing pregnancy was defined as one that continued for at least 12 weeks of gestation and showed signs of proper cardiac function. On the other hand, those pregnancies that were abnormal had dropped levels of β-HCG concentrations and led to empty gestational sacs that showed no embryonic cardiac function. As a measuring tool for detecting levels of β-HCG, Chemiluminescent microparticle immunoassays were used whereby the measuring range established was between 0.0-15,000 mIU/mL. HCG levels above 10 IU/L signified early pregnancy.

'''Results Summary'''

Out of the 171 patients that participated in this study, only 139 were included due to the missing data on the levels of β-HCG concentrations at day 14 and 16 post embryonic transfer. In total there were 39 abnormal pregnancies that involved ectopic pregnancy, abortions and biochemical pregnancies (sufficient HCG levels detected but no visible gestational sac). Overall the patients were categorised into two groups which were patients with ‘ongoing pregnancy’ (n=100) and ‘without ongoing pregnancy’ (n=39). The Mann-Whitney test (statistical testing) was then used to compare the levels of β-HCG levels in both groups. It was found that the group with ongoing pregnancy had a median serum β-HCG level of 600 mIU/ml, whereas the other group had a median serum β-HCG level of 178 mIU/ml. This indicated a significant difference of P < 0.05 when comparing the two groups. It was also found that when serum β-HCG levels reached 347 mIU/ml, there was a 73.6% chance that the pregnancy was ongoing. Furthermore, there was no definite correlation established between age and the rate of ongoing pregnancy as both categories had patients of similar age groups with a combined range of 23-41 year old patients. Overall, the study revealed that early serum β-HCG is a potential predictor of successful outcomes in invitro fertilisation.

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 19:11, 6 October 2014 (EST) These are relevant references and your descriptions/abstracts are good (5/5).

===Lab 2===

[[File:Phase-contrast images of embryos at different developmental stages via neogenin expression.png|300px]]

Phase-contrast images of embryos at different developmental stages via neogenin expression.<ref><pubmed>25013897</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0101989 PLos One]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:17, 21 August 2014 (EST) This is all correct. The image is very large (4.8 MB), perhaps a small version could have been uploaded. You can adjust the resolution and size in most image editing programs. (5/5)

<references/>

===Lab 3===

'''Parathyroid gland'''

<pubmed>22808183</pubmed>
<pubmed>22649358</pubmed>
<pubmed>21881196</pubmed>
<pubmed>21904825</pubmed>

'''Thymus'''

<pubmed>21733645</pubmed>
<pubmed>20836742</pubmed>
<pubmed>21263742</pubmed>
<pubmed>512270</pubmed>

'''Pancreas'''

<pubmed>22761699</pubmed>
<pubmed>22893718</pubmed>
<pubmed>24496309</pubmed>
<pubmed>24595965</pubmed>
<pubmed>23822675</pubmed>
<pubmed>22968764</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===

'''1. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

'''Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1'''

Glioblastoma multiforme (GBM) is known to belong to a very life threatening form of brain cancer. Research is currently focused on finding treatments regarding such abnormalities, such as the application of neuronal stem cells in reducing the population of tumours, however there were many problems that occurred with such treatment. Recently, Human umbilical cord blood derived stem cells (hUCBSC) has been extensively used as they are useful mesenchymal stem cells that are easy to isolate and are more available. GBM is caused by the overexpression of cyclin D1 and its subsequent binding to Cdk 4/Cdk 6 which defines the rate limiting step required for the cell to progress further on to the cell cycle from the G1 phase. In order to stop this over expression, scientists have used hUCBSC to inhibit the cell from progressing on with the cell cycle.

When (hUCBSC) were cultured with U251 and 5310 cells, flow cytometry technology revealed that the cells underwent G1 arrest showing an increase in the G0-G1/S phase ratio. There was also a 54% reduction in levels of cyclin D1 when hUCBSC was cultured with U251 in comparison to the control. Immunoprecipiation revealed that hUCBSC treated cells when immuno blotted with Cdk 4 and Cdk 6 antibodies, down regulated expression of both Cdk 4 and Cdk 6. Western blot also showed the same down regulating pattern of the individual expression and genes which confirmed that there was cell cycle arrest, thus preventing tumours from forming.

As such, this study helps researchers to grasp the foundation of using hUCBSC as a treatment for glioblastoma and to further build on such research. Since it is evident that hUCBSC is effective in reducing cyclin D1 expression; analysing glioblastomal hierarchy will aid in providing the missing links needed to create the clinical treatment.

<pubmed>21455311</pubmed>

'''2. There are a number of developmental vascular "shunts" present in the embryo, that are closed postnatally. Identify these shunts and their anatomical location.'''

Three major vascular shunts include:

• '''Ductus venosus''' - is a shunt of oxygenated blood from umbilical vein to IVC, bypassing the liver. The ductus venosus constricts and closes soon after birth and becomes the ligamentum venosum

• '''Foramen ovale''' - is a flap valve in the atrial septum between the right and left atrium that shunts highly oxygenated blood . The remnant of the foramen ovale is known as the fossa ovalis.

• '''Ductus arteriosus''' - is a shunt from the descending aorta to the left pulmonary artery near the bifurcation of the pulmonary trunk. Permanent closure takes 4-6 weeks by fibrosis, and the remnant is referred to as the ligamentum arteriosum.

===Lab 5===

'''Select an abnormality of either gastrointestinal or respiratory development and write a brief description of developmental causes(s) for this abnormality. Your answer should be added to your own student page, be brief (2-3 paragraphs) and referenced.'''

'''Midgut volvulus'''

The embryonic development of the midgut has a number of steps which ensures its proper formation. These include the viability of the superior mesenteric artery to divide the midgut into the cephalad (pre-arterial region) and caudad (post-arterial region). <ref><pubmed>15378215</pubmed></ref>During the fourth gestational week, the gastrointestinal system is composed of a centrally positioned linear tube in the abdomen. At approximately 6 weeks of gestational age, the midgut undergoes a process of U-shaped herniation causing the two portions of the midguts to face the opposite directions in relation to the superior mesenteric artery. From this moment, a number of rotation events occur to ensure the complete development of the gastrointestinal tract as it becomes set in the posterior abdominal wall.<ref><pubmed>7277164</pubmed></ref>

In some cases malrotations can occur during the developmental process of the midgut which involves the complete twisting of the midgut in relation to the axis of the superior mesenteric artery. In extreme cases this can lead to midgut volvulus which results in a narrowed mesenteric base that can obstruct the passage of blood and lead to tissue necrosis. Other complications resulting from midgut volvulus include intestinal ischaemia, peritonitis, mucosal necrosis and sepsis which can eventually lead to death if left untreated. <ref><pubmed>14655161</pubmed></ref>

Malrotation is known to occur within 1 in 500 live births and out of those who develop midgut volvusos, 68-71% are neonates. <ref><pubmed>22217896</pubmed></ref>Although the actual cause of malrotation is unknown, researchers have made links to congenital syndromes such as Down syndrome and the VACTERL. It is also hypothesized that any embryonic interference during the normal patterns of rotation and fetal development can lead to midgut volvulus. Treatment of midgut volvulus is dependent on when the disease is diagnosed. <ref><pubmed>18800265</pubmed></ref>Normally a sigmoidoscopy is carried out as well as the Ladd procedure to resect dead gastrointestinal tissues. Transduodenal bands of ladd may also be divided to widen the mesenteric pedicle and prevent obstruction of blood flow. <ref><pubmed>22208840</pubmed></ref>Overall, research is still being conducted on the specific causes of malrotation and other numerous treatments.

<references/>

===Lab 6===

Group work

===Lab 7===

'''1.Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

'''Novel genes upregulated when NOTCH signaling is disrupted during hypothalamic development.'''

It is known that the hypothalamus first develops from the ventral region of the diencephalon and signaling mechanisms such as the sonic hedgehog and bone morphogenic protein pathways are responsible for pattern arrangement. Neurogenesis is the key process required to ensure proper hypothalamus development which relies on many signaling pathways to produce neurons and glia. The Notch signaling pathway is currently known to inhibit neuronal differentiation and preserve neural progenitor identity. As a result of various studies and research, the combined theory has been implemented in this study to determine the effect of downregulating Notch signaling pathways in its effect on hypothalamic development.

Results show that when Notch signaling is inactivated, novel genes such as Dll1, Hes5, Hey1 and Ascl1 are upregulated in the rostral hypothalamus, subsequently leading to the early formation of hypothalamic neurons. This is also seen when embryos that are treated with DAPT (a chemical which inhibits cell differentiation mechanisms regulated by the Notch pathway) had an overexpression of cells differentiated into neurons in a clustered formation. This was compared to the control embryos which had differentiated cells in a scattered arrangement. As such, this research showed that Notch is a powerful signaling mechanism that is used to inhibit cell differentiation in order to control the number of cells differentiated into neurons or glia. This modulating ability of the Notch pathway is imperative in the early developing hypothalamus as it controls expression of cells and hence prevents any form of defects that can be harmful both prenatally and postnatally. Further research needs to be conducted on the Notch pathway to provide procedures where its mechanism can be used to resolve defects in the embryo and hence ensure proper hypothalamic development.

<pubmed>24360028</pubmed>

'''2.Identify the embryonic layers and tissues that contribute to the developing teeth.'''

'''Odontoblasts''' - neural crest-derived mesenchymal cells which establish the outer dental pulp. It differentiates via the enamel epithelium and releases dentin from dentinogenesis.

'''Ameloblasts''' - are derived from oral epithelium tissue of ectodermal origin and make up the inner enamel. They make pre-ameloblasts and produce enamel.

'''Periodontal ligament''' – is comprised of connective tissues which holds the tooth in place in the alveolar bone. It also encloses the cementum coating of the tooth root.

===Lab 8===

'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

'''Embryonic development of the ovary'''

The Gonads are known to be formed from the combination of primitive germ cells, adjacent mesenchyme and the mesothelium of the posterior abdominal wall. It isn’t until fifth week of embryonic development that the formation of Gonads occurs. The primordial germ cells first migrate from the embryonic yolk sac towards the hindgut along the dorsal mesentery. These cells then travel to the mesenchyme forming genital ridges positioned medially to the mesonephros by the sixth week of development. Coelomic epithelium and the mesonephros cells also proliferate at this stage. These cells then incorporate into the primary sex cords in which the process is driven by the genes stella, fragilis, and BMP-4 before the seventh week of embryonic development.<ref><pubmed>23409002</pubmed></ref>

The gonads are known to be indifferent until the sixth embryonic week as the gonads appear the same, however sex differentiation based on sex chromosomes determine the sex of the Gonad (XX for female and XY for males). The indifferent gonads are situated well inside the Wolffian body and are comprised of an inner medulla and outer cortex which contains precursors for ovarian stroma and parenchyma respectively.<ref><pubmed>3712511</pubmed></ref> In embryos consisting of XX sex chromosomes, the cortex of the indifferent gonad differentiates into an ovary meanwhile the medulla regresses by week eight of embryonic development. However, the sex cords leads to the formation of rete ovarii which is a complex of tubules and cords that arises from the mesonephros.

Another important event that occurs during the sixth week of development is the formation of the mullerian ducts which are responsible for female gonad formation and prevention of male gonad development. The established XX genotype of the female embryo prevents testosterone from being produced and hence causes the regression of the mesonephric duct since this form is only needed for male gonad expression. Also since there is no production of anti-mullarian hormone, the paramesonephric duct is able to be maintained driving female gonad expression. As of 10 weeks of development, ovaries first become recognizable and the growth of female external genitalia begins to occur.

[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]

<references/>

''' 2.Include an image from the historic genital embryology section of the online notes in your description.'''

[[File:Gray1112.jpg|400px]]

Figure 1. Longitudinal Section of Ovary of Cat Embryo of 9.4 cm long

===Lab 9===

'''Group project 1'''

The introduction was written quite well as it explains what the respiratory system is about and the origin of its development. It also briefly highlights the difference between the embryonic and fetal stage which is important in enabling the viewers to have an understanding on what the project will be focusing on. I also like how the group distinguished between the two zones of the respiratory tract and adequately described the features and function of each. The content in the lung development stages clearly relates to the topic and underlines fetal development. The group briefly mentioned the key features in each stage instead of pasting a whole lot of information; this makes it easier for viewers to understand. Overall the content relates to the learning objectives of embryology and the level of research is good as exemplified under ‘Current Research and Findings’ and ‘abnormalities’ (many forms of diseases described). The project however could benefit from having a ‘Glossary’ list so that viewers can understand some uncommon words.

The images under introduction and the image used for Meconium aspiration syndrome have not been referenced properly as there is missing information such as ((Template: Student Image)), description, copyright information and proper references for some. The image used under the ‘current research and findings’ subheading is a good example for the group to copy the referencing style. It is also vital that the group adds a brief description of what the image illustrates as a caption to help viewers understand the relation of the content and image (this is seen in the image under ‘surfactant’). More images could be added such as in the ‘lung development stage’ and under abnormalities. If images for lung development stages aren’t easily accessible, it is perhaps a good idea to draw them. The table format used for ‘lung development stages’ makes it easy for the viewers to navigate which is a good feature used in the project.

In terms of referencing, there are many in-cite references missing such as in the ‘introduction’ and in ‘lung development stages’. It is important to have these references formatted correctly under the one ‘references’ subheading. There seems to be many ‘references’ subheadings making it harder for viewers to navigate. Some references are shown as ‘ </li> which needs to be fixed right away. Overall, the content seems well written, formatted and concise making it easy to understand. However the problems related to referencing needs to be corrected as this is inconsistent throughout the project.

'''Group project 2'''

The introduction is well addressed as it sufficiently describes what the renal system is about and its function. Not to mention its anatomical structure as well as the difference between the embryonic and fetal stages of development. This differentiation enables viewers to understand what the content will be focused on, which is fetal development. Also, it helps focus the viewer’s attention on how the project will be divided as the group mentions abnormalities in the last paragraph. Overall the introduction has the right amount of information from each subheading and is very easy to comprehend.

There isn’t any information under ‘historic findings’. If there are any difficulties in finding some historic findings, members of the group can go to pubmed and on the side will be dates such as 1920 that could contain key historical events when renal is entered on search. The use of a development timeline was great as they outlined the major events that occur in a concise manner. Although, I believe a glossary is needed for words like ‘metanephros’ since the viewers would not know what that is. The content under current research models is interesting and correctly describes what the studies were about. Overall, the content used in the project was relating to the topic (fetal development of the kidney) and clearly showed extensive research. I really like how the group divided the different parts of the renal system as well as describing their anatomical positions. The abnormalities listed are also interesting and very easy to understand. I’m hoping to see information under the Horseshoe kidney disease.

In terms of images, there should be an image under introduction perhaps having all features of the renal system. Most images are missing the ‘student template’ aspect of the referencing and needs to be added right away. Other aspects such as description, copyright and referencing were correct. I also like the use of captions to describe what the images are about, however some are missing on the page such as the one under ‘anatomical position’ and ‘urethra’. The image used for the ‘development of the kidney’ should be removed from the page as it isn’t permissible. It should be replaced with an image relating to the content and have all the correct copyright and referencing information. Overall, I like the number of images used and its significance to the renal system. They accurately relate to the content of the project.

There is use of in-cite referencing which is good, however some references are just listed and should be placed under the proper ‘references’ subheading such as the ones under ‘ureter’ and ‘renal agenesis’. Some references in the ‘references’ list are used over again and can be fixed by combining it under one reference number. To make the project even more appealing, the group could format the information under ‘developmental timeline’ or even ’historic findings’ in a table. Overall, I think this project is great and by making edits based on the peer-reviews received could enhance their project.

'''Group project 3'''

The introduction is good as it accurately describes what the GIT system is about and the anatomical positions of the features in this system. It also briefly highlights the development stages at embryonic and fetal stages, however ‘embryonic development’ should be mentioned in a little more detail to understand how far in development the fetal stage begins. I also think the introduction should include a sentence or two describing how abnormalities in such organs can lead to these diseases. Basically a bit from each major subheading should be incorporated including current research as an introduction is a summary of the whole page. As for the ‘timeline’, it would’ve been more appropriate to place the timelines under each section, e.g foregut timeline under the ‘foregut’ subheading. This is because viewers would be confused on why there is so much difference in development in one section of the page. A glossary list should be incorporated in a separate subheading to define some of these words such as hematopoiesis so that viewers can fully grasp the information.

The information under recent findings is quite interesting and relatable to the content which is GIT fetal development. However, I believe more findings could be incorporated under this subheading. The information under each organ of the three ‘guts’ are quite detailed in fetal development which is good and shouldn’t be too difficult for the viewers to understand. However, I believe the group could include information on the function of these organs as well. The structure of the information under ‘guts’ does not flow in the sense that the midgut includes features and structure whereas the other ‘guts’ do not. The innvervation and bloody supply of the hindgut should be incorporated in a paragraph instead of being listed like that. All the deformities should be places under one subheading to make it easier for viewers to navigate. The abnormalities were also concise and related to the topic. Overall, the content is relating to the topic of the project and addresses key points. It also shows good amount of research, however there seems to be too much information in some parts which could be reduced a bit. The project needs a coherent flow of the structure.

As for images, there needs to be an image under introduction which includes all features of the GIT tract. There are a lot of potential images missing under each subheading except for the ‘midgut’ section. This shows that there has been one person working on this section or one section being focused on in comparison the others. The information used to reference the images is missing in some images such as the ‘Human- fetal week 10 sagittal plane D.jpg’ (although this is uploaded from a different user so this is understandable. However images such a ‘GIT 2.jpg’ need more information including ‘student template’ as well as the reference where the image idea may have come from. Also, if this is a hand-drawn image then please state this as one member did in ‘Week 11 midgut herniation.png’. Overall, I enjoy the use of self-drawn images as it makes it easier to show what the content is saying without going through the stress of looking for an image online that doesn’t relate to the content. However more images definitely need to be added. The use of captions is also good and indicates what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘Liver, Gallbladder and Bile Duct’ (the [6],[7] should be placed next to the text not above the text. The use of a ‘references’ subheading is good the same references have been combined into one number showing that the group knows how to make the references set out. The use of a table in formatting the ‘Percentage of Foetuses Herniated’ is great and shows more that the group has done research. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 4'''

The project doesn’t have an introduction yet; however information such as what the genital system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of genital development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. As for system development, I can see how there is dot-point description above the table which summarises the same thing. This structure is a bit confusing for me. I believe if the information was summarised into paragraphs and then tabulated it would make more sense. It’s best to format all that information into that table. The use of a table is a great way for the viewers to differentiate between the two sexes and understand the information more easily. I hope to see the table filled out completely soon. A glossary subheading should also be placed on the project page and have keywords defined to make viewers completely understand the content.

As for current findings, the information again is in dot points which should be paragraphed instead. However, the current findings are indeed interesting and the right amount of information is used to describe them in both sexes. The content under historic findings such as the ‘female genital development’ doesn’t show any historical events. There are no dates which show when something related was discovered. The ‘male genital development’ however shows dates and discoveries. In my opinion, if this information were tabulated rather than paragraphed, it’d be easier for viewers to navigate and understand. There is a good amount of detail under the abnormalities which relates to the key topic and is easy to understand. Overall, the content is relatable to the genital development of the fetus and underlines all the keys points. However, if this information were paragraphed in some areas and mentioned above, it would make the content easier to navigate and comprehend.

In terms of images, there are many places where images are missing such as introduction, system development and current models. I believe there needs to be more images on this page that relate to the content to make it more appealing and understandable to the viewers. The image called ‘File:Flow Diagram of Fetal Development of External Genitalia.pptx’ isn’t permissible and needs to be removed. The use of a hand drawn image on the testes is great, however there is information missing on referencing, student template and copyright laws. On the other hand, there are some images which correctly follow the uploading picture procedures such as the image on the ‘abnormalities of the vagina’; group members should follow this procedure. Captions should be added to each image to address what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘system development’. The use of a ‘references’ subheading is good, the same references have been combined into one number showing that the group knows how to make the references set out. However reference 20 and 21 are the same, please fix this. Also there are references under each subheading which should be placed all under one ‘references’ subheading. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 5'''

The introduction is a great summary of what the project page will discuss making sure to highlight every aspect. However, the introduction should also mention more about the integumentary system listing all the organs involved, their function, anatomical position and the difference between the embryonic and fetal stages of integumentary development. The content presented on the page is fantastic. All information under the subheadings looks complete and has key information related to the topic. I like how the timeline is divided into each organ making it easy to understand and navigate. The use of the table to format the information is a brilliant idea and has been presented beautifully with images in each textbox. Also the content under current research is relating to the topic and shows extensive research. The use of the purple background is appealing to the viewer highlighting its significance. I do however believe that the information under ‘historic findings’ should be formatted into a table to make it easier to navigate. The content under ‘abnormalities’ has the right amount of information and clearly relates to the key topic of the project.

In terms of images, I believe a satisfactory amount of images have been used which clearly describes the content. However, some images are missing the all the copyright information needed as well as the description, references and student template such as those in the ‘development overview’ table. This should be added right away to ensure these images do not get deleted. The use of captions on these pictures is important to highlight what the image is referring to and this is present in the page. Although, images could be added under current research as this section looks like it could use more images. Great job on the images under abnormalities, they accurately relate to the content mentioned.

There are some incite references missing such as in the development overview. I’m not sure if the references listed below are supposed to the references for it, however all references should be placed under one ‘references’ subheading. The same references have been combined into one number showing that the group knows how to make the references set out. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections. Overall, this is a great project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 7'''

The introduction is great as it mentions the features of the neural system, their anatomical positions and highlights the key events in the embryonic and fetal stages of development. The last paragraph of the introduction clearly addresses how the page will be divided and what the viewers are to expect which is good. The content under all subheadings are relating to the key topic and are formatted appropriately. I really like the image used under the subheading ‘Development during fetal period’ as it presents a diagrammatic representation of the content mentioned. The use of a table to briefly describe the events that occur at certain periods of fetal development is really helpful in grasping the main details. Some information is missing such as in ‘spinal cord development’, ‘Meninges development’, ‘future research’ and some ‘abnormalities’. This should be added right away. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the neural system and view dates on the side that may contain key findings. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

In terms of images, there are still many potential spaces for images such as under ‘introduction’, ‘current research’ and some ‘abnormalities’. The images used under ‘Development during fetal period’ are great and relate to the content. All images have correct description, referencing, copyright issues and ‘student template’, which shows that members of the group have followed correct ‘uploading image’ procedures. The images however need a caption to describe what the image is showing.

There needs to be more use of incite referencing such as in the ‘introduction’, ‘brain development’ and ‘abnormalities’. There is a huge list of references under ‘current research models and findings’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. References 7 and 8 are the same reference under the ‘references’ subheading and need to be combined into one number. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 8'''

The project doesn’t have an introduction yet; however information such as what the Musculoskeletal system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of musculoskeletal development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. I like the ‘making gains’ subheading as it adds humour to the page and engages the viewers. The general timeline needs information including what events take place at certain phases of fetal development. This could be present in a table to make the information more clear. It’s good that the project has information on the embryonic development so that the viewers can understand how the fetus arises to that point in development (fetal period).
All of the content seems to relate to the key topic and is appropriately paragraphed. However much of the content is still missing such as in ‘recent findings’ and ‘introduction’. More information could be added under the associated ‘trimesters’ and ‘abnormalities’. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the musculoskeletal system and view dates on the side that may contain key findings for historical events. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

There are no images on this page and definitely needs to be added with the appropriate information such as the description, referencing, copyright issues and ‘student template’. If images are not readily available, it is best to draw them. Also captions should be added on the page to state what the images are showing. As for referencing, there are some sections which shows incite referencing such as in the content under ‘Molecular and Cellular regulation of fetal myogenesis’ and some that don’t have any like in ‘tendon development’. There needs to be references in all sections. There is a huge list of references under ‘abnormalities’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. Number 15 of the reference list has an error in it and needs to be fixed right away. Overall, this is a working progress and if the group makes edits based on the peer-reviews received, this could enhance their project.

===Lab 10===

'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

'''''TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction.'''''

A major feature of the olfactory region is the olfactory bulb which contains mitral cells that serve to relay olfactory messages via sensory neurons of the olfactory epithelium to the piriform cortex of the brain. Within the granular cells and glomerular layers are interneurons which control the message output via synaptic linkages between mitral and tufted cell projection neurons. These interneurons continue to grow postnatally via neural stem cells located in the dorsolateral ganglionic eminence (dLGE) which consists of the subventricular zone and subependymal zone. When neuroblasts migrate to the dLGE, this stimulates dLGE-derived interneuron progenitors to migrate radially in the growing bulbs where they mature into the granular or glomerular cell layer. There has been research showing how teashirt zinc finger family member 1 (TSHZ1) is vital for the development of the olfactory bulb. In mice, it was found that olfactory bulb neuroblast differentiation required Tshz1 expression or else a large proportion of interneurons of the granular cell layer will not be present and radial migration of neuroblasts will be impaired. The basis of the previous studies was then replicated in humans suffering from congenital aural atresia that had TSHZ1 loss-of-function mutations.

Coronal sections 500-μm in size was obtained from the subjects which then underwent Nissl staining with cholineacetyl transferase histochemistry to observe the change in patterns of normal and abnormal olfactory development. In some parts of the experiment, mice were used as subjects to observe how congenital aural atresia may also affect them. In situ hybridization was used to investigate this effect on mice whereby Tshz1 positive and negative gene transcripts were obtained and amplified using polymerase chain reaction (PCR). Primers of the targeted gene and splicing enzymes were used to make sure the correct transcripts were produced.

Through immunoflourenscing and immunohistology, it was found that Tshz1 mutation lead to an abnormal distribution and differentiation of granule cell neurons of the developing olfactory bulb. Green fluoresce protein was integrated in the Tshz1 locus in both Tshz1+ and Tshz1- subjects. Through immunostaining of olfactory bulbs, it was shown that there was a consistent outer granule cell ring distribution of GFP+ cells in comparison to the unevenly distributed GFP+ cell located in the inner granule cell layer. DAPI staining revealed that the structure of the olfactory bulb in Tshz1 positive subjects were more layered and structure compared to deformed structure seen in Tshz1 mutants. The granule cell and external plexiform layers were indistinguishable and the glomerular layer had multilayers, thereby showing the abnormality in Tshz1 mutants.

Microarray hybridization was used to sort out gene expression in Tshz1 positive and negative subjects. Out of all the gene transcripts profiled, it was noted that the most significantly changed transcripts was Prokr2. Expression of PK2 was also downregulated in the rostral migratory stream of the subjects. Prokr2 expression was therefore examined in the developing olfactory bulb of Tshz1 positive and mutant mice using in situ hybridization. It was found that Tshz1 mRNA expression was seen in both the outer granule cell layer and the inner layers of the olfactory bulb mainly consisting of immature cells. Prokr2 expression was observed only in the inner layers of the OB in Tshz1 positive subjects and in mutants, Prokr2 expression was greatly downregulated. Overall, it was established that Tshz1 is needed to control the expression of Prokr2 which radially migrates neuroblasts. In addition, the PK2 family and its associated receptor are imperative factors required for normal olfactory bulb development.

<pubmed>24487590</pubmed>

'''Wiki link: https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Smell_Development'''

===Lab 11===

'''Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

'''Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration.'''

As cardiovascular disease continues to be the number one cause of death in the older population, there is significant research based on using stem cells as a tool to regenerate functional and healthy cardiomyctes in patients who’ve suffered from myocardial infarction. In particular, human induced pluripotent stem cells (hiPSCs) are used in this study to observe how these cells can generate cardiovascular cell sheets that may be used to treat infarcted heart tissue. Not to mention how hiPSCs may overcome obstacles such as poor engraftment of the cells injected in the heat and immunorejection, thereby placing the research more towards clinical practice.

'''Main findings'''

Data obtained from the study showed that there was simultaneous induction of cardiomyocytes and vascular cells using human IPSCs. It was shown that the levels of gene expression of cardiac mesoderm/progenitor genes (KDR/ISL1) were heightened on the day they were due to differentiate and when Dkk1 (a canonical Wnt antagonist) was added, the rate of differentiation of cardiomyocytes from mesoderm cells was increased. However when VEGF was added, this stimulated the induction of cardiomyocytes and vascular cells at the same time.

<ref><pubmed>25336194</pubmed></ref>

<references/>

User:Z3418837

2014-10-27T11:28:06Z

Z3418837: /* Lab 11 */

==Lab Attendance==
*Lab 1 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 6 August 2014 (EST)
*Lab 2 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:11, 13 August 2014 (EST)
*Lab 3 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:12, 20 August 2014 (EST)
*Lab 4 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:55, 27 August 2014 (EST)
*Lab 5 -- Absent
*Lab 6 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:44, 10 September 2014 (EST)
*Lab 7 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:40, 17 September 2014 (EST)
*Lab 8 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:11, 24 September 2014 (EST)
*Lab 9 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:08, 8 October 2014 (EST)
*Lab 10 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 15 October 2014 (EST)
*Lab 11 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 22 October 2014 (EST)
*Lab 12

==Individual Assessment==

==='''Lab 1'''===

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 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>

'''Your Lab assessment now requires you to find a 2 recent research references on fertilisation or in vitro fertilisation. Paste each reference on your page, as shown in the class. Write below each reference a brief summary of the research article methods and findings. The summary for each need not be more than 3-4 paragraphs in length. This will need to be completed before next weeks laboratory'''.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/25077107 PMID25077107]

<pubmed>25077107</pubmed>

This study was designed to investigate whether the levels of vitamin D is an imperative factor when it comes to the clinical success of implantation and pregnancy rates in infertile women via invitro fertilisation.

'''Method summary'''

A cohort of 173 women were evaluated and selected for this study based on their age, follicle-stimulating hormone levels and their consent to undergo invitro fertilisation. The following study was conducted at Mount Sinai Hospital where proper facilities were available. Blood tests were then conducted for each patient to determine their levels of Vitamin D via the serum 25-hydroxy-vitamin D (25[OH]D) levels. Following the results of the blood test, the cohort were then categorised into two groups which was either vitamin D sufficient (≥ 75 nmol/L) or insufficient ( < 75 nmol/L) based on serum levels of 25(OH)D.

Each patient then underwent IVF cycles whereby standard agonists that contained the active ingredient 0.5 mg/d of buserelin acetate in conjunction with cetrolix acetate as the standard antagonist were used to control the length of the luteal phase and estradiol levels. The length and dose of the treatment were varied for each individual based on their demographic data. Serial transvaginal ultrasonograpy and serum lutenizing hormone assays were then used to check ovarian response. When 3 or more dominant follicles (≥ 17 mm) were produced, 10 000 IU of human chorionic gonadotropin was added to enhance nuclear maturation. Oocyte retrieval was then conducted via transvaginal ultrasound whereby it was fertilised and the resulting embryo was transferred 3-5 days post-fertilisation. The rate of pregnancy per IVF cycle was then used as the primary outcome for this study whereby the visibility of the intrauterine sac of the embryo determined implantation.

'''Results summary'''

Out of the 182 patients that participated in this study, it was found that only 173 patients could continue on with this trial as they satisfied the criteria, however only 162 were fit for embryo transfer. Following the results from the blood test, it was noted that 53.8% of patients had insufficient levels of 25(OH)D and 45.1% had sufficient amounts. It was discovered that 71.8% of those with sufficient levels of 25(OH)D were more likely to proceed with embryo transfer on day 5 compared to 58.9% (p = 0.054) of those assigned to the ‘insufficient 25(OH)D’ category. Other factors such as oocyte retrieval and frequency of intracytoplasmic sperm injection were fairly similar in both groups. The study revealed that there was a higher clinical pregnancy rate per IVF cycle for those assigned to the sufficient 25(OH)D level category by 52.5% compared to those with insufficient amounts of 25(OH)D which was 34.7% (p < 0.001). Similarly, there was a significant clinical pregnancy rate per embryo transfer of 54.7% in comparison to 37.9% in woman belonging to the sufficient and insufficient category respectively. It was also noted that the implantation rate was greater in the sufficient category compared to the insufficient group, however the difference was only minimal (p= 0.6). Overall, the results suggest that serum 25(OH)D levels may be a predictor of clinical pregnancy.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/24672163 PMID24672163]

<pubmed>24672163</pubmed>

The process of achieving pregnancy via invitro fertilisation needs to be monitored and controlled with respect to the demographics of the individual in order to achieve a successful outcome. This study focuses on predicting the value of β-human chorionic gonadotrophin (β-HCG) that can lead to clinical success.

'''Method summary'''

Data analysis was taken from 171 female patients using the statistical package for social sciences program whereby all IVF cycles were monitored. The cycles that showed fresh multi-cell embryos (day 3) or blastocysts (day 5) were deemed fit for the trial and were the ones that were further used in this study. Serum β-HCG concentrations were then taken 14 days after the embryo was transferred whereby a second test was done on day 16 only if the first test revealed a positive β-HCG result. This was done to predict values that could enable doctors to evaluate a healthy intrauterine pregnancy or a problematic ectopic pregnancy. After 6-7 weeks of pregnancy, ultrasounds were conducted to check cardiac activity as well as the amount of gestational sacs. This was then repeated at 12 weeks of pregnancy to ensure there was no chance of abortion.

A continuing pregnancy was defined as one that continued for at least 12 weeks of gestation and showed signs of proper cardiac function. On the other hand, those pregnancies that were abnormal had dropped levels of β-HCG concentrations and led to empty gestational sacs that showed no embryonic cardiac function. As a measuring tool for detecting levels of β-HCG, Chemiluminescent microparticle immunoassays were used whereby the measuring range established was between 0.0-15,000 mIU/mL. HCG levels above 10 IU/L signified early pregnancy.

'''Results Summary'''

Out of the 171 patients that participated in this study, only 139 were included due to the missing data on the levels of β-HCG concentrations at day 14 and 16 post embryonic transfer. In total there were 39 abnormal pregnancies that involved ectopic pregnancy, abortions and biochemical pregnancies (sufficient HCG levels detected but no visible gestational sac). Overall the patients were categorised into two groups which were patients with ‘ongoing pregnancy’ (n=100) and ‘without ongoing pregnancy’ (n=39). The Mann-Whitney test (statistical testing) was then used to compare the levels of β-HCG levels in both groups. It was found that the group with ongoing pregnancy had a median serum β-HCG level of 600 mIU/ml, whereas the other group had a median serum β-HCG level of 178 mIU/ml. This indicated a significant difference of P < 0.05 when comparing the two groups. It was also found that when serum β-HCG levels reached 347 mIU/ml, there was a 73.6% chance that the pregnancy was ongoing. Furthermore, there was no definite correlation established between age and the rate of ongoing pregnancy as both categories had patients of similar age groups with a combined range of 23-41 year old patients. Overall, the study revealed that early serum β-HCG is a potential predictor of successful outcomes in invitro fertilisation.

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 19:11, 6 October 2014 (EST) These are relevant references and your descriptions/abstracts are good (5/5).

===Lab 2===

[[File:Phase-contrast images of embryos at different developmental stages via neogenin expression.png|300px]]

Phase-contrast images of embryos at different developmental stages via neogenin expression.<ref><pubmed>25013897</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0101989 PLos One]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:17, 21 August 2014 (EST) This is all correct. The image is very large (4.8 MB), perhaps a small version could have been uploaded. You can adjust the resolution and size in most image editing programs. (5/5)

<references/>

===Lab 3===

'''Parathyroid gland'''

<pubmed>22808183</pubmed>
<pubmed>22649358</pubmed>
<pubmed>21881196</pubmed>
<pubmed>21904825</pubmed>

'''Thymus'''

<pubmed>21733645</pubmed>
<pubmed>20836742</pubmed>
<pubmed>21263742</pubmed>
<pubmed>512270</pubmed>

'''Pancreas'''

<pubmed>22761699</pubmed>
<pubmed>22893718</pubmed>
<pubmed>24496309</pubmed>
<pubmed>24595965</pubmed>
<pubmed>23822675</pubmed>
<pubmed>22968764</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===

'''1. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

'''Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1'''

Glioblastoma multiforme (GBM) is known to belong to a very life threatening form of brain cancer. Research is currently focused on finding treatments regarding such abnormalities, such as the application of neuronal stem cells in reducing the population of tumours, however there were many problems that occurred with such treatment. Recently, Human umbilical cord blood derived stem cells (hUCBSC) has been extensively used as they are useful mesenchymal stem cells that are easy to isolate and are more available. GBM is caused by the overexpression of cyclin D1 and its subsequent binding to Cdk 4/Cdk 6 which defines the rate limiting step required for the cell to progress further on to the cell cycle from the G1 phase. In order to stop this over expression, scientists have used hUCBSC to inhibit the cell from progressing on with the cell cycle.

When (hUCBSC) were cultured with U251 and 5310 cells, flow cytometry technology revealed that the cells underwent G1 arrest showing an increase in the G0-G1/S phase ratio. There was also a 54% reduction in levels of cyclin D1 when hUCBSC was cultured with U251 in comparison to the control. Immunoprecipiation revealed that hUCBSC treated cells when immuno blotted with Cdk 4 and Cdk 6 antibodies, down regulated expression of both Cdk 4 and Cdk 6. Western blot also showed the same down regulating pattern of the individual expression and genes which confirmed that there was cell cycle arrest, thus preventing tumours from forming.

As such, this study helps researchers to grasp the foundation of using hUCBSC as a treatment for glioblastoma and to further build on such research. Since it is evident that hUCBSC is effective in reducing cyclin D1 expression; analysing glioblastomal hierarchy will aid in providing the missing links needed to create the clinical treatment.

<pubmed>21455311</pubmed>

'''2. There are a number of developmental vascular "shunts" present in the embryo, that are closed postnatally. Identify these shunts and their anatomical location.'''

Three major vascular shunts include:

• '''Ductus venosus''' - is a shunt of oxygenated blood from umbilical vein to IVC, bypassing the liver. The ductus venosus constricts and closes soon after birth and becomes the ligamentum venosum

• '''Foramen ovale''' - is a flap valve in the atrial septum between the right and left atrium that shunts highly oxygenated blood . The remnant of the foramen ovale is known as the fossa ovalis.

• '''Ductus arteriosus''' - is a shunt from the descending aorta to the left pulmonary artery near the bifurcation of the pulmonary trunk. Permanent closure takes 4-6 weeks by fibrosis, and the remnant is referred to as the ligamentum arteriosum.

===Lab 5===

'''Select an abnormality of either gastrointestinal or respiratory development and write a brief description of developmental causes(s) for this abnormality. Your answer should be added to your own student page, be brief (2-3 paragraphs) and referenced.'''

'''Midgut volvulus'''

The embryonic development of the midgut has a number of steps which ensures its proper formation. These include the viability of the superior mesenteric artery to divide the midgut into the cephalad (pre-arterial region) and caudad (post-arterial region). <ref><pubmed>15378215</pubmed></ref>During the fourth gestational week, the gastrointestinal system is composed of a centrally positioned linear tube in the abdomen. At approximately 6 weeks of gestational age, the midgut undergoes a process of U-shaped herniation causing the two portions of the midguts to face the opposite directions in relation to the superior mesenteric artery. From this moment, a number of rotation events occur to ensure the complete development of the gastrointestinal tract as it becomes set in the posterior abdominal wall.<ref><pubmed>7277164</pubmed></ref>

In some cases malrotations can occur during the developmental process of the midgut which involves the complete twisting of the midgut in relation to the axis of the superior mesenteric artery. In extreme cases this can lead to midgut volvulus which results in a narrowed mesenteric base that can obstruct the passage of blood and lead to tissue necrosis. Other complications resulting from midgut volvulus include intestinal ischaemia, peritonitis, mucosal necrosis and sepsis which can eventually lead to death if left untreated. <ref><pubmed>14655161</pubmed></ref>

Malrotation is known to occur within 1 in 500 live births and out of those who develop midgut volvusos, 68-71% are neonates. <ref><pubmed>22217896</pubmed></ref>Although the actual cause of malrotation is unknown, researchers have made links to congenital syndromes such as Down syndrome and the VACTERL. It is also hypothesized that any embryonic interference during the normal patterns of rotation and fetal development can lead to midgut volvulus. Treatment of midgut volvulus is dependent on when the disease is diagnosed. <ref><pubmed>18800265</pubmed></ref>Normally a sigmoidoscopy is carried out as well as the Ladd procedure to resect dead gastrointestinal tissues. Transduodenal bands of ladd may also be divided to widen the mesenteric pedicle and prevent obstruction of blood flow. <ref><pubmed>22208840</pubmed></ref>Overall, research is still being conducted on the specific causes of malrotation and other numerous treatments.

<references/>

===Lab 6===

Group work

===Lab 7===

'''1.Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

'''Novel genes upregulated when NOTCH signaling is disrupted during hypothalamic development.'''

It is known that the hypothalamus first develops from the ventral region of the diencephalon and signaling mechanisms such as the sonic hedgehog and bone morphogenic protein pathways are responsible for pattern arrangement. Neurogenesis is the key process required to ensure proper hypothalamus development which relies on many signaling pathways to produce neurons and glia. The Notch signaling pathway is currently known to inhibit neuronal differentiation and preserve neural progenitor identity. As a result of various studies and research, the combined theory has been implemented in this study to determine the effect of downregulating Notch signaling pathways in its effect on hypothalamic development.

Results show that when Notch signaling is inactivated, novel genes such as Dll1, Hes5, Hey1 and Ascl1 are upregulated in the rostral hypothalamus, subsequently leading to the early formation of hypothalamic neurons. This is also seen when embryos that are treated with DAPT (a chemical which inhibits cell differentiation mechanisms regulated by the Notch pathway) had an overexpression of cells differentiated into neurons in a clustered formation. This was compared to the control embryos which had differentiated cells in a scattered arrangement. As such, this research showed that Notch is a powerful signaling mechanism that is used to inhibit cell differentiation in order to control the number of cells differentiated into neurons or glia. This modulating ability of the Notch pathway is imperative in the early developing hypothalamus as it controls expression of cells and hence prevents any form of defects that can be harmful both prenatally and postnatally. Further research needs to be conducted on the Notch pathway to provide procedures where its mechanism can be used to resolve defects in the embryo and hence ensure proper hypothalamic development.

<pubmed>24360028</pubmed>

'''2.Identify the embryonic layers and tissues that contribute to the developing teeth.'''

'''Odontoblasts''' - neural crest-derived mesenchymal cells which establish the outer dental pulp. It differentiates via the enamel epithelium and releases dentin from dentinogenesis.

'''Ameloblasts''' - are derived from oral epithelium tissue of ectodermal origin and make up the inner enamel. They make pre-ameloblasts and produce enamel.

'''Periodontal ligament''' – is comprised of connective tissues which holds the tooth in place in the alveolar bone. It also encloses the cementum coating of the tooth root.

===Lab 8===

'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

'''Embryonic development of the ovary'''

The Gonads are known to be formed from the combination of primitive germ cells, adjacent mesenchyme and the mesothelium of the posterior abdominal wall. It isn’t until fifth week of embryonic development that the formation of Gonads occurs. The primordial germ cells first migrate from the embryonic yolk sac towards the hindgut along the dorsal mesentery. These cells then travel to the mesenchyme forming genital ridges positioned medially to the mesonephros by the sixth week of development. Coelomic epithelium and the mesonephros cells also proliferate at this stage. These cells then incorporate into the primary sex cords in which the process is driven by the genes stella, fragilis, and BMP-4 before the seventh week of embryonic development.<ref><pubmed>23409002</pubmed></ref>

The gonads are known to be indifferent until the sixth embryonic week as the gonads appear the same, however sex differentiation based on sex chromosomes determine the sex of the Gonad (XX for female and XY for males). The indifferent gonads are situated well inside the Wolffian body and are comprised of an inner medulla and outer cortex which contains precursors for ovarian stroma and parenchyma respectively.<ref><pubmed>3712511</pubmed></ref> In embryos consisting of XX sex chromosomes, the cortex of the indifferent gonad differentiates into an ovary meanwhile the medulla regresses by week eight of embryonic development. However, the sex cords leads to the formation of rete ovarii which is a complex of tubules and cords that arises from the mesonephros.

Another important event that occurs during the sixth week of development is the formation of the mullerian ducts which are responsible for female gonad formation and prevention of male gonad development. The established XX genotype of the female embryo prevents testosterone from being produced and hence causes the regression of the mesonephric duct since this form is only needed for male gonad expression. Also since there is no production of anti-mullarian hormone, the paramesonephric duct is able to be maintained driving female gonad expression. As of 10 weeks of development, ovaries first become recognizable and the growth of female external genitalia begins to occur.

[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]

<references/>

''' 2.Include an image from the historic genital embryology section of the online notes in your description.'''

[[File:Gray1112.jpg|400px]]

Figure 1. Longitudinal Section of Ovary of Cat Embryo of 9.4 cm long

===Lab 9===

'''Group project 1'''

The introduction was written quite well as it explains what the respiratory system is about and the origin of its development. It also briefly highlights the difference between the embryonic and fetal stage which is important in enabling the viewers to have an understanding on what the project will be focusing on. I also like how the group distinguished between the two zones of the respiratory tract and adequately described the features and function of each. The content in the lung development stages clearly relates to the topic and underlines fetal development. The group briefly mentioned the key features in each stage instead of pasting a whole lot of information; this makes it easier for viewers to understand. Overall the content relates to the learning objectives of embryology and the level of research is good as exemplified under ‘Current Research and Findings’ and ‘abnormalities’ (many forms of diseases described). The project however could benefit from having a ‘Glossary’ list so that viewers can understand some uncommon words.

The images under introduction and the image used for Meconium aspiration syndrome have not been referenced properly as there is missing information such as ((Template: Student Image)), description, copyright information and proper references for some. The image used under the ‘current research and findings’ subheading is a good example for the group to copy the referencing style. It is also vital that the group adds a brief description of what the image illustrates as a caption to help viewers understand the relation of the content and image (this is seen in the image under ‘surfactant’). More images could be added such as in the ‘lung development stage’ and under abnormalities. If images for lung development stages aren’t easily accessible, it is perhaps a good idea to draw them. The table format used for ‘lung development stages’ makes it easy for the viewers to navigate which is a good feature used in the project.

In terms of referencing, there are many in-cite references missing such as in the ‘introduction’ and in ‘lung development stages’. It is important to have these references formatted correctly under the one ‘references’ subheading. There seems to be many ‘references’ subheadings making it harder for viewers to navigate. Some references are shown as ‘ </li> which needs to be fixed right away. Overall, the content seems well written, formatted and concise making it easy to understand. However the problems related to referencing needs to be corrected as this is inconsistent throughout the project.

'''Group project 2'''

The introduction is well addressed as it sufficiently describes what the renal system is about and its function. Not to mention its anatomical structure as well as the difference between the embryonic and fetal stages of development. This differentiation enables viewers to understand what the content will be focused on, which is fetal development. Also, it helps focus the viewer’s attention on how the project will be divided as the group mentions abnormalities in the last paragraph. Overall the introduction has the right amount of information from each subheading and is very easy to comprehend.

There isn’t any information under ‘historic findings’. If there are any difficulties in finding some historic findings, members of the group can go to pubmed and on the side will be dates such as 1920 that could contain key historical events when renal is entered on search. The use of a development timeline was great as they outlined the major events that occur in a concise manner. Although, I believe a glossary is needed for words like ‘metanephros’ since the viewers would not know what that is. The content under current research models is interesting and correctly describes what the studies were about. Overall, the content used in the project was relating to the topic (fetal development of the kidney) and clearly showed extensive research. I really like how the group divided the different parts of the renal system as well as describing their anatomical positions. The abnormalities listed are also interesting and very easy to understand. I’m hoping to see information under the Horseshoe kidney disease.

In terms of images, there should be an image under introduction perhaps having all features of the renal system. Most images are missing the ‘student template’ aspect of the referencing and needs to be added right away. Other aspects such as description, copyright and referencing were correct. I also like the use of captions to describe what the images are about, however some are missing on the page such as the one under ‘anatomical position’ and ‘urethra’. The image used for the ‘development of the kidney’ should be removed from the page as it isn’t permissible. It should be replaced with an image relating to the content and have all the correct copyright and referencing information. Overall, I like the number of images used and its significance to the renal system. They accurately relate to the content of the project.

There is use of in-cite referencing which is good, however some references are just listed and should be placed under the proper ‘references’ subheading such as the ones under ‘ureter’ and ‘renal agenesis’. Some references in the ‘references’ list are used over again and can be fixed by combining it under one reference number. To make the project even more appealing, the group could format the information under ‘developmental timeline’ or even ’historic findings’ in a table. Overall, I think this project is great and by making edits based on the peer-reviews received could enhance their project.

'''Group project 3'''

The introduction is good as it accurately describes what the GIT system is about and the anatomical positions of the features in this system. It also briefly highlights the development stages at embryonic and fetal stages, however ‘embryonic development’ should be mentioned in a little more detail to understand how far in development the fetal stage begins. I also think the introduction should include a sentence or two describing how abnormalities in such organs can lead to these diseases. Basically a bit from each major subheading should be incorporated including current research as an introduction is a summary of the whole page. As for the ‘timeline’, it would’ve been more appropriate to place the timelines under each section, e.g foregut timeline under the ‘foregut’ subheading. This is because viewers would be confused on why there is so much difference in development in one section of the page. A glossary list should be incorporated in a separate subheading to define some of these words such as hematopoiesis so that viewers can fully grasp the information.

The information under recent findings is quite interesting and relatable to the content which is GIT fetal development. However, I believe more findings could be incorporated under this subheading. The information under each organ of the three ‘guts’ are quite detailed in fetal development which is good and shouldn’t be too difficult for the viewers to understand. However, I believe the group could include information on the function of these organs as well. The structure of the information under ‘guts’ does not flow in the sense that the midgut includes features and structure whereas the other ‘guts’ do not. The innvervation and bloody supply of the hindgut should be incorporated in a paragraph instead of being listed like that. All the deformities should be places under one subheading to make it easier for viewers to navigate. The abnormalities were also concise and related to the topic. Overall, the content is relating to the topic of the project and addresses key points. It also shows good amount of research, however there seems to be too much information in some parts which could be reduced a bit. The project needs a coherent flow of the structure.

As for images, there needs to be an image under introduction which includes all features of the GIT tract. There are a lot of potential images missing under each subheading except for the ‘midgut’ section. This shows that there has been one person working on this section or one section being focused on in comparison the others. The information used to reference the images is missing in some images such as the ‘Human- fetal week 10 sagittal plane D.jpg’ (although this is uploaded from a different user so this is understandable. However images such a ‘GIT 2.jpg’ need more information including ‘student template’ as well as the reference where the image idea may have come from. Also, if this is a hand-drawn image then please state this as one member did in ‘Week 11 midgut herniation.png’. Overall, I enjoy the use of self-drawn images as it makes it easier to show what the content is saying without going through the stress of looking for an image online that doesn’t relate to the content. However more images definitely need to be added. The use of captions is also good and indicates what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘Liver, Gallbladder and Bile Duct’ (the [6],[7] should be placed next to the text not above the text. The use of a ‘references’ subheading is good the same references have been combined into one number showing that the group knows how to make the references set out. The use of a table in formatting the ‘Percentage of Foetuses Herniated’ is great and shows more that the group has done research. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 4'''

The project doesn’t have an introduction yet; however information such as what the genital system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of genital development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. As for system development, I can see how there is dot-point description above the table which summarises the same thing. This structure is a bit confusing for me. I believe if the information was summarised into paragraphs and then tabulated it would make more sense. It’s best to format all that information into that table. The use of a table is a great way for the viewers to differentiate between the two sexes and understand the information more easily. I hope to see the table filled out completely soon. A glossary subheading should also be placed on the project page and have keywords defined to make viewers completely understand the content.

As for current findings, the information again is in dot points which should be paragraphed instead. However, the current findings are indeed interesting and the right amount of information is used to describe them in both sexes. The content under historic findings such as the ‘female genital development’ doesn’t show any historical events. There are no dates which show when something related was discovered. The ‘male genital development’ however shows dates and discoveries. In my opinion, if this information were tabulated rather than paragraphed, it’d be easier for viewers to navigate and understand. There is a good amount of detail under the abnormalities which relates to the key topic and is easy to understand. Overall, the content is relatable to the genital development of the fetus and underlines all the keys points. However, if this information were paragraphed in some areas and mentioned above, it would make the content easier to navigate and comprehend.

In terms of images, there are many places where images are missing such as introduction, system development and current models. I believe there needs to be more images on this page that relate to the content to make it more appealing and understandable to the viewers. The image called ‘File:Flow Diagram of Fetal Development of External Genitalia.pptx’ isn’t permissible and needs to be removed. The use of a hand drawn image on the testes is great, however there is information missing on referencing, student template and copyright laws. On the other hand, there are some images which correctly follow the uploading picture procedures such as the image on the ‘abnormalities of the vagina’; group members should follow this procedure. Captions should be added to each image to address what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘system development’. The use of a ‘references’ subheading is good, the same references have been combined into one number showing that the group knows how to make the references set out. However reference 20 and 21 are the same, please fix this. Also there are references under each subheading which should be placed all under one ‘references’ subheading. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 5'''

The introduction is a great summary of what the project page will discuss making sure to highlight every aspect. However, the introduction should also mention more about the integumentary system listing all the organs involved, their function, anatomical position and the difference between the embryonic and fetal stages of integumentary development. The content presented on the page is fantastic. All information under the subheadings looks complete and has key information related to the topic. I like how the timeline is divided into each organ making it easy to understand and navigate. The use of the table to format the information is a brilliant idea and has been presented beautifully with images in each textbox. Also the content under current research is relating to the topic and shows extensive research. The use of the purple background is appealing to the viewer highlighting its significance. I do however believe that the information under ‘historic findings’ should be formatted into a table to make it easier to navigate. The content under ‘abnormalities’ has the right amount of information and clearly relates to the key topic of the project.

In terms of images, I believe a satisfactory amount of images have been used which clearly describes the content. However, some images are missing the all the copyright information needed as well as the description, references and student template such as those in the ‘development overview’ table. This should be added right away to ensure these images do not get deleted. The use of captions on these pictures is important to highlight what the image is referring to and this is present in the page. Although, images could be added under current research as this section looks like it could use more images. Great job on the images under abnormalities, they accurately relate to the content mentioned.

There are some incite references missing such as in the development overview. I’m not sure if the references listed below are supposed to the references for it, however all references should be placed under one ‘references’ subheading. The same references have been combined into one number showing that the group knows how to make the references set out. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections. Overall, this is a great project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 7'''

The introduction is great as it mentions the features of the neural system, their anatomical positions and highlights the key events in the embryonic and fetal stages of development. The last paragraph of the introduction clearly addresses how the page will be divided and what the viewers are to expect which is good. The content under all subheadings are relating to the key topic and are formatted appropriately. I really like the image used under the subheading ‘Development during fetal period’ as it presents a diagrammatic representation of the content mentioned. The use of a table to briefly describe the events that occur at certain periods of fetal development is really helpful in grasping the main details. Some information is missing such as in ‘spinal cord development’, ‘Meninges development’, ‘future research’ and some ‘abnormalities’. This should be added right away. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the neural system and view dates on the side that may contain key findings. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

In terms of images, there are still many potential spaces for images such as under ‘introduction’, ‘current research’ and some ‘abnormalities’. The images used under ‘Development during fetal period’ are great and relate to the content. All images have correct description, referencing, copyright issues and ‘student template’, which shows that members of the group have followed correct ‘uploading image’ procedures. The images however need a caption to describe what the image is showing.

There needs to be more use of incite referencing such as in the ‘introduction’, ‘brain development’ and ‘abnormalities’. There is a huge list of references under ‘current research models and findings’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. References 7 and 8 are the same reference under the ‘references’ subheading and need to be combined into one number. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 8'''

The project doesn’t have an introduction yet; however information such as what the Musculoskeletal system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of musculoskeletal development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. I like the ‘making gains’ subheading as it adds humour to the page and engages the viewers. The general timeline needs information including what events take place at certain phases of fetal development. This could be present in a table to make the information more clear. It’s good that the project has information on the embryonic development so that the viewers can understand how the fetus arises to that point in development (fetal period).
All of the content seems to relate to the key topic and is appropriately paragraphed. However much of the content is still missing such as in ‘recent findings’ and ‘introduction’. More information could be added under the associated ‘trimesters’ and ‘abnormalities’. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the musculoskeletal system and view dates on the side that may contain key findings for historical events. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

There are no images on this page and definitely needs to be added with the appropriate information such as the description, referencing, copyright issues and ‘student template’. If images are not readily available, it is best to draw them. Also captions should be added on the page to state what the images are showing. As for referencing, there are some sections which shows incite referencing such as in the content under ‘Molecular and Cellular regulation of fetal myogenesis’ and some that don’t have any like in ‘tendon development’. There needs to be references in all sections. There is a huge list of references under ‘abnormalities’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. Number 15 of the reference list has an error in it and needs to be fixed right away. Overall, this is a working progress and if the group makes edits based on the peer-reviews received, this could enhance their project.

===Lab 10===

'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

'''''TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction.'''''

A major feature of the olfactory region is the olfactory bulb which contains mitral cells that serve to relay olfactory messages via sensory neurons of the olfactory epithelium to the piriform cortex of the brain. Within the granular cells and glomerular layers are interneurons which control the message output via synaptic linkages between mitral and tufted cell projection neurons. These interneurons continue to grow postnatally via neural stem cells located in the dorsolateral ganglionic eminence (dLGE) which consists of the subventricular zone and subependymal zone. When neuroblasts migrate to the dLGE, this stimulates dLGE-derived interneuron progenitors to migrate radially in the growing bulbs where they mature into the granular or glomerular cell layer. There has been research showing how teashirt zinc finger family member 1 (TSHZ1) is vital for the development of the olfactory bulb. In mice, it was found that olfactory bulb neuroblast differentiation required Tshz1 expression or else a large proportion of interneurons of the granular cell layer will not be present and radial migration of neuroblasts will be impaired. The basis of the previous studies was then replicated in humans suffering from congenital aural atresia that had TSHZ1 loss-of-function mutations.

Coronal sections 500-μm in size was obtained from the subjects which then underwent Nissl staining with cholineacetyl transferase histochemistry to observe the change in patterns of normal and abnormal olfactory development. In some parts of the experiment, mice were used as subjects to observe how congenital aural atresia may also affect them. In situ hybridization was used to investigate this effect on mice whereby Tshz1 positive and negative gene transcripts were obtained and amplified using polymerase chain reaction (PCR). Primers of the targeted gene and splicing enzymes were used to make sure the correct transcripts were produced.

Through immunoflourenscing and immunohistology, it was found that Tshz1 mutation lead to an abnormal distribution and differentiation of granule cell neurons of the developing olfactory bulb. Green fluoresce protein was integrated in the Tshz1 locus in both Tshz1+ and Tshz1- subjects. Through immunostaining of olfactory bulbs, it was shown that there was a consistent outer granule cell ring distribution of GFP+ cells in comparison to the unevenly distributed GFP+ cell located in the inner granule cell layer. DAPI staining revealed that the structure of the olfactory bulb in Tshz1 positive subjects were more layered and structure compared to deformed structure seen in Tshz1 mutants. The granule cell and external plexiform layers were indistinguishable and the glomerular layer had multilayers, thereby showing the abnormality in Tshz1 mutants.

Microarray hybridization was used to sort out gene expression in Tshz1 positive and negative subjects. Out of all the gene transcripts profiled, it was noted that the most significantly changed transcripts was Prokr2. Expression of PK2 was also downregulated in the rostral migratory stream of the subjects. Prokr2 expression was therefore examined in the developing olfactory bulb of Tshz1 positive and mutant mice using in situ hybridization. It was found that Tshz1 mRNA expression was seen in both the outer granule cell layer and the inner layers of the olfactory bulb mainly consisting of immature cells. Prokr2 expression was observed only in the inner layers of the OB in Tshz1 positive subjects and in mutants, Prokr2 expression was greatly downregulated. Overall, it was established that Tshz1 is needed to control the expression of Prokr2 which radially migrates neuroblasts. In addition, the PK2 family and its associated receptor are imperative factors required for normal olfactory bulb development.

<pubmed>24487590</pubmed>

'''Wiki link: https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Smell_Development'''

===Lab 11===

'''Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

'''Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration.'''

As cardiovascular disease continues to be the number one cause of death in the older population, there is significant research based on using stem cells as a tool to regenerate functional and healthy cardiomyctes in patients who’ve suffered from myocardial infarction. In particular, human induced pluripotent stem cells (hiPSCs) are used in this study to observe how these cells can generate cardiovascular cell sheets that may be used to treat infarcted heart tissue. Not to mention how hiPSCs may overcome obstacles such as poor engraftment of the cells injected in the heat and immunorejection, thereby placing the research more towards clinical practice.

'''Main findings'''

<ref><pubmed>25336194</pubmed></ref>

<references/>

User:Z3418837

2014-10-27T11:25:47Z

Z3418837: /* Lab 11 */

==Lab Attendance==
*Lab 1 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 6 August 2014 (EST)
*Lab 2 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:11, 13 August 2014 (EST)
*Lab 3 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:12, 20 August 2014 (EST)
*Lab 4 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:55, 27 August 2014 (EST)
*Lab 5 -- Absent
*Lab 6 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:44, 10 September 2014 (EST)
*Lab 7 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:40, 17 September 2014 (EST)
*Lab 8 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:11, 24 September 2014 (EST)
*Lab 9 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:08, 8 October 2014 (EST)
*Lab 10 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 15 October 2014 (EST)
*Lab 11 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 22 October 2014 (EST)
*Lab 12

==Individual Assessment==

==='''Lab 1'''===

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 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>

'''Your Lab assessment now requires you to find a 2 recent research references on fertilisation or in vitro fertilisation. Paste each reference on your page, as shown in the class. Write below each reference a brief summary of the research article methods and findings. The summary for each need not be more than 3-4 paragraphs in length. This will need to be completed before next weeks laboratory'''.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/25077107 PMID25077107]

<pubmed>25077107</pubmed>

This study was designed to investigate whether the levels of vitamin D is an imperative factor when it comes to the clinical success of implantation and pregnancy rates in infertile women via invitro fertilisation.

'''Method summary'''

A cohort of 173 women were evaluated and selected for this study based on their age, follicle-stimulating hormone levels and their consent to undergo invitro fertilisation. The following study was conducted at Mount Sinai Hospital where proper facilities were available. Blood tests were then conducted for each patient to determine their levels of Vitamin D via the serum 25-hydroxy-vitamin D (25[OH]D) levels. Following the results of the blood test, the cohort were then categorised into two groups which was either vitamin D sufficient (≥ 75 nmol/L) or insufficient ( < 75 nmol/L) based on serum levels of 25(OH)D.

Each patient then underwent IVF cycles whereby standard agonists that contained the active ingredient 0.5 mg/d of buserelin acetate in conjunction with cetrolix acetate as the standard antagonist were used to control the length of the luteal phase and estradiol levels. The length and dose of the treatment were varied for each individual based on their demographic data. Serial transvaginal ultrasonograpy and serum lutenizing hormone assays were then used to check ovarian response. When 3 or more dominant follicles (≥ 17 mm) were produced, 10 000 IU of human chorionic gonadotropin was added to enhance nuclear maturation. Oocyte retrieval was then conducted via transvaginal ultrasound whereby it was fertilised and the resulting embryo was transferred 3-5 days post-fertilisation. The rate of pregnancy per IVF cycle was then used as the primary outcome for this study whereby the visibility of the intrauterine sac of the embryo determined implantation.

'''Results summary'''

Out of the 182 patients that participated in this study, it was found that only 173 patients could continue on with this trial as they satisfied the criteria, however only 162 were fit for embryo transfer. Following the results from the blood test, it was noted that 53.8% of patients had insufficient levels of 25(OH)D and 45.1% had sufficient amounts. It was discovered that 71.8% of those with sufficient levels of 25(OH)D were more likely to proceed with embryo transfer on day 5 compared to 58.9% (p = 0.054) of those assigned to the ‘insufficient 25(OH)D’ category. Other factors such as oocyte retrieval and frequency of intracytoplasmic sperm injection were fairly similar in both groups. The study revealed that there was a higher clinical pregnancy rate per IVF cycle for those assigned to the sufficient 25(OH)D level category by 52.5% compared to those with insufficient amounts of 25(OH)D which was 34.7% (p < 0.001). Similarly, there was a significant clinical pregnancy rate per embryo transfer of 54.7% in comparison to 37.9% in woman belonging to the sufficient and insufficient category respectively. It was also noted that the implantation rate was greater in the sufficient category compared to the insufficient group, however the difference was only minimal (p= 0.6). Overall, the results suggest that serum 25(OH)D levels may be a predictor of clinical pregnancy.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/24672163 PMID24672163]

<pubmed>24672163</pubmed>

The process of achieving pregnancy via invitro fertilisation needs to be monitored and controlled with respect to the demographics of the individual in order to achieve a successful outcome. This study focuses on predicting the value of β-human chorionic gonadotrophin (β-HCG) that can lead to clinical success.

'''Method summary'''

Data analysis was taken from 171 female patients using the statistical package for social sciences program whereby all IVF cycles were monitored. The cycles that showed fresh multi-cell embryos (day 3) or blastocysts (day 5) were deemed fit for the trial and were the ones that were further used in this study. Serum β-HCG concentrations were then taken 14 days after the embryo was transferred whereby a second test was done on day 16 only if the first test revealed a positive β-HCG result. This was done to predict values that could enable doctors to evaluate a healthy intrauterine pregnancy or a problematic ectopic pregnancy. After 6-7 weeks of pregnancy, ultrasounds were conducted to check cardiac activity as well as the amount of gestational sacs. This was then repeated at 12 weeks of pregnancy to ensure there was no chance of abortion.

A continuing pregnancy was defined as one that continued for at least 12 weeks of gestation and showed signs of proper cardiac function. On the other hand, those pregnancies that were abnormal had dropped levels of β-HCG concentrations and led to empty gestational sacs that showed no embryonic cardiac function. As a measuring tool for detecting levels of β-HCG, Chemiluminescent microparticle immunoassays were used whereby the measuring range established was between 0.0-15,000 mIU/mL. HCG levels above 10 IU/L signified early pregnancy.

'''Results Summary'''

Out of the 171 patients that participated in this study, only 139 were included due to the missing data on the levels of β-HCG concentrations at day 14 and 16 post embryonic transfer. In total there were 39 abnormal pregnancies that involved ectopic pregnancy, abortions and biochemical pregnancies (sufficient HCG levels detected but no visible gestational sac). Overall the patients were categorised into two groups which were patients with ‘ongoing pregnancy’ (n=100) and ‘without ongoing pregnancy’ (n=39). The Mann-Whitney test (statistical testing) was then used to compare the levels of β-HCG levels in both groups. It was found that the group with ongoing pregnancy had a median serum β-HCG level of 600 mIU/ml, whereas the other group had a median serum β-HCG level of 178 mIU/ml. This indicated a significant difference of P < 0.05 when comparing the two groups. It was also found that when serum β-HCG levels reached 347 mIU/ml, there was a 73.6% chance that the pregnancy was ongoing. Furthermore, there was no definite correlation established between age and the rate of ongoing pregnancy as both categories had patients of similar age groups with a combined range of 23-41 year old patients. Overall, the study revealed that early serum β-HCG is a potential predictor of successful outcomes in invitro fertilisation.

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 19:11, 6 October 2014 (EST) These are relevant references and your descriptions/abstracts are good (5/5).

===Lab 2===

[[File:Phase-contrast images of embryos at different developmental stages via neogenin expression.png|300px]]

Phase-contrast images of embryos at different developmental stages via neogenin expression.<ref><pubmed>25013897</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0101989 PLos One]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:17, 21 August 2014 (EST) This is all correct. The image is very large (4.8 MB), perhaps a small version could have been uploaded. You can adjust the resolution and size in most image editing programs. (5/5)

<references/>

===Lab 3===

'''Parathyroid gland'''

<pubmed>22808183</pubmed>
<pubmed>22649358</pubmed>
<pubmed>21881196</pubmed>
<pubmed>21904825</pubmed>

'''Thymus'''

<pubmed>21733645</pubmed>
<pubmed>20836742</pubmed>
<pubmed>21263742</pubmed>
<pubmed>512270</pubmed>

'''Pancreas'''

<pubmed>22761699</pubmed>
<pubmed>22893718</pubmed>
<pubmed>24496309</pubmed>
<pubmed>24595965</pubmed>
<pubmed>23822675</pubmed>
<pubmed>22968764</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===

'''1. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

'''Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1'''

Glioblastoma multiforme (GBM) is known to belong to a very life threatening form of brain cancer. Research is currently focused on finding treatments regarding such abnormalities, such as the application of neuronal stem cells in reducing the population of tumours, however there were many problems that occurred with such treatment. Recently, Human umbilical cord blood derived stem cells (hUCBSC) has been extensively used as they are useful mesenchymal stem cells that are easy to isolate and are more available. GBM is caused by the overexpression of cyclin D1 and its subsequent binding to Cdk 4/Cdk 6 which defines the rate limiting step required for the cell to progress further on to the cell cycle from the G1 phase. In order to stop this over expression, scientists have used hUCBSC to inhibit the cell from progressing on with the cell cycle.

When (hUCBSC) were cultured with U251 and 5310 cells, flow cytometry technology revealed that the cells underwent G1 arrest showing an increase in the G0-G1/S phase ratio. There was also a 54% reduction in levels of cyclin D1 when hUCBSC was cultured with U251 in comparison to the control. Immunoprecipiation revealed that hUCBSC treated cells when immuno blotted with Cdk 4 and Cdk 6 antibodies, down regulated expression of both Cdk 4 and Cdk 6. Western blot also showed the same down regulating pattern of the individual expression and genes which confirmed that there was cell cycle arrest, thus preventing tumours from forming.

As such, this study helps researchers to grasp the foundation of using hUCBSC as a treatment for glioblastoma and to further build on such research. Since it is evident that hUCBSC is effective in reducing cyclin D1 expression; analysing glioblastomal hierarchy will aid in providing the missing links needed to create the clinical treatment.

<pubmed>21455311</pubmed>

'''2. There are a number of developmental vascular "shunts" present in the embryo, that are closed postnatally. Identify these shunts and their anatomical location.'''

Three major vascular shunts include:

• '''Ductus venosus''' - is a shunt of oxygenated blood from umbilical vein to IVC, bypassing the liver. The ductus venosus constricts and closes soon after birth and becomes the ligamentum venosum

• '''Foramen ovale''' - is a flap valve in the atrial septum between the right and left atrium that shunts highly oxygenated blood . The remnant of the foramen ovale is known as the fossa ovalis.

• '''Ductus arteriosus''' - is a shunt from the descending aorta to the left pulmonary artery near the bifurcation of the pulmonary trunk. Permanent closure takes 4-6 weeks by fibrosis, and the remnant is referred to as the ligamentum arteriosum.

===Lab 5===

'''Select an abnormality of either gastrointestinal or respiratory development and write a brief description of developmental causes(s) for this abnormality. Your answer should be added to your own student page, be brief (2-3 paragraphs) and referenced.'''

'''Midgut volvulus'''

The embryonic development of the midgut has a number of steps which ensures its proper formation. These include the viability of the superior mesenteric artery to divide the midgut into the cephalad (pre-arterial region) and caudad (post-arterial region). <ref><pubmed>15378215</pubmed></ref>During the fourth gestational week, the gastrointestinal system is composed of a centrally positioned linear tube in the abdomen. At approximately 6 weeks of gestational age, the midgut undergoes a process of U-shaped herniation causing the two portions of the midguts to face the opposite directions in relation to the superior mesenteric artery. From this moment, a number of rotation events occur to ensure the complete development of the gastrointestinal tract as it becomes set in the posterior abdominal wall.<ref><pubmed>7277164</pubmed></ref>

In some cases malrotations can occur during the developmental process of the midgut which involves the complete twisting of the midgut in relation to the axis of the superior mesenteric artery. In extreme cases this can lead to midgut volvulus which results in a narrowed mesenteric base that can obstruct the passage of blood and lead to tissue necrosis. Other complications resulting from midgut volvulus include intestinal ischaemia, peritonitis, mucosal necrosis and sepsis which can eventually lead to death if left untreated. <ref><pubmed>14655161</pubmed></ref>

Malrotation is known to occur within 1 in 500 live births and out of those who develop midgut volvusos, 68-71% are neonates. <ref><pubmed>22217896</pubmed></ref>Although the actual cause of malrotation is unknown, researchers have made links to congenital syndromes such as Down syndrome and the VACTERL. It is also hypothesized that any embryonic interference during the normal patterns of rotation and fetal development can lead to midgut volvulus. Treatment of midgut volvulus is dependent on when the disease is diagnosed. <ref><pubmed>18800265</pubmed></ref>Normally a sigmoidoscopy is carried out as well as the Ladd procedure to resect dead gastrointestinal tissues. Transduodenal bands of ladd may also be divided to widen the mesenteric pedicle and prevent obstruction of blood flow. <ref><pubmed>22208840</pubmed></ref>Overall, research is still being conducted on the specific causes of malrotation and other numerous treatments.

<references/>

===Lab 6===

Group work

===Lab 7===

'''1.Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

'''Novel genes upregulated when NOTCH signaling is disrupted during hypothalamic development.'''

It is known that the hypothalamus first develops from the ventral region of the diencephalon and signaling mechanisms such as the sonic hedgehog and bone morphogenic protein pathways are responsible for pattern arrangement. Neurogenesis is the key process required to ensure proper hypothalamus development which relies on many signaling pathways to produce neurons and glia. The Notch signaling pathway is currently known to inhibit neuronal differentiation and preserve neural progenitor identity. As a result of various studies and research, the combined theory has been implemented in this study to determine the effect of downregulating Notch signaling pathways in its effect on hypothalamic development.

Results show that when Notch signaling is inactivated, novel genes such as Dll1, Hes5, Hey1 and Ascl1 are upregulated in the rostral hypothalamus, subsequently leading to the early formation of hypothalamic neurons. This is also seen when embryos that are treated with DAPT (a chemical which inhibits cell differentiation mechanisms regulated by the Notch pathway) had an overexpression of cells differentiated into neurons in a clustered formation. This was compared to the control embryos which had differentiated cells in a scattered arrangement. As such, this research showed that Notch is a powerful signaling mechanism that is used to inhibit cell differentiation in order to control the number of cells differentiated into neurons or glia. This modulating ability of the Notch pathway is imperative in the early developing hypothalamus as it controls expression of cells and hence prevents any form of defects that can be harmful both prenatally and postnatally. Further research needs to be conducted on the Notch pathway to provide procedures where its mechanism can be used to resolve defects in the embryo and hence ensure proper hypothalamic development.

<pubmed>24360028</pubmed>

'''2.Identify the embryonic layers and tissues that contribute to the developing teeth.'''

'''Odontoblasts''' - neural crest-derived mesenchymal cells which establish the outer dental pulp. It differentiates via the enamel epithelium and releases dentin from dentinogenesis.

'''Ameloblasts''' - are derived from oral epithelium tissue of ectodermal origin and make up the inner enamel. They make pre-ameloblasts and produce enamel.

'''Periodontal ligament''' – is comprised of connective tissues which holds the tooth in place in the alveolar bone. It also encloses the cementum coating of the tooth root.

===Lab 8===

'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

'''Embryonic development of the ovary'''

The Gonads are known to be formed from the combination of primitive germ cells, adjacent mesenchyme and the mesothelium of the posterior abdominal wall. It isn’t until fifth week of embryonic development that the formation of Gonads occurs. The primordial germ cells first migrate from the embryonic yolk sac towards the hindgut along the dorsal mesentery. These cells then travel to the mesenchyme forming genital ridges positioned medially to the mesonephros by the sixth week of development. Coelomic epithelium and the mesonephros cells also proliferate at this stage. These cells then incorporate into the primary sex cords in which the process is driven by the genes stella, fragilis, and BMP-4 before the seventh week of embryonic development.<ref><pubmed>23409002</pubmed></ref>

The gonads are known to be indifferent until the sixth embryonic week as the gonads appear the same, however sex differentiation based on sex chromosomes determine the sex of the Gonad (XX for female and XY for males). The indifferent gonads are situated well inside the Wolffian body and are comprised of an inner medulla and outer cortex which contains precursors for ovarian stroma and parenchyma respectively.<ref><pubmed>3712511</pubmed></ref> In embryos consisting of XX sex chromosomes, the cortex of the indifferent gonad differentiates into an ovary meanwhile the medulla regresses by week eight of embryonic development. However, the sex cords leads to the formation of rete ovarii which is a complex of tubules and cords that arises from the mesonephros.

Another important event that occurs during the sixth week of development is the formation of the mullerian ducts which are responsible for female gonad formation and prevention of male gonad development. The established XX genotype of the female embryo prevents testosterone from being produced and hence causes the regression of the mesonephric duct since this form is only needed for male gonad expression. Also since there is no production of anti-mullarian hormone, the paramesonephric duct is able to be maintained driving female gonad expression. As of 10 weeks of development, ovaries first become recognizable and the growth of female external genitalia begins to occur.

[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]

<references/>

''' 2.Include an image from the historic genital embryology section of the online notes in your description.'''

[[File:Gray1112.jpg|400px]]

Figure 1. Longitudinal Section of Ovary of Cat Embryo of 9.4 cm long

===Lab 9===

'''Group project 1'''

The introduction was written quite well as it explains what the respiratory system is about and the origin of its development. It also briefly highlights the difference between the embryonic and fetal stage which is important in enabling the viewers to have an understanding on what the project will be focusing on. I also like how the group distinguished between the two zones of the respiratory tract and adequately described the features and function of each. The content in the lung development stages clearly relates to the topic and underlines fetal development. The group briefly mentioned the key features in each stage instead of pasting a whole lot of information; this makes it easier for viewers to understand. Overall the content relates to the learning objectives of embryology and the level of research is good as exemplified under ‘Current Research and Findings’ and ‘abnormalities’ (many forms of diseases described). The project however could benefit from having a ‘Glossary’ list so that viewers can understand some uncommon words.

The images under introduction and the image used for Meconium aspiration syndrome have not been referenced properly as there is missing information such as ((Template: Student Image)), description, copyright information and proper references for some. The image used under the ‘current research and findings’ subheading is a good example for the group to copy the referencing style. It is also vital that the group adds a brief description of what the image illustrates as a caption to help viewers understand the relation of the content and image (this is seen in the image under ‘surfactant’). More images could be added such as in the ‘lung development stage’ and under abnormalities. If images for lung development stages aren’t easily accessible, it is perhaps a good idea to draw them. The table format used for ‘lung development stages’ makes it easy for the viewers to navigate which is a good feature used in the project.

In terms of referencing, there are many in-cite references missing such as in the ‘introduction’ and in ‘lung development stages’. It is important to have these references formatted correctly under the one ‘references’ subheading. There seems to be many ‘references’ subheadings making it harder for viewers to navigate. Some references are shown as ‘ </li> which needs to be fixed right away. Overall, the content seems well written, formatted and concise making it easy to understand. However the problems related to referencing needs to be corrected as this is inconsistent throughout the project.

'''Group project 2'''

The introduction is well addressed as it sufficiently describes what the renal system is about and its function. Not to mention its anatomical structure as well as the difference between the embryonic and fetal stages of development. This differentiation enables viewers to understand what the content will be focused on, which is fetal development. Also, it helps focus the viewer’s attention on how the project will be divided as the group mentions abnormalities in the last paragraph. Overall the introduction has the right amount of information from each subheading and is very easy to comprehend.

There isn’t any information under ‘historic findings’. If there are any difficulties in finding some historic findings, members of the group can go to pubmed and on the side will be dates such as 1920 that could contain key historical events when renal is entered on search. The use of a development timeline was great as they outlined the major events that occur in a concise manner. Although, I believe a glossary is needed for words like ‘metanephros’ since the viewers would not know what that is. The content under current research models is interesting and correctly describes what the studies were about. Overall, the content used in the project was relating to the topic (fetal development of the kidney) and clearly showed extensive research. I really like how the group divided the different parts of the renal system as well as describing their anatomical positions. The abnormalities listed are also interesting and very easy to understand. I’m hoping to see information under the Horseshoe kidney disease.

In terms of images, there should be an image under introduction perhaps having all features of the renal system. Most images are missing the ‘student template’ aspect of the referencing and needs to be added right away. Other aspects such as description, copyright and referencing were correct. I also like the use of captions to describe what the images are about, however some are missing on the page such as the one under ‘anatomical position’ and ‘urethra’. The image used for the ‘development of the kidney’ should be removed from the page as it isn’t permissible. It should be replaced with an image relating to the content and have all the correct copyright and referencing information. Overall, I like the number of images used and its significance to the renal system. They accurately relate to the content of the project.

There is use of in-cite referencing which is good, however some references are just listed and should be placed under the proper ‘references’ subheading such as the ones under ‘ureter’ and ‘renal agenesis’. Some references in the ‘references’ list are used over again and can be fixed by combining it under one reference number. To make the project even more appealing, the group could format the information under ‘developmental timeline’ or even ’historic findings’ in a table. Overall, I think this project is great and by making edits based on the peer-reviews received could enhance their project.

'''Group project 3'''

The introduction is good as it accurately describes what the GIT system is about and the anatomical positions of the features in this system. It also briefly highlights the development stages at embryonic and fetal stages, however ‘embryonic development’ should be mentioned in a little more detail to understand how far in development the fetal stage begins. I also think the introduction should include a sentence or two describing how abnormalities in such organs can lead to these diseases. Basically a bit from each major subheading should be incorporated including current research as an introduction is a summary of the whole page. As for the ‘timeline’, it would’ve been more appropriate to place the timelines under each section, e.g foregut timeline under the ‘foregut’ subheading. This is because viewers would be confused on why there is so much difference in development in one section of the page. A glossary list should be incorporated in a separate subheading to define some of these words such as hematopoiesis so that viewers can fully grasp the information.

The information under recent findings is quite interesting and relatable to the content which is GIT fetal development. However, I believe more findings could be incorporated under this subheading. The information under each organ of the three ‘guts’ are quite detailed in fetal development which is good and shouldn’t be too difficult for the viewers to understand. However, I believe the group could include information on the function of these organs as well. The structure of the information under ‘guts’ does not flow in the sense that the midgut includes features and structure whereas the other ‘guts’ do not. The innvervation and bloody supply of the hindgut should be incorporated in a paragraph instead of being listed like that. All the deformities should be places under one subheading to make it easier for viewers to navigate. The abnormalities were also concise and related to the topic. Overall, the content is relating to the topic of the project and addresses key points. It also shows good amount of research, however there seems to be too much information in some parts which could be reduced a bit. The project needs a coherent flow of the structure.

As for images, there needs to be an image under introduction which includes all features of the GIT tract. There are a lot of potential images missing under each subheading except for the ‘midgut’ section. This shows that there has been one person working on this section or one section being focused on in comparison the others. The information used to reference the images is missing in some images such as the ‘Human- fetal week 10 sagittal plane D.jpg’ (although this is uploaded from a different user so this is understandable. However images such a ‘GIT 2.jpg’ need more information including ‘student template’ as well as the reference where the image idea may have come from. Also, if this is a hand-drawn image then please state this as one member did in ‘Week 11 midgut herniation.png’. Overall, I enjoy the use of self-drawn images as it makes it easier to show what the content is saying without going through the stress of looking for an image online that doesn’t relate to the content. However more images definitely need to be added. The use of captions is also good and indicates what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘Liver, Gallbladder and Bile Duct’ (the [6],[7] should be placed next to the text not above the text. The use of a ‘references’ subheading is good the same references have been combined into one number showing that the group knows how to make the references set out. The use of a table in formatting the ‘Percentage of Foetuses Herniated’ is great and shows more that the group has done research. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 4'''

The project doesn’t have an introduction yet; however information such as what the genital system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of genital development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. As for system development, I can see how there is dot-point description above the table which summarises the same thing. This structure is a bit confusing for me. I believe if the information was summarised into paragraphs and then tabulated it would make more sense. It’s best to format all that information into that table. The use of a table is a great way for the viewers to differentiate between the two sexes and understand the information more easily. I hope to see the table filled out completely soon. A glossary subheading should also be placed on the project page and have keywords defined to make viewers completely understand the content.

As for current findings, the information again is in dot points which should be paragraphed instead. However, the current findings are indeed interesting and the right amount of information is used to describe them in both sexes. The content under historic findings such as the ‘female genital development’ doesn’t show any historical events. There are no dates which show when something related was discovered. The ‘male genital development’ however shows dates and discoveries. In my opinion, if this information were tabulated rather than paragraphed, it’d be easier for viewers to navigate and understand. There is a good amount of detail under the abnormalities which relates to the key topic and is easy to understand. Overall, the content is relatable to the genital development of the fetus and underlines all the keys points. However, if this information were paragraphed in some areas and mentioned above, it would make the content easier to navigate and comprehend.

In terms of images, there are many places where images are missing such as introduction, system development and current models. I believe there needs to be more images on this page that relate to the content to make it more appealing and understandable to the viewers. The image called ‘File:Flow Diagram of Fetal Development of External Genitalia.pptx’ isn’t permissible and needs to be removed. The use of a hand drawn image on the testes is great, however there is information missing on referencing, student template and copyright laws. On the other hand, there are some images which correctly follow the uploading picture procedures such as the image on the ‘abnormalities of the vagina’; group members should follow this procedure. Captions should be added to each image to address what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘system development’. The use of a ‘references’ subheading is good, the same references have been combined into one number showing that the group knows how to make the references set out. However reference 20 and 21 are the same, please fix this. Also there are references under each subheading which should be placed all under one ‘references’ subheading. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 5'''

The introduction is a great summary of what the project page will discuss making sure to highlight every aspect. However, the introduction should also mention more about the integumentary system listing all the organs involved, their function, anatomical position and the difference between the embryonic and fetal stages of integumentary development. The content presented on the page is fantastic. All information under the subheadings looks complete and has key information related to the topic. I like how the timeline is divided into each organ making it easy to understand and navigate. The use of the table to format the information is a brilliant idea and has been presented beautifully with images in each textbox. Also the content under current research is relating to the topic and shows extensive research. The use of the purple background is appealing to the viewer highlighting its significance. I do however believe that the information under ‘historic findings’ should be formatted into a table to make it easier to navigate. The content under ‘abnormalities’ has the right amount of information and clearly relates to the key topic of the project.

In terms of images, I believe a satisfactory amount of images have been used which clearly describes the content. However, some images are missing the all the copyright information needed as well as the description, references and student template such as those in the ‘development overview’ table. This should be added right away to ensure these images do not get deleted. The use of captions on these pictures is important to highlight what the image is referring to and this is present in the page. Although, images could be added under current research as this section looks like it could use more images. Great job on the images under abnormalities, they accurately relate to the content mentioned.

There are some incite references missing such as in the development overview. I’m not sure if the references listed below are supposed to the references for it, however all references should be placed under one ‘references’ subheading. The same references have been combined into one number showing that the group knows how to make the references set out. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections. Overall, this is a great project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 7'''

The introduction is great as it mentions the features of the neural system, their anatomical positions and highlights the key events in the embryonic and fetal stages of development. The last paragraph of the introduction clearly addresses how the page will be divided and what the viewers are to expect which is good. The content under all subheadings are relating to the key topic and are formatted appropriately. I really like the image used under the subheading ‘Development during fetal period’ as it presents a diagrammatic representation of the content mentioned. The use of a table to briefly describe the events that occur at certain periods of fetal development is really helpful in grasping the main details. Some information is missing such as in ‘spinal cord development’, ‘Meninges development’, ‘future research’ and some ‘abnormalities’. This should be added right away. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the neural system and view dates on the side that may contain key findings. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

In terms of images, there are still many potential spaces for images such as under ‘introduction’, ‘current research’ and some ‘abnormalities’. The images used under ‘Development during fetal period’ are great and relate to the content. All images have correct description, referencing, copyright issues and ‘student template’, which shows that members of the group have followed correct ‘uploading image’ procedures. The images however need a caption to describe what the image is showing.

There needs to be more use of incite referencing such as in the ‘introduction’, ‘brain development’ and ‘abnormalities’. There is a huge list of references under ‘current research models and findings’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. References 7 and 8 are the same reference under the ‘references’ subheading and need to be combined into one number. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 8'''

The project doesn’t have an introduction yet; however information such as what the Musculoskeletal system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of musculoskeletal development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. I like the ‘making gains’ subheading as it adds humour to the page and engages the viewers. The general timeline needs information including what events take place at certain phases of fetal development. This could be present in a table to make the information more clear. It’s good that the project has information on the embryonic development so that the viewers can understand how the fetus arises to that point in development (fetal period).
All of the content seems to relate to the key topic and is appropriately paragraphed. However much of the content is still missing such as in ‘recent findings’ and ‘introduction’. More information could be added under the associated ‘trimesters’ and ‘abnormalities’. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the musculoskeletal system and view dates on the side that may contain key findings for historical events. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

There are no images on this page and definitely needs to be added with the appropriate information such as the description, referencing, copyright issues and ‘student template’. If images are not readily available, it is best to draw them. Also captions should be added on the page to state what the images are showing. As for referencing, there are some sections which shows incite referencing such as in the content under ‘Molecular and Cellular regulation of fetal myogenesis’ and some that don’t have any like in ‘tendon development’. There needs to be references in all sections. There is a huge list of references under ‘abnormalities’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. Number 15 of the reference list has an error in it and needs to be fixed right away. Overall, this is a working progress and if the group makes edits based on the peer-reviews received, this could enhance their project.

===Lab 10===

'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

'''''TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction.'''''

A major feature of the olfactory region is the olfactory bulb which contains mitral cells that serve to relay olfactory messages via sensory neurons of the olfactory epithelium to the piriform cortex of the brain. Within the granular cells and glomerular layers are interneurons which control the message output via synaptic linkages between mitral and tufted cell projection neurons. These interneurons continue to grow postnatally via neural stem cells located in the dorsolateral ganglionic eminence (dLGE) which consists of the subventricular zone and subependymal zone. When neuroblasts migrate to the dLGE, this stimulates dLGE-derived interneuron progenitors to migrate radially in the growing bulbs where they mature into the granular or glomerular cell layer. There has been research showing how teashirt zinc finger family member 1 (TSHZ1) is vital for the development of the olfactory bulb. In mice, it was found that olfactory bulb neuroblast differentiation required Tshz1 expression or else a large proportion of interneurons of the granular cell layer will not be present and radial migration of neuroblasts will be impaired. The basis of the previous studies was then replicated in humans suffering from congenital aural atresia that had TSHZ1 loss-of-function mutations.

Coronal sections 500-μm in size was obtained from the subjects which then underwent Nissl staining with cholineacetyl transferase histochemistry to observe the change in patterns of normal and abnormal olfactory development. In some parts of the experiment, mice were used as subjects to observe how congenital aural atresia may also affect them. In situ hybridization was used to investigate this effect on mice whereby Tshz1 positive and negative gene transcripts were obtained and amplified using polymerase chain reaction (PCR). Primers of the targeted gene and splicing enzymes were used to make sure the correct transcripts were produced.

Through immunoflourenscing and immunohistology, it was found that Tshz1 mutation lead to an abnormal distribution and differentiation of granule cell neurons of the developing olfactory bulb. Green fluoresce protein was integrated in the Tshz1 locus in both Tshz1+ and Tshz1- subjects. Through immunostaining of olfactory bulbs, it was shown that there was a consistent outer granule cell ring distribution of GFP+ cells in comparison to the unevenly distributed GFP+ cell located in the inner granule cell layer. DAPI staining revealed that the structure of the olfactory bulb in Tshz1 positive subjects were more layered and structure compared to deformed structure seen in Tshz1 mutants. The granule cell and external plexiform layers were indistinguishable and the glomerular layer had multilayers, thereby showing the abnormality in Tshz1 mutants.

Microarray hybridization was used to sort out gene expression in Tshz1 positive and negative subjects. Out of all the gene transcripts profiled, it was noted that the most significantly changed transcripts was Prokr2. Expression of PK2 was also downregulated in the rostral migratory stream of the subjects. Prokr2 expression was therefore examined in the developing olfactory bulb of Tshz1 positive and mutant mice using in situ hybridization. It was found that Tshz1 mRNA expression was seen in both the outer granule cell layer and the inner layers of the olfactory bulb mainly consisting of immature cells. Prokr2 expression was observed only in the inner layers of the OB in Tshz1 positive subjects and in mutants, Prokr2 expression was greatly downregulated. Overall, it was established that Tshz1 is needed to control the expression of Prokr2 which radially migrates neuroblasts. In addition, the PK2 family and its associated receptor are imperative factors required for normal olfactory bulb development.

<pubmed>24487590</pubmed>

'''Wiki link: https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Smell_Development'''

===Lab 11===

'''Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

'''Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration.'''

As cardiovascular disease continues to be the number one cause of death in the older population, there is significant research based on using stem cells as a tool to regenerate functional and healthy cardiomyctes in patients who’ve suffered from myocardial infarction. In particular, human induced pluripotent stem cells (hiPSCs) are used in this study to observe how these cells can generate cardiovascular cell sheets that may be used to treat infarcted heart tissue. Not to mention how hiPSCs may overcome obstacles such as poor engraftment of the cells injected in the heat and immunorejection, thereby placing the research more towards clinical practice.

'''Main findings'''

<ref><pubmed>25336194</pubmed><ref>

<references/>

User:Z3418837

2014-10-27T11:22:40Z

Z3418837: /* Lab 11 */

==Lab Attendance==
*Lab 1 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 6 August 2014 (EST)
*Lab 2 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:11, 13 August 2014 (EST)
*Lab 3 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:12, 20 August 2014 (EST)
*Lab 4 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:55, 27 August 2014 (EST)
*Lab 5 -- Absent
*Lab 6 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:44, 10 September 2014 (EST)
*Lab 7 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:40, 17 September 2014 (EST)
*Lab 8 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:11, 24 September 2014 (EST)
*Lab 9 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:08, 8 October 2014 (EST)
*Lab 10 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 15 October 2014 (EST)
*Lab 11 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 22 October 2014 (EST)
*Lab 12

==Individual Assessment==

==='''Lab 1'''===

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 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>

'''Your Lab assessment now requires you to find a 2 recent research references on fertilisation or in vitro fertilisation. Paste each reference on your page, as shown in the class. Write below each reference a brief summary of the research article methods and findings. The summary for each need not be more than 3-4 paragraphs in length. This will need to be completed before next weeks laboratory'''.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/25077107 PMID25077107]

<pubmed>25077107</pubmed>

This study was designed to investigate whether the levels of vitamin D is an imperative factor when it comes to the clinical success of implantation and pregnancy rates in infertile women via invitro fertilisation.

'''Method summary'''

A cohort of 173 women were evaluated and selected for this study based on their age, follicle-stimulating hormone levels and their consent to undergo invitro fertilisation. The following study was conducted at Mount Sinai Hospital where proper facilities were available. Blood tests were then conducted for each patient to determine their levels of Vitamin D via the serum 25-hydroxy-vitamin D (25[OH]D) levels. Following the results of the blood test, the cohort were then categorised into two groups which was either vitamin D sufficient (≥ 75 nmol/L) or insufficient ( < 75 nmol/L) based on serum levels of 25(OH)D.

Each patient then underwent IVF cycles whereby standard agonists that contained the active ingredient 0.5 mg/d of buserelin acetate in conjunction with cetrolix acetate as the standard antagonist were used to control the length of the luteal phase and estradiol levels. The length and dose of the treatment were varied for each individual based on their demographic data. Serial transvaginal ultrasonograpy and serum lutenizing hormone assays were then used to check ovarian response. When 3 or more dominant follicles (≥ 17 mm) were produced, 10 000 IU of human chorionic gonadotropin was added to enhance nuclear maturation. Oocyte retrieval was then conducted via transvaginal ultrasound whereby it was fertilised and the resulting embryo was transferred 3-5 days post-fertilisation. The rate of pregnancy per IVF cycle was then used as the primary outcome for this study whereby the visibility of the intrauterine sac of the embryo determined implantation.

'''Results summary'''

Out of the 182 patients that participated in this study, it was found that only 173 patients could continue on with this trial as they satisfied the criteria, however only 162 were fit for embryo transfer. Following the results from the blood test, it was noted that 53.8% of patients had insufficient levels of 25(OH)D and 45.1% had sufficient amounts. It was discovered that 71.8% of those with sufficient levels of 25(OH)D were more likely to proceed with embryo transfer on day 5 compared to 58.9% (p = 0.054) of those assigned to the ‘insufficient 25(OH)D’ category. Other factors such as oocyte retrieval and frequency of intracytoplasmic sperm injection were fairly similar in both groups. The study revealed that there was a higher clinical pregnancy rate per IVF cycle for those assigned to the sufficient 25(OH)D level category by 52.5% compared to those with insufficient amounts of 25(OH)D which was 34.7% (p < 0.001). Similarly, there was a significant clinical pregnancy rate per embryo transfer of 54.7% in comparison to 37.9% in woman belonging to the sufficient and insufficient category respectively. It was also noted that the implantation rate was greater in the sufficient category compared to the insufficient group, however the difference was only minimal (p= 0.6). Overall, the results suggest that serum 25(OH)D levels may be a predictor of clinical pregnancy.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/24672163 PMID24672163]

<pubmed>24672163</pubmed>

The process of achieving pregnancy via invitro fertilisation needs to be monitored and controlled with respect to the demographics of the individual in order to achieve a successful outcome. This study focuses on predicting the value of β-human chorionic gonadotrophin (β-HCG) that can lead to clinical success.

'''Method summary'''

Data analysis was taken from 171 female patients using the statistical package for social sciences program whereby all IVF cycles were monitored. The cycles that showed fresh multi-cell embryos (day 3) or blastocysts (day 5) were deemed fit for the trial and were the ones that were further used in this study. Serum β-HCG concentrations were then taken 14 days after the embryo was transferred whereby a second test was done on day 16 only if the first test revealed a positive β-HCG result. This was done to predict values that could enable doctors to evaluate a healthy intrauterine pregnancy or a problematic ectopic pregnancy. After 6-7 weeks of pregnancy, ultrasounds were conducted to check cardiac activity as well as the amount of gestational sacs. This was then repeated at 12 weeks of pregnancy to ensure there was no chance of abortion.

A continuing pregnancy was defined as one that continued for at least 12 weeks of gestation and showed signs of proper cardiac function. On the other hand, those pregnancies that were abnormal had dropped levels of β-HCG concentrations and led to empty gestational sacs that showed no embryonic cardiac function. As a measuring tool for detecting levels of β-HCG, Chemiluminescent microparticle immunoassays were used whereby the measuring range established was between 0.0-15,000 mIU/mL. HCG levels above 10 IU/L signified early pregnancy.

'''Results Summary'''

Out of the 171 patients that participated in this study, only 139 were included due to the missing data on the levels of β-HCG concentrations at day 14 and 16 post embryonic transfer. In total there were 39 abnormal pregnancies that involved ectopic pregnancy, abortions and biochemical pregnancies (sufficient HCG levels detected but no visible gestational sac). Overall the patients were categorised into two groups which were patients with ‘ongoing pregnancy’ (n=100) and ‘without ongoing pregnancy’ (n=39). The Mann-Whitney test (statistical testing) was then used to compare the levels of β-HCG levels in both groups. It was found that the group with ongoing pregnancy had a median serum β-HCG level of 600 mIU/ml, whereas the other group had a median serum β-HCG level of 178 mIU/ml. This indicated a significant difference of P < 0.05 when comparing the two groups. It was also found that when serum β-HCG levels reached 347 mIU/ml, there was a 73.6% chance that the pregnancy was ongoing. Furthermore, there was no definite correlation established between age and the rate of ongoing pregnancy as both categories had patients of similar age groups with a combined range of 23-41 year old patients. Overall, the study revealed that early serum β-HCG is a potential predictor of successful outcomes in invitro fertilisation.

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 19:11, 6 October 2014 (EST) These are relevant references and your descriptions/abstracts are good (5/5).

===Lab 2===

[[File:Phase-contrast images of embryos at different developmental stages via neogenin expression.png|300px]]

Phase-contrast images of embryos at different developmental stages via neogenin expression.<ref><pubmed>25013897</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0101989 PLos One]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:17, 21 August 2014 (EST) This is all correct. The image is very large (4.8 MB), perhaps a small version could have been uploaded. You can adjust the resolution and size in most image editing programs. (5/5)

<references/>

===Lab 3===

'''Parathyroid gland'''

<pubmed>22808183</pubmed>
<pubmed>22649358</pubmed>
<pubmed>21881196</pubmed>
<pubmed>21904825</pubmed>

'''Thymus'''

<pubmed>21733645</pubmed>
<pubmed>20836742</pubmed>
<pubmed>21263742</pubmed>
<pubmed>512270</pubmed>

'''Pancreas'''

<pubmed>22761699</pubmed>
<pubmed>22893718</pubmed>
<pubmed>24496309</pubmed>
<pubmed>24595965</pubmed>
<pubmed>23822675</pubmed>
<pubmed>22968764</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===

'''1. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

'''Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1'''

Glioblastoma multiforme (GBM) is known to belong to a very life threatening form of brain cancer. Research is currently focused on finding treatments regarding such abnormalities, such as the application of neuronal stem cells in reducing the population of tumours, however there were many problems that occurred with such treatment. Recently, Human umbilical cord blood derived stem cells (hUCBSC) has been extensively used as they are useful mesenchymal stem cells that are easy to isolate and are more available. GBM is caused by the overexpression of cyclin D1 and its subsequent binding to Cdk 4/Cdk 6 which defines the rate limiting step required for the cell to progress further on to the cell cycle from the G1 phase. In order to stop this over expression, scientists have used hUCBSC to inhibit the cell from progressing on with the cell cycle.

When (hUCBSC) were cultured with U251 and 5310 cells, flow cytometry technology revealed that the cells underwent G1 arrest showing an increase in the G0-G1/S phase ratio. There was also a 54% reduction in levels of cyclin D1 when hUCBSC was cultured with U251 in comparison to the control. Immunoprecipiation revealed that hUCBSC treated cells when immuno blotted with Cdk 4 and Cdk 6 antibodies, down regulated expression of both Cdk 4 and Cdk 6. Western blot also showed the same down regulating pattern of the individual expression and genes which confirmed that there was cell cycle arrest, thus preventing tumours from forming.

As such, this study helps researchers to grasp the foundation of using hUCBSC as a treatment for glioblastoma and to further build on such research. Since it is evident that hUCBSC is effective in reducing cyclin D1 expression; analysing glioblastomal hierarchy will aid in providing the missing links needed to create the clinical treatment.

<pubmed>21455311</pubmed>

'''2. There are a number of developmental vascular "shunts" present in the embryo, that are closed postnatally. Identify these shunts and their anatomical location.'''

Three major vascular shunts include:

• '''Ductus venosus''' - is a shunt of oxygenated blood from umbilical vein to IVC, bypassing the liver. The ductus venosus constricts and closes soon after birth and becomes the ligamentum venosum

• '''Foramen ovale''' - is a flap valve in the atrial septum between the right and left atrium that shunts highly oxygenated blood . The remnant of the foramen ovale is known as the fossa ovalis.

• '''Ductus arteriosus''' - is a shunt from the descending aorta to the left pulmonary artery near the bifurcation of the pulmonary trunk. Permanent closure takes 4-6 weeks by fibrosis, and the remnant is referred to as the ligamentum arteriosum.

===Lab 5===

'''Select an abnormality of either gastrointestinal or respiratory development and write a brief description of developmental causes(s) for this abnormality. Your answer should be added to your own student page, be brief (2-3 paragraphs) and referenced.'''

'''Midgut volvulus'''

The embryonic development of the midgut has a number of steps which ensures its proper formation. These include the viability of the superior mesenteric artery to divide the midgut into the cephalad (pre-arterial region) and caudad (post-arterial region). <ref><pubmed>15378215</pubmed></ref>During the fourth gestational week, the gastrointestinal system is composed of a centrally positioned linear tube in the abdomen. At approximately 6 weeks of gestational age, the midgut undergoes a process of U-shaped herniation causing the two portions of the midguts to face the opposite directions in relation to the superior mesenteric artery. From this moment, a number of rotation events occur to ensure the complete development of the gastrointestinal tract as it becomes set in the posterior abdominal wall.<ref><pubmed>7277164</pubmed></ref>

In some cases malrotations can occur during the developmental process of the midgut which involves the complete twisting of the midgut in relation to the axis of the superior mesenteric artery. In extreme cases this can lead to midgut volvulus which results in a narrowed mesenteric base that can obstruct the passage of blood and lead to tissue necrosis. Other complications resulting from midgut volvulus include intestinal ischaemia, peritonitis, mucosal necrosis and sepsis which can eventually lead to death if left untreated. <ref><pubmed>14655161</pubmed></ref>

Malrotation is known to occur within 1 in 500 live births and out of those who develop midgut volvusos, 68-71% are neonates. <ref><pubmed>22217896</pubmed></ref>Although the actual cause of malrotation is unknown, researchers have made links to congenital syndromes such as Down syndrome and the VACTERL. It is also hypothesized that any embryonic interference during the normal patterns of rotation and fetal development can lead to midgut volvulus. Treatment of midgut volvulus is dependent on when the disease is diagnosed. <ref><pubmed>18800265</pubmed></ref>Normally a sigmoidoscopy is carried out as well as the Ladd procedure to resect dead gastrointestinal tissues. Transduodenal bands of ladd may also be divided to widen the mesenteric pedicle and prevent obstruction of blood flow. <ref><pubmed>22208840</pubmed></ref>Overall, research is still being conducted on the specific causes of malrotation and other numerous treatments.

<references/>

===Lab 6===

Group work

===Lab 7===

'''1.Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

'''Novel genes upregulated when NOTCH signaling is disrupted during hypothalamic development.'''

It is known that the hypothalamus first develops from the ventral region of the diencephalon and signaling mechanisms such as the sonic hedgehog and bone morphogenic protein pathways are responsible for pattern arrangement. Neurogenesis is the key process required to ensure proper hypothalamus development which relies on many signaling pathways to produce neurons and glia. The Notch signaling pathway is currently known to inhibit neuronal differentiation and preserve neural progenitor identity. As a result of various studies and research, the combined theory has been implemented in this study to determine the effect of downregulating Notch signaling pathways in its effect on hypothalamic development.

Results show that when Notch signaling is inactivated, novel genes such as Dll1, Hes5, Hey1 and Ascl1 are upregulated in the rostral hypothalamus, subsequently leading to the early formation of hypothalamic neurons. This is also seen when embryos that are treated with DAPT (a chemical which inhibits cell differentiation mechanisms regulated by the Notch pathway) had an overexpression of cells differentiated into neurons in a clustered formation. This was compared to the control embryos which had differentiated cells in a scattered arrangement. As such, this research showed that Notch is a powerful signaling mechanism that is used to inhibit cell differentiation in order to control the number of cells differentiated into neurons or glia. This modulating ability of the Notch pathway is imperative in the early developing hypothalamus as it controls expression of cells and hence prevents any form of defects that can be harmful both prenatally and postnatally. Further research needs to be conducted on the Notch pathway to provide procedures where its mechanism can be used to resolve defects in the embryo and hence ensure proper hypothalamic development.

<pubmed>24360028</pubmed>

'''2.Identify the embryonic layers and tissues that contribute to the developing teeth.'''

'''Odontoblasts''' - neural crest-derived mesenchymal cells which establish the outer dental pulp. It differentiates via the enamel epithelium and releases dentin from dentinogenesis.

'''Ameloblasts''' - are derived from oral epithelium tissue of ectodermal origin and make up the inner enamel. They make pre-ameloblasts and produce enamel.

'''Periodontal ligament''' – is comprised of connective tissues which holds the tooth in place in the alveolar bone. It also encloses the cementum coating of the tooth root.

===Lab 8===

'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

'''Embryonic development of the ovary'''

The Gonads are known to be formed from the combination of primitive germ cells, adjacent mesenchyme and the mesothelium of the posterior abdominal wall. It isn’t until fifth week of embryonic development that the formation of Gonads occurs. The primordial germ cells first migrate from the embryonic yolk sac towards the hindgut along the dorsal mesentery. These cells then travel to the mesenchyme forming genital ridges positioned medially to the mesonephros by the sixth week of development. Coelomic epithelium and the mesonephros cells also proliferate at this stage. These cells then incorporate into the primary sex cords in which the process is driven by the genes stella, fragilis, and BMP-4 before the seventh week of embryonic development.<ref><pubmed>23409002</pubmed></ref>

The gonads are known to be indifferent until the sixth embryonic week as the gonads appear the same, however sex differentiation based on sex chromosomes determine the sex of the Gonad (XX for female and XY for males). The indifferent gonads are situated well inside the Wolffian body and are comprised of an inner medulla and outer cortex which contains precursors for ovarian stroma and parenchyma respectively.<ref><pubmed>3712511</pubmed></ref> In embryos consisting of XX sex chromosomes, the cortex of the indifferent gonad differentiates into an ovary meanwhile the medulla regresses by week eight of embryonic development. However, the sex cords leads to the formation of rete ovarii which is a complex of tubules and cords that arises from the mesonephros.

Another important event that occurs during the sixth week of development is the formation of the mullerian ducts which are responsible for female gonad formation and prevention of male gonad development. The established XX genotype of the female embryo prevents testosterone from being produced and hence causes the regression of the mesonephric duct since this form is only needed for male gonad expression. Also since there is no production of anti-mullarian hormone, the paramesonephric duct is able to be maintained driving female gonad expression. As of 10 weeks of development, ovaries first become recognizable and the growth of female external genitalia begins to occur.

[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]

<references/>

''' 2.Include an image from the historic genital embryology section of the online notes in your description.'''

[[File:Gray1112.jpg|400px]]

Figure 1. Longitudinal Section of Ovary of Cat Embryo of 9.4 cm long

===Lab 9===

'''Group project 1'''

The introduction was written quite well as it explains what the respiratory system is about and the origin of its development. It also briefly highlights the difference between the embryonic and fetal stage which is important in enabling the viewers to have an understanding on what the project will be focusing on. I also like how the group distinguished between the two zones of the respiratory tract and adequately described the features and function of each. The content in the lung development stages clearly relates to the topic and underlines fetal development. The group briefly mentioned the key features in each stage instead of pasting a whole lot of information; this makes it easier for viewers to understand. Overall the content relates to the learning objectives of embryology and the level of research is good as exemplified under ‘Current Research and Findings’ and ‘abnormalities’ (many forms of diseases described). The project however could benefit from having a ‘Glossary’ list so that viewers can understand some uncommon words.

The images under introduction and the image used for Meconium aspiration syndrome have not been referenced properly as there is missing information such as ((Template: Student Image)), description, copyright information and proper references for some. The image used under the ‘current research and findings’ subheading is a good example for the group to copy the referencing style. It is also vital that the group adds a brief description of what the image illustrates as a caption to help viewers understand the relation of the content and image (this is seen in the image under ‘surfactant’). More images could be added such as in the ‘lung development stage’ and under abnormalities. If images for lung development stages aren’t easily accessible, it is perhaps a good idea to draw them. The table format used for ‘lung development stages’ makes it easy for the viewers to navigate which is a good feature used in the project.

In terms of referencing, there are many in-cite references missing such as in the ‘introduction’ and in ‘lung development stages’. It is important to have these references formatted correctly under the one ‘references’ subheading. There seems to be many ‘references’ subheadings making it harder for viewers to navigate. Some references are shown as ‘ </li> which needs to be fixed right away. Overall, the content seems well written, formatted and concise making it easy to understand. However the problems related to referencing needs to be corrected as this is inconsistent throughout the project.

'''Group project 2'''

The introduction is well addressed as it sufficiently describes what the renal system is about and its function. Not to mention its anatomical structure as well as the difference between the embryonic and fetal stages of development. This differentiation enables viewers to understand what the content will be focused on, which is fetal development. Also, it helps focus the viewer’s attention on how the project will be divided as the group mentions abnormalities in the last paragraph. Overall the introduction has the right amount of information from each subheading and is very easy to comprehend.

There isn’t any information under ‘historic findings’. If there are any difficulties in finding some historic findings, members of the group can go to pubmed and on the side will be dates such as 1920 that could contain key historical events when renal is entered on search. The use of a development timeline was great as they outlined the major events that occur in a concise manner. Although, I believe a glossary is needed for words like ‘metanephros’ since the viewers would not know what that is. The content under current research models is interesting and correctly describes what the studies were about. Overall, the content used in the project was relating to the topic (fetal development of the kidney) and clearly showed extensive research. I really like how the group divided the different parts of the renal system as well as describing their anatomical positions. The abnormalities listed are also interesting and very easy to understand. I’m hoping to see information under the Horseshoe kidney disease.

In terms of images, there should be an image under introduction perhaps having all features of the renal system. Most images are missing the ‘student template’ aspect of the referencing and needs to be added right away. Other aspects such as description, copyright and referencing were correct. I also like the use of captions to describe what the images are about, however some are missing on the page such as the one under ‘anatomical position’ and ‘urethra’. The image used for the ‘development of the kidney’ should be removed from the page as it isn’t permissible. It should be replaced with an image relating to the content and have all the correct copyright and referencing information. Overall, I like the number of images used and its significance to the renal system. They accurately relate to the content of the project.

There is use of in-cite referencing which is good, however some references are just listed and should be placed under the proper ‘references’ subheading such as the ones under ‘ureter’ and ‘renal agenesis’. Some references in the ‘references’ list are used over again and can be fixed by combining it under one reference number. To make the project even more appealing, the group could format the information under ‘developmental timeline’ or even ’historic findings’ in a table. Overall, I think this project is great and by making edits based on the peer-reviews received could enhance their project.

'''Group project 3'''

The introduction is good as it accurately describes what the GIT system is about and the anatomical positions of the features in this system. It also briefly highlights the development stages at embryonic and fetal stages, however ‘embryonic development’ should be mentioned in a little more detail to understand how far in development the fetal stage begins. I also think the introduction should include a sentence or two describing how abnormalities in such organs can lead to these diseases. Basically a bit from each major subheading should be incorporated including current research as an introduction is a summary of the whole page. As for the ‘timeline’, it would’ve been more appropriate to place the timelines under each section, e.g foregut timeline under the ‘foregut’ subheading. This is because viewers would be confused on why there is so much difference in development in one section of the page. A glossary list should be incorporated in a separate subheading to define some of these words such as hematopoiesis so that viewers can fully grasp the information.

The information under recent findings is quite interesting and relatable to the content which is GIT fetal development. However, I believe more findings could be incorporated under this subheading. The information under each organ of the three ‘guts’ are quite detailed in fetal development which is good and shouldn’t be too difficult for the viewers to understand. However, I believe the group could include information on the function of these organs as well. The structure of the information under ‘guts’ does not flow in the sense that the midgut includes features and structure whereas the other ‘guts’ do not. The innvervation and bloody supply of the hindgut should be incorporated in a paragraph instead of being listed like that. All the deformities should be places under one subheading to make it easier for viewers to navigate. The abnormalities were also concise and related to the topic. Overall, the content is relating to the topic of the project and addresses key points. It also shows good amount of research, however there seems to be too much information in some parts which could be reduced a bit. The project needs a coherent flow of the structure.

As for images, there needs to be an image under introduction which includes all features of the GIT tract. There are a lot of potential images missing under each subheading except for the ‘midgut’ section. This shows that there has been one person working on this section or one section being focused on in comparison the others. The information used to reference the images is missing in some images such as the ‘Human- fetal week 10 sagittal plane D.jpg’ (although this is uploaded from a different user so this is understandable. However images such a ‘GIT 2.jpg’ need more information including ‘student template’ as well as the reference where the image idea may have come from. Also, if this is a hand-drawn image then please state this as one member did in ‘Week 11 midgut herniation.png’. Overall, I enjoy the use of self-drawn images as it makes it easier to show what the content is saying without going through the stress of looking for an image online that doesn’t relate to the content. However more images definitely need to be added. The use of captions is also good and indicates what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘Liver, Gallbladder and Bile Duct’ (the [6],[7] should be placed next to the text not above the text. The use of a ‘references’ subheading is good the same references have been combined into one number showing that the group knows how to make the references set out. The use of a table in formatting the ‘Percentage of Foetuses Herniated’ is great and shows more that the group has done research. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 4'''

The project doesn’t have an introduction yet; however information such as what the genital system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of genital development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. As for system development, I can see how there is dot-point description above the table which summarises the same thing. This structure is a bit confusing for me. I believe if the information was summarised into paragraphs and then tabulated it would make more sense. It’s best to format all that information into that table. The use of a table is a great way for the viewers to differentiate between the two sexes and understand the information more easily. I hope to see the table filled out completely soon. A glossary subheading should also be placed on the project page and have keywords defined to make viewers completely understand the content.

As for current findings, the information again is in dot points which should be paragraphed instead. However, the current findings are indeed interesting and the right amount of information is used to describe them in both sexes. The content under historic findings such as the ‘female genital development’ doesn’t show any historical events. There are no dates which show when something related was discovered. The ‘male genital development’ however shows dates and discoveries. In my opinion, if this information were tabulated rather than paragraphed, it’d be easier for viewers to navigate and understand. There is a good amount of detail under the abnormalities which relates to the key topic and is easy to understand. Overall, the content is relatable to the genital development of the fetus and underlines all the keys points. However, if this information were paragraphed in some areas and mentioned above, it would make the content easier to navigate and comprehend.

In terms of images, there are many places where images are missing such as introduction, system development and current models. I believe there needs to be more images on this page that relate to the content to make it more appealing and understandable to the viewers. The image called ‘File:Flow Diagram of Fetal Development of External Genitalia.pptx’ isn’t permissible and needs to be removed. The use of a hand drawn image on the testes is great, however there is information missing on referencing, student template and copyright laws. On the other hand, there are some images which correctly follow the uploading picture procedures such as the image on the ‘abnormalities of the vagina’; group members should follow this procedure. Captions should be added to each image to address what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘system development’. The use of a ‘references’ subheading is good, the same references have been combined into one number showing that the group knows how to make the references set out. However reference 20 and 21 are the same, please fix this. Also there are references under each subheading which should be placed all under one ‘references’ subheading. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 5'''

The introduction is a great summary of what the project page will discuss making sure to highlight every aspect. However, the introduction should also mention more about the integumentary system listing all the organs involved, their function, anatomical position and the difference between the embryonic and fetal stages of integumentary development. The content presented on the page is fantastic. All information under the subheadings looks complete and has key information related to the topic. I like how the timeline is divided into each organ making it easy to understand and navigate. The use of the table to format the information is a brilliant idea and has been presented beautifully with images in each textbox. Also the content under current research is relating to the topic and shows extensive research. The use of the purple background is appealing to the viewer highlighting its significance. I do however believe that the information under ‘historic findings’ should be formatted into a table to make it easier to navigate. The content under ‘abnormalities’ has the right amount of information and clearly relates to the key topic of the project.

In terms of images, I believe a satisfactory amount of images have been used which clearly describes the content. However, some images are missing the all the copyright information needed as well as the description, references and student template such as those in the ‘development overview’ table. This should be added right away to ensure these images do not get deleted. The use of captions on these pictures is important to highlight what the image is referring to and this is present in the page. Although, images could be added under current research as this section looks like it could use more images. Great job on the images under abnormalities, they accurately relate to the content mentioned.

There are some incite references missing such as in the development overview. I’m not sure if the references listed below are supposed to the references for it, however all references should be placed under one ‘references’ subheading. The same references have been combined into one number showing that the group knows how to make the references set out. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections. Overall, this is a great project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 7'''

The introduction is great as it mentions the features of the neural system, their anatomical positions and highlights the key events in the embryonic and fetal stages of development. The last paragraph of the introduction clearly addresses how the page will be divided and what the viewers are to expect which is good. The content under all subheadings are relating to the key topic and are formatted appropriately. I really like the image used under the subheading ‘Development during fetal period’ as it presents a diagrammatic representation of the content mentioned. The use of a table to briefly describe the events that occur at certain periods of fetal development is really helpful in grasping the main details. Some information is missing such as in ‘spinal cord development’, ‘Meninges development’, ‘future research’ and some ‘abnormalities’. This should be added right away. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the neural system and view dates on the side that may contain key findings. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

In terms of images, there are still many potential spaces for images such as under ‘introduction’, ‘current research’ and some ‘abnormalities’. The images used under ‘Development during fetal period’ are great and relate to the content. All images have correct description, referencing, copyright issues and ‘student template’, which shows that members of the group have followed correct ‘uploading image’ procedures. The images however need a caption to describe what the image is showing.

There needs to be more use of incite referencing such as in the ‘introduction’, ‘brain development’ and ‘abnormalities’. There is a huge list of references under ‘current research models and findings’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. References 7 and 8 are the same reference under the ‘references’ subheading and need to be combined into one number. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 8'''

The project doesn’t have an introduction yet; however information such as what the Musculoskeletal system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of musculoskeletal development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. I like the ‘making gains’ subheading as it adds humour to the page and engages the viewers. The general timeline needs information including what events take place at certain phases of fetal development. This could be present in a table to make the information more clear. It’s good that the project has information on the embryonic development so that the viewers can understand how the fetus arises to that point in development (fetal period).
All of the content seems to relate to the key topic and is appropriately paragraphed. However much of the content is still missing such as in ‘recent findings’ and ‘introduction’. More information could be added under the associated ‘trimesters’ and ‘abnormalities’. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the musculoskeletal system and view dates on the side that may contain key findings for historical events. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

There are no images on this page and definitely needs to be added with the appropriate information such as the description, referencing, copyright issues and ‘student template’. If images are not readily available, it is best to draw them. Also captions should be added on the page to state what the images are showing. As for referencing, there are some sections which shows incite referencing such as in the content under ‘Molecular and Cellular regulation of fetal myogenesis’ and some that don’t have any like in ‘tendon development’. There needs to be references in all sections. There is a huge list of references under ‘abnormalities’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. Number 15 of the reference list has an error in it and needs to be fixed right away. Overall, this is a working progress and if the group makes edits based on the peer-reviews received, this could enhance their project.

===Lab 10===

'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

'''''TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction.'''''

A major feature of the olfactory region is the olfactory bulb which contains mitral cells that serve to relay olfactory messages via sensory neurons of the olfactory epithelium to the piriform cortex of the brain. Within the granular cells and glomerular layers are interneurons which control the message output via synaptic linkages between mitral and tufted cell projection neurons. These interneurons continue to grow postnatally via neural stem cells located in the dorsolateral ganglionic eminence (dLGE) which consists of the subventricular zone and subependymal zone. When neuroblasts migrate to the dLGE, this stimulates dLGE-derived interneuron progenitors to migrate radially in the growing bulbs where they mature into the granular or glomerular cell layer. There has been research showing how teashirt zinc finger family member 1 (TSHZ1) is vital for the development of the olfactory bulb. In mice, it was found that olfactory bulb neuroblast differentiation required Tshz1 expression or else a large proportion of interneurons of the granular cell layer will not be present and radial migration of neuroblasts will be impaired. The basis of the previous studies was then replicated in humans suffering from congenital aural atresia that had TSHZ1 loss-of-function mutations.

Coronal sections 500-μm in size was obtained from the subjects which then underwent Nissl staining with cholineacetyl transferase histochemistry to observe the change in patterns of normal and abnormal olfactory development. In some parts of the experiment, mice were used as subjects to observe how congenital aural atresia may also affect them. In situ hybridization was used to investigate this effect on mice whereby Tshz1 positive and negative gene transcripts were obtained and amplified using polymerase chain reaction (PCR). Primers of the targeted gene and splicing enzymes were used to make sure the correct transcripts were produced.

Through immunoflourenscing and immunohistology, it was found that Tshz1 mutation lead to an abnormal distribution and differentiation of granule cell neurons of the developing olfactory bulb. Green fluoresce protein was integrated in the Tshz1 locus in both Tshz1+ and Tshz1- subjects. Through immunostaining of olfactory bulbs, it was shown that there was a consistent outer granule cell ring distribution of GFP+ cells in comparison to the unevenly distributed GFP+ cell located in the inner granule cell layer. DAPI staining revealed that the structure of the olfactory bulb in Tshz1 positive subjects were more layered and structure compared to deformed structure seen in Tshz1 mutants. The granule cell and external plexiform layers were indistinguishable and the glomerular layer had multilayers, thereby showing the abnormality in Tshz1 mutants.

Microarray hybridization was used to sort out gene expression in Tshz1 positive and negative subjects. Out of all the gene transcripts profiled, it was noted that the most significantly changed transcripts was Prokr2. Expression of PK2 was also downregulated in the rostral migratory stream of the subjects. Prokr2 expression was therefore examined in the developing olfactory bulb of Tshz1 positive and mutant mice using in situ hybridization. It was found that Tshz1 mRNA expression was seen in both the outer granule cell layer and the inner layers of the olfactory bulb mainly consisting of immature cells. Prokr2 expression was observed only in the inner layers of the OB in Tshz1 positive subjects and in mutants, Prokr2 expression was greatly downregulated. Overall, it was established that Tshz1 is needed to control the expression of Prokr2 which radially migrates neuroblasts. In addition, the PK2 family and its associated receptor are imperative factors required for normal olfactory bulb development.

<pubmed>24487590</pubmed>

'''Wiki link: https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Smell_Development'''

===Lab 11===

'''Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

As cardiovascular disease continues to be the number one cause of death in the older population, there is significant research based on using stem cells as a tool to regenerate functional and healthy cardiomyctes in patients who’ve suffered from myocardial infarction. In particular, human induced pluripotent stem cells (hiPSCs) are used in this study to observe how these cells can generate cardiovascular cell sheets that may be used to treat infarcted heart tissue. Not to mention how hiPSCs may overcome obstacles such as poor engraftment of the cells injected in the heat and immunorejection, thereby placing the research more towards clinical practice.

'''Main findings'''

<pubmed>25336194</pubmed>

User:Z3418837

2014-10-27T10:49:46Z

Z3418837: /* Lab 11 */

==Lab Attendance==
*Lab 1 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 6 August 2014 (EST)
*Lab 2 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:11, 13 August 2014 (EST)
*Lab 3 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:12, 20 August 2014 (EST)
*Lab 4 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:55, 27 August 2014 (EST)
*Lab 5 -- Absent
*Lab 6 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:44, 10 September 2014 (EST)
*Lab 7 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:40, 17 September 2014 (EST)
*Lab 8 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:11, 24 September 2014 (EST)
*Lab 9 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:08, 8 October 2014 (EST)
*Lab 10 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 15 October 2014 (EST)
*Lab 11 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 22 October 2014 (EST)
*Lab 12

==Individual Assessment==

==='''Lab 1'''===

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 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>

'''Your Lab assessment now requires you to find a 2 recent research references on fertilisation or in vitro fertilisation. Paste each reference on your page, as shown in the class. Write below each reference a brief summary of the research article methods and findings. The summary for each need not be more than 3-4 paragraphs in length. This will need to be completed before next weeks laboratory'''.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/25077107 PMID25077107]

<pubmed>25077107</pubmed>

This study was designed to investigate whether the levels of vitamin D is an imperative factor when it comes to the clinical success of implantation and pregnancy rates in infertile women via invitro fertilisation.

'''Method summary'''

A cohort of 173 women were evaluated and selected for this study based on their age, follicle-stimulating hormone levels and their consent to undergo invitro fertilisation. The following study was conducted at Mount Sinai Hospital where proper facilities were available. Blood tests were then conducted for each patient to determine their levels of Vitamin D via the serum 25-hydroxy-vitamin D (25[OH]D) levels. Following the results of the blood test, the cohort were then categorised into two groups which was either vitamin D sufficient (≥ 75 nmol/L) or insufficient ( < 75 nmol/L) based on serum levels of 25(OH)D.

Each patient then underwent IVF cycles whereby standard agonists that contained the active ingredient 0.5 mg/d of buserelin acetate in conjunction with cetrolix acetate as the standard antagonist were used to control the length of the luteal phase and estradiol levels. The length and dose of the treatment were varied for each individual based on their demographic data. Serial transvaginal ultrasonograpy and serum lutenizing hormone assays were then used to check ovarian response. When 3 or more dominant follicles (≥ 17 mm) were produced, 10 000 IU of human chorionic gonadotropin was added to enhance nuclear maturation. Oocyte retrieval was then conducted via transvaginal ultrasound whereby it was fertilised and the resulting embryo was transferred 3-5 days post-fertilisation. The rate of pregnancy per IVF cycle was then used as the primary outcome for this study whereby the visibility of the intrauterine sac of the embryo determined implantation.

'''Results summary'''

Out of the 182 patients that participated in this study, it was found that only 173 patients could continue on with this trial as they satisfied the criteria, however only 162 were fit for embryo transfer. Following the results from the blood test, it was noted that 53.8% of patients had insufficient levels of 25(OH)D and 45.1% had sufficient amounts. It was discovered that 71.8% of those with sufficient levels of 25(OH)D were more likely to proceed with embryo transfer on day 5 compared to 58.9% (p = 0.054) of those assigned to the ‘insufficient 25(OH)D’ category. Other factors such as oocyte retrieval and frequency of intracytoplasmic sperm injection were fairly similar in both groups. The study revealed that there was a higher clinical pregnancy rate per IVF cycle for those assigned to the sufficient 25(OH)D level category by 52.5% compared to those with insufficient amounts of 25(OH)D which was 34.7% (p < 0.001). Similarly, there was a significant clinical pregnancy rate per embryo transfer of 54.7% in comparison to 37.9% in woman belonging to the sufficient and insufficient category respectively. It was also noted that the implantation rate was greater in the sufficient category compared to the insufficient group, however the difference was only minimal (p= 0.6). Overall, the results suggest that serum 25(OH)D levels may be a predictor of clinical pregnancy.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/24672163 PMID24672163]

<pubmed>24672163</pubmed>

The process of achieving pregnancy via invitro fertilisation needs to be monitored and controlled with respect to the demographics of the individual in order to achieve a successful outcome. This study focuses on predicting the value of β-human chorionic gonadotrophin (β-HCG) that can lead to clinical success.

'''Method summary'''

Data analysis was taken from 171 female patients using the statistical package for social sciences program whereby all IVF cycles were monitored. The cycles that showed fresh multi-cell embryos (day 3) or blastocysts (day 5) were deemed fit for the trial and were the ones that were further used in this study. Serum β-HCG concentrations were then taken 14 days after the embryo was transferred whereby a second test was done on day 16 only if the first test revealed a positive β-HCG result. This was done to predict values that could enable doctors to evaluate a healthy intrauterine pregnancy or a problematic ectopic pregnancy. After 6-7 weeks of pregnancy, ultrasounds were conducted to check cardiac activity as well as the amount of gestational sacs. This was then repeated at 12 weeks of pregnancy to ensure there was no chance of abortion.

A continuing pregnancy was defined as one that continued for at least 12 weeks of gestation and showed signs of proper cardiac function. On the other hand, those pregnancies that were abnormal had dropped levels of β-HCG concentrations and led to empty gestational sacs that showed no embryonic cardiac function. As a measuring tool for detecting levels of β-HCG, Chemiluminescent microparticle immunoassays were used whereby the measuring range established was between 0.0-15,000 mIU/mL. HCG levels above 10 IU/L signified early pregnancy.

'''Results Summary'''

Out of the 171 patients that participated in this study, only 139 were included due to the missing data on the levels of β-HCG concentrations at day 14 and 16 post embryonic transfer. In total there were 39 abnormal pregnancies that involved ectopic pregnancy, abortions and biochemical pregnancies (sufficient HCG levels detected but no visible gestational sac). Overall the patients were categorised into two groups which were patients with ‘ongoing pregnancy’ (n=100) and ‘without ongoing pregnancy’ (n=39). The Mann-Whitney test (statistical testing) was then used to compare the levels of β-HCG levels in both groups. It was found that the group with ongoing pregnancy had a median serum β-HCG level of 600 mIU/ml, whereas the other group had a median serum β-HCG level of 178 mIU/ml. This indicated a significant difference of P < 0.05 when comparing the two groups. It was also found that when serum β-HCG levels reached 347 mIU/ml, there was a 73.6% chance that the pregnancy was ongoing. Furthermore, there was no definite correlation established between age and the rate of ongoing pregnancy as both categories had patients of similar age groups with a combined range of 23-41 year old patients. Overall, the study revealed that early serum β-HCG is a potential predictor of successful outcomes in invitro fertilisation.

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 19:11, 6 October 2014 (EST) These are relevant references and your descriptions/abstracts are good (5/5).

===Lab 2===

[[File:Phase-contrast images of embryos at different developmental stages via neogenin expression.png|300px]]

Phase-contrast images of embryos at different developmental stages via neogenin expression.<ref><pubmed>25013897</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0101989 PLos One]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:17, 21 August 2014 (EST) This is all correct. The image is very large (4.8 MB), perhaps a small version could have been uploaded. You can adjust the resolution and size in most image editing programs. (5/5)

<references/>

===Lab 3===

'''Parathyroid gland'''

<pubmed>22808183</pubmed>
<pubmed>22649358</pubmed>
<pubmed>21881196</pubmed>
<pubmed>21904825</pubmed>

'''Thymus'''

<pubmed>21733645</pubmed>
<pubmed>20836742</pubmed>
<pubmed>21263742</pubmed>
<pubmed>512270</pubmed>

'''Pancreas'''

<pubmed>22761699</pubmed>
<pubmed>22893718</pubmed>
<pubmed>24496309</pubmed>
<pubmed>24595965</pubmed>
<pubmed>23822675</pubmed>
<pubmed>22968764</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===

'''1. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

'''Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1'''

Glioblastoma multiforme (GBM) is known to belong to a very life threatening form of brain cancer. Research is currently focused on finding treatments regarding such abnormalities, such as the application of neuronal stem cells in reducing the population of tumours, however there were many problems that occurred with such treatment. Recently, Human umbilical cord blood derived stem cells (hUCBSC) has been extensively used as they are useful mesenchymal stem cells that are easy to isolate and are more available. GBM is caused by the overexpression of cyclin D1 and its subsequent binding to Cdk 4/Cdk 6 which defines the rate limiting step required for the cell to progress further on to the cell cycle from the G1 phase. In order to stop this over expression, scientists have used hUCBSC to inhibit the cell from progressing on with the cell cycle.

When (hUCBSC) were cultured with U251 and 5310 cells, flow cytometry technology revealed that the cells underwent G1 arrest showing an increase in the G0-G1/S phase ratio. There was also a 54% reduction in levels of cyclin D1 when hUCBSC was cultured with U251 in comparison to the control. Immunoprecipiation revealed that hUCBSC treated cells when immuno blotted with Cdk 4 and Cdk 6 antibodies, down regulated expression of both Cdk 4 and Cdk 6. Western blot also showed the same down regulating pattern of the individual expression and genes which confirmed that there was cell cycle arrest, thus preventing tumours from forming.

As such, this study helps researchers to grasp the foundation of using hUCBSC as a treatment for glioblastoma and to further build on such research. Since it is evident that hUCBSC is effective in reducing cyclin D1 expression; analysing glioblastomal hierarchy will aid in providing the missing links needed to create the clinical treatment.

<pubmed>21455311</pubmed>

'''2. There are a number of developmental vascular "shunts" present in the embryo, that are closed postnatally. Identify these shunts and their anatomical location.'''

Three major vascular shunts include:

• '''Ductus venosus''' - is a shunt of oxygenated blood from umbilical vein to IVC, bypassing the liver. The ductus venosus constricts and closes soon after birth and becomes the ligamentum venosum

• '''Foramen ovale''' - is a flap valve in the atrial septum between the right and left atrium that shunts highly oxygenated blood . The remnant of the foramen ovale is known as the fossa ovalis.

• '''Ductus arteriosus''' - is a shunt from the descending aorta to the left pulmonary artery near the bifurcation of the pulmonary trunk. Permanent closure takes 4-6 weeks by fibrosis, and the remnant is referred to as the ligamentum arteriosum.

===Lab 5===

'''Select an abnormality of either gastrointestinal or respiratory development and write a brief description of developmental causes(s) for this abnormality. Your answer should be added to your own student page, be brief (2-3 paragraphs) and referenced.'''

'''Midgut volvulus'''

The embryonic development of the midgut has a number of steps which ensures its proper formation. These include the viability of the superior mesenteric artery to divide the midgut into the cephalad (pre-arterial region) and caudad (post-arterial region). <ref><pubmed>15378215</pubmed></ref>During the fourth gestational week, the gastrointestinal system is composed of a centrally positioned linear tube in the abdomen. At approximately 6 weeks of gestational age, the midgut undergoes a process of U-shaped herniation causing the two portions of the midguts to face the opposite directions in relation to the superior mesenteric artery. From this moment, a number of rotation events occur to ensure the complete development of the gastrointestinal tract as it becomes set in the posterior abdominal wall.<ref><pubmed>7277164</pubmed></ref>

In some cases malrotations can occur during the developmental process of the midgut which involves the complete twisting of the midgut in relation to the axis of the superior mesenteric artery. In extreme cases this can lead to midgut volvulus which results in a narrowed mesenteric base that can obstruct the passage of blood and lead to tissue necrosis. Other complications resulting from midgut volvulus include intestinal ischaemia, peritonitis, mucosal necrosis and sepsis which can eventually lead to death if left untreated. <ref><pubmed>14655161</pubmed></ref>

Malrotation is known to occur within 1 in 500 live births and out of those who develop midgut volvusos, 68-71% are neonates. <ref><pubmed>22217896</pubmed></ref>Although the actual cause of malrotation is unknown, researchers have made links to congenital syndromes such as Down syndrome and the VACTERL. It is also hypothesized that any embryonic interference during the normal patterns of rotation and fetal development can lead to midgut volvulus. Treatment of midgut volvulus is dependent on when the disease is diagnosed. <ref><pubmed>18800265</pubmed></ref>Normally a sigmoidoscopy is carried out as well as the Ladd procedure to resect dead gastrointestinal tissues. Transduodenal bands of ladd may also be divided to widen the mesenteric pedicle and prevent obstruction of blood flow. <ref><pubmed>22208840</pubmed></ref>Overall, research is still being conducted on the specific causes of malrotation and other numerous treatments.

<references/>

===Lab 6===

Group work

===Lab 7===

'''1.Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

'''Novel genes upregulated when NOTCH signaling is disrupted during hypothalamic development.'''

It is known that the hypothalamus first develops from the ventral region of the diencephalon and signaling mechanisms such as the sonic hedgehog and bone morphogenic protein pathways are responsible for pattern arrangement. Neurogenesis is the key process required to ensure proper hypothalamus development which relies on many signaling pathways to produce neurons and glia. The Notch signaling pathway is currently known to inhibit neuronal differentiation and preserve neural progenitor identity. As a result of various studies and research, the combined theory has been implemented in this study to determine the effect of downregulating Notch signaling pathways in its effect on hypothalamic development.

Results show that when Notch signaling is inactivated, novel genes such as Dll1, Hes5, Hey1 and Ascl1 are upregulated in the rostral hypothalamus, subsequently leading to the early formation of hypothalamic neurons. This is also seen when embryos that are treated with DAPT (a chemical which inhibits cell differentiation mechanisms regulated by the Notch pathway) had an overexpression of cells differentiated into neurons in a clustered formation. This was compared to the control embryos which had differentiated cells in a scattered arrangement. As such, this research showed that Notch is a powerful signaling mechanism that is used to inhibit cell differentiation in order to control the number of cells differentiated into neurons or glia. This modulating ability of the Notch pathway is imperative in the early developing hypothalamus as it controls expression of cells and hence prevents any form of defects that can be harmful both prenatally and postnatally. Further research needs to be conducted on the Notch pathway to provide procedures where its mechanism can be used to resolve defects in the embryo and hence ensure proper hypothalamic development.

<pubmed>24360028</pubmed>

'''2.Identify the embryonic layers and tissues that contribute to the developing teeth.'''

'''Odontoblasts''' - neural crest-derived mesenchymal cells which establish the outer dental pulp. It differentiates via the enamel epithelium and releases dentin from dentinogenesis.

'''Ameloblasts''' - are derived from oral epithelium tissue of ectodermal origin and make up the inner enamel. They make pre-ameloblasts and produce enamel.

'''Periodontal ligament''' – is comprised of connective tissues which holds the tooth in place in the alveolar bone. It also encloses the cementum coating of the tooth root.

===Lab 8===

'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

'''Embryonic development of the ovary'''

The Gonads are known to be formed from the combination of primitive germ cells, adjacent mesenchyme and the mesothelium of the posterior abdominal wall. It isn’t until fifth week of embryonic development that the formation of Gonads occurs. The primordial germ cells first migrate from the embryonic yolk sac towards the hindgut along the dorsal mesentery. These cells then travel to the mesenchyme forming genital ridges positioned medially to the mesonephros by the sixth week of development. Coelomic epithelium and the mesonephros cells also proliferate at this stage. These cells then incorporate into the primary sex cords in which the process is driven by the genes stella, fragilis, and BMP-4 before the seventh week of embryonic development.<ref><pubmed>23409002</pubmed></ref>

The gonads are known to be indifferent until the sixth embryonic week as the gonads appear the same, however sex differentiation based on sex chromosomes determine the sex of the Gonad (XX for female and XY for males). The indifferent gonads are situated well inside the Wolffian body and are comprised of an inner medulla and outer cortex which contains precursors for ovarian stroma and parenchyma respectively.<ref><pubmed>3712511</pubmed></ref> In embryos consisting of XX sex chromosomes, the cortex of the indifferent gonad differentiates into an ovary meanwhile the medulla regresses by week eight of embryonic development. However, the sex cords leads to the formation of rete ovarii which is a complex of tubules and cords that arises from the mesonephros.

Another important event that occurs during the sixth week of development is the formation of the mullerian ducts which are responsible for female gonad formation and prevention of male gonad development. The established XX genotype of the female embryo prevents testosterone from being produced and hence causes the regression of the mesonephric duct since this form is only needed for male gonad expression. Also since there is no production of anti-mullarian hormone, the paramesonephric duct is able to be maintained driving female gonad expression. As of 10 weeks of development, ovaries first become recognizable and the growth of female external genitalia begins to occur.

[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]

<references/>

''' 2.Include an image from the historic genital embryology section of the online notes in your description.'''

[[File:Gray1112.jpg|400px]]

Figure 1. Longitudinal Section of Ovary of Cat Embryo of 9.4 cm long

===Lab 9===

'''Group project 1'''

The introduction was written quite well as it explains what the respiratory system is about and the origin of its development. It also briefly highlights the difference between the embryonic and fetal stage which is important in enabling the viewers to have an understanding on what the project will be focusing on. I also like how the group distinguished between the two zones of the respiratory tract and adequately described the features and function of each. The content in the lung development stages clearly relates to the topic and underlines fetal development. The group briefly mentioned the key features in each stage instead of pasting a whole lot of information; this makes it easier for viewers to understand. Overall the content relates to the learning objectives of embryology and the level of research is good as exemplified under ‘Current Research and Findings’ and ‘abnormalities’ (many forms of diseases described). The project however could benefit from having a ‘Glossary’ list so that viewers can understand some uncommon words.

The images under introduction and the image used for Meconium aspiration syndrome have not been referenced properly as there is missing information such as ((Template: Student Image)), description, copyright information and proper references for some. The image used under the ‘current research and findings’ subheading is a good example for the group to copy the referencing style. It is also vital that the group adds a brief description of what the image illustrates as a caption to help viewers understand the relation of the content and image (this is seen in the image under ‘surfactant’). More images could be added such as in the ‘lung development stage’ and under abnormalities. If images for lung development stages aren’t easily accessible, it is perhaps a good idea to draw them. The table format used for ‘lung development stages’ makes it easy for the viewers to navigate which is a good feature used in the project.

In terms of referencing, there are many in-cite references missing such as in the ‘introduction’ and in ‘lung development stages’. It is important to have these references formatted correctly under the one ‘references’ subheading. There seems to be many ‘references’ subheadings making it harder for viewers to navigate. Some references are shown as ‘ </li> which needs to be fixed right away. Overall, the content seems well written, formatted and concise making it easy to understand. However the problems related to referencing needs to be corrected as this is inconsistent throughout the project.

'''Group project 2'''

The introduction is well addressed as it sufficiently describes what the renal system is about and its function. Not to mention its anatomical structure as well as the difference between the embryonic and fetal stages of development. This differentiation enables viewers to understand what the content will be focused on, which is fetal development. Also, it helps focus the viewer’s attention on how the project will be divided as the group mentions abnormalities in the last paragraph. Overall the introduction has the right amount of information from each subheading and is very easy to comprehend.

There isn’t any information under ‘historic findings’. If there are any difficulties in finding some historic findings, members of the group can go to pubmed and on the side will be dates such as 1920 that could contain key historical events when renal is entered on search. The use of a development timeline was great as they outlined the major events that occur in a concise manner. Although, I believe a glossary is needed for words like ‘metanephros’ since the viewers would not know what that is. The content under current research models is interesting and correctly describes what the studies were about. Overall, the content used in the project was relating to the topic (fetal development of the kidney) and clearly showed extensive research. I really like how the group divided the different parts of the renal system as well as describing their anatomical positions. The abnormalities listed are also interesting and very easy to understand. I’m hoping to see information under the Horseshoe kidney disease.

In terms of images, there should be an image under introduction perhaps having all features of the renal system. Most images are missing the ‘student template’ aspect of the referencing and needs to be added right away. Other aspects such as description, copyright and referencing were correct. I also like the use of captions to describe what the images are about, however some are missing on the page such as the one under ‘anatomical position’ and ‘urethra’. The image used for the ‘development of the kidney’ should be removed from the page as it isn’t permissible. It should be replaced with an image relating to the content and have all the correct copyright and referencing information. Overall, I like the number of images used and its significance to the renal system. They accurately relate to the content of the project.

There is use of in-cite referencing which is good, however some references are just listed and should be placed under the proper ‘references’ subheading such as the ones under ‘ureter’ and ‘renal agenesis’. Some references in the ‘references’ list are used over again and can be fixed by combining it under one reference number. To make the project even more appealing, the group could format the information under ‘developmental timeline’ or even ’historic findings’ in a table. Overall, I think this project is great and by making edits based on the peer-reviews received could enhance their project.

'''Group project 3'''

The introduction is good as it accurately describes what the GIT system is about and the anatomical positions of the features in this system. It also briefly highlights the development stages at embryonic and fetal stages, however ‘embryonic development’ should be mentioned in a little more detail to understand how far in development the fetal stage begins. I also think the introduction should include a sentence or two describing how abnormalities in such organs can lead to these diseases. Basically a bit from each major subheading should be incorporated including current research as an introduction is a summary of the whole page. As for the ‘timeline’, it would’ve been more appropriate to place the timelines under each section, e.g foregut timeline under the ‘foregut’ subheading. This is because viewers would be confused on why there is so much difference in development in one section of the page. A glossary list should be incorporated in a separate subheading to define some of these words such as hematopoiesis so that viewers can fully grasp the information.

The information under recent findings is quite interesting and relatable to the content which is GIT fetal development. However, I believe more findings could be incorporated under this subheading. The information under each organ of the three ‘guts’ are quite detailed in fetal development which is good and shouldn’t be too difficult for the viewers to understand. However, I believe the group could include information on the function of these organs as well. The structure of the information under ‘guts’ does not flow in the sense that the midgut includes features and structure whereas the other ‘guts’ do not. The innvervation and bloody supply of the hindgut should be incorporated in a paragraph instead of being listed like that. All the deformities should be places under one subheading to make it easier for viewers to navigate. The abnormalities were also concise and related to the topic. Overall, the content is relating to the topic of the project and addresses key points. It also shows good amount of research, however there seems to be too much information in some parts which could be reduced a bit. The project needs a coherent flow of the structure.

As for images, there needs to be an image under introduction which includes all features of the GIT tract. There are a lot of potential images missing under each subheading except for the ‘midgut’ section. This shows that there has been one person working on this section or one section being focused on in comparison the others. The information used to reference the images is missing in some images such as the ‘Human- fetal week 10 sagittal plane D.jpg’ (although this is uploaded from a different user so this is understandable. However images such a ‘GIT 2.jpg’ need more information including ‘student template’ as well as the reference where the image idea may have come from. Also, if this is a hand-drawn image then please state this as one member did in ‘Week 11 midgut herniation.png’. Overall, I enjoy the use of self-drawn images as it makes it easier to show what the content is saying without going through the stress of looking for an image online that doesn’t relate to the content. However more images definitely need to be added. The use of captions is also good and indicates what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘Liver, Gallbladder and Bile Duct’ (the [6],[7] should be placed next to the text not above the text. The use of a ‘references’ subheading is good the same references have been combined into one number showing that the group knows how to make the references set out. The use of a table in formatting the ‘Percentage of Foetuses Herniated’ is great and shows more that the group has done research. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 4'''

The project doesn’t have an introduction yet; however information such as what the genital system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of genital development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. As for system development, I can see how there is dot-point description above the table which summarises the same thing. This structure is a bit confusing for me. I believe if the information was summarised into paragraphs and then tabulated it would make more sense. It’s best to format all that information into that table. The use of a table is a great way for the viewers to differentiate between the two sexes and understand the information more easily. I hope to see the table filled out completely soon. A glossary subheading should also be placed on the project page and have keywords defined to make viewers completely understand the content.

As for current findings, the information again is in dot points which should be paragraphed instead. However, the current findings are indeed interesting and the right amount of information is used to describe them in both sexes. The content under historic findings such as the ‘female genital development’ doesn’t show any historical events. There are no dates which show when something related was discovered. The ‘male genital development’ however shows dates and discoveries. In my opinion, if this information were tabulated rather than paragraphed, it’d be easier for viewers to navigate and understand. There is a good amount of detail under the abnormalities which relates to the key topic and is easy to understand. Overall, the content is relatable to the genital development of the fetus and underlines all the keys points. However, if this information were paragraphed in some areas and mentioned above, it would make the content easier to navigate and comprehend.

In terms of images, there are many places where images are missing such as introduction, system development and current models. I believe there needs to be more images on this page that relate to the content to make it more appealing and understandable to the viewers. The image called ‘File:Flow Diagram of Fetal Development of External Genitalia.pptx’ isn’t permissible and needs to be removed. The use of a hand drawn image on the testes is great, however there is information missing on referencing, student template and copyright laws. On the other hand, there are some images which correctly follow the uploading picture procedures such as the image on the ‘abnormalities of the vagina’; group members should follow this procedure. Captions should be added to each image to address what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘system development’. The use of a ‘references’ subheading is good, the same references have been combined into one number showing that the group knows how to make the references set out. However reference 20 and 21 are the same, please fix this. Also there are references under each subheading which should be placed all under one ‘references’ subheading. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 5'''

The introduction is a great summary of what the project page will discuss making sure to highlight every aspect. However, the introduction should also mention more about the integumentary system listing all the organs involved, their function, anatomical position and the difference between the embryonic and fetal stages of integumentary development. The content presented on the page is fantastic. All information under the subheadings looks complete and has key information related to the topic. I like how the timeline is divided into each organ making it easy to understand and navigate. The use of the table to format the information is a brilliant idea and has been presented beautifully with images in each textbox. Also the content under current research is relating to the topic and shows extensive research. The use of the purple background is appealing to the viewer highlighting its significance. I do however believe that the information under ‘historic findings’ should be formatted into a table to make it easier to navigate. The content under ‘abnormalities’ has the right amount of information and clearly relates to the key topic of the project.

In terms of images, I believe a satisfactory amount of images have been used which clearly describes the content. However, some images are missing the all the copyright information needed as well as the description, references and student template such as those in the ‘development overview’ table. This should be added right away to ensure these images do not get deleted. The use of captions on these pictures is important to highlight what the image is referring to and this is present in the page. Although, images could be added under current research as this section looks like it could use more images. Great job on the images under abnormalities, they accurately relate to the content mentioned.

There are some incite references missing such as in the development overview. I’m not sure if the references listed below are supposed to the references for it, however all references should be placed under one ‘references’ subheading. The same references have been combined into one number showing that the group knows how to make the references set out. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections. Overall, this is a great project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 7'''

The introduction is great as it mentions the features of the neural system, their anatomical positions and highlights the key events in the embryonic and fetal stages of development. The last paragraph of the introduction clearly addresses how the page will be divided and what the viewers are to expect which is good. The content under all subheadings are relating to the key topic and are formatted appropriately. I really like the image used under the subheading ‘Development during fetal period’ as it presents a diagrammatic representation of the content mentioned. The use of a table to briefly describe the events that occur at certain periods of fetal development is really helpful in grasping the main details. Some information is missing such as in ‘spinal cord development’, ‘Meninges development’, ‘future research’ and some ‘abnormalities’. This should be added right away. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the neural system and view dates on the side that may contain key findings. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

In terms of images, there are still many potential spaces for images such as under ‘introduction’, ‘current research’ and some ‘abnormalities’. The images used under ‘Development during fetal period’ are great and relate to the content. All images have correct description, referencing, copyright issues and ‘student template’, which shows that members of the group have followed correct ‘uploading image’ procedures. The images however need a caption to describe what the image is showing.

There needs to be more use of incite referencing such as in the ‘introduction’, ‘brain development’ and ‘abnormalities’. There is a huge list of references under ‘current research models and findings’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. References 7 and 8 are the same reference under the ‘references’ subheading and need to be combined into one number. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 8'''

The project doesn’t have an introduction yet; however information such as what the Musculoskeletal system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of musculoskeletal development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. I like the ‘making gains’ subheading as it adds humour to the page and engages the viewers. The general timeline needs information including what events take place at certain phases of fetal development. This could be present in a table to make the information more clear. It’s good that the project has information on the embryonic development so that the viewers can understand how the fetus arises to that point in development (fetal period).
All of the content seems to relate to the key topic and is appropriately paragraphed. However much of the content is still missing such as in ‘recent findings’ and ‘introduction’. More information could be added under the associated ‘trimesters’ and ‘abnormalities’. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the musculoskeletal system and view dates on the side that may contain key findings for historical events. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

There are no images on this page and definitely needs to be added with the appropriate information such as the description, referencing, copyright issues and ‘student template’. If images are not readily available, it is best to draw them. Also captions should be added on the page to state what the images are showing. As for referencing, there are some sections which shows incite referencing such as in the content under ‘Molecular and Cellular regulation of fetal myogenesis’ and some that don’t have any like in ‘tendon development’. There needs to be references in all sections. There is a huge list of references under ‘abnormalities’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. Number 15 of the reference list has an error in it and needs to be fixed right away. Overall, this is a working progress and if the group makes edits based on the peer-reviews received, this could enhance their project.

===Lab 10===

'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

'''''TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction.'''''

A major feature of the olfactory region is the olfactory bulb which contains mitral cells that serve to relay olfactory messages via sensory neurons of the olfactory epithelium to the piriform cortex of the brain. Within the granular cells and glomerular layers are interneurons which control the message output via synaptic linkages between mitral and tufted cell projection neurons. These interneurons continue to grow postnatally via neural stem cells located in the dorsolateral ganglionic eminence (dLGE) which consists of the subventricular zone and subependymal zone. When neuroblasts migrate to the dLGE, this stimulates dLGE-derived interneuron progenitors to migrate radially in the growing bulbs where they mature into the granular or glomerular cell layer. There has been research showing how teashirt zinc finger family member 1 (TSHZ1) is vital for the development of the olfactory bulb. In mice, it was found that olfactory bulb neuroblast differentiation required Tshz1 expression or else a large proportion of interneurons of the granular cell layer will not be present and radial migration of neuroblasts will be impaired. The basis of the previous studies was then replicated in humans suffering from congenital aural atresia that had TSHZ1 loss-of-function mutations.

Coronal sections 500-μm in size was obtained from the subjects which then underwent Nissl staining with cholineacetyl transferase histochemistry to observe the change in patterns of normal and abnormal olfactory development. In some parts of the experiment, mice were used as subjects to observe how congenital aural atresia may also affect them. In situ hybridization was used to investigate this effect on mice whereby Tshz1 positive and negative gene transcripts were obtained and amplified using polymerase chain reaction (PCR). Primers of the targeted gene and splicing enzymes were used to make sure the correct transcripts were produced.

Through immunoflourenscing and immunohistology, it was found that Tshz1 mutation lead to an abnormal distribution and differentiation of granule cell neurons of the developing olfactory bulb. Green fluoresce protein was integrated in the Tshz1 locus in both Tshz1+ and Tshz1- subjects. Through immunostaining of olfactory bulbs, it was shown that there was a consistent outer granule cell ring distribution of GFP+ cells in comparison to the unevenly distributed GFP+ cell located in the inner granule cell layer. DAPI staining revealed that the structure of the olfactory bulb in Tshz1 positive subjects were more layered and structure compared to deformed structure seen in Tshz1 mutants. The granule cell and external plexiform layers were indistinguishable and the glomerular layer had multilayers, thereby showing the abnormality in Tshz1 mutants.

Microarray hybridization was used to sort out gene expression in Tshz1 positive and negative subjects. Out of all the gene transcripts profiled, it was noted that the most significantly changed transcripts was Prokr2. Expression of PK2 was also downregulated in the rostral migratory stream of the subjects. Prokr2 expression was therefore examined in the developing olfactory bulb of Tshz1 positive and mutant mice using in situ hybridization. It was found that Tshz1 mRNA expression was seen in both the outer granule cell layer and the inner layers of the olfactory bulb mainly consisting of immature cells. Prokr2 expression was observed only in the inner layers of the OB in Tshz1 positive subjects and in mutants, Prokr2 expression was greatly downregulated. Overall, it was established that Tshz1 is needed to control the expression of Prokr2 which radially migrates neuroblasts. In addition, the PK2 family and its associated receptor are imperative factors required for normal olfactory bulb development.

<pubmed>24487590</pubmed>

'''Wiki link: https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Smell_Development'''

===Lab 11===

'''Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.'''

User:Z3418837

2014-10-27T10:47:43Z

Z3418837: /* Lab 10 */

==Lab Attendance==
*Lab 1 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 6 August 2014 (EST)
*Lab 2 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:11, 13 August 2014 (EST)
*Lab 3 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 11:12, 20 August 2014 (EST)
*Lab 4 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:55, 27 August 2014 (EST)
*Lab 5 -- Absent
*Lab 6 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:44, 10 September 2014 (EST)
*Lab 7 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:40, 17 September 2014 (EST)
*Lab 8 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:11, 24 September 2014 (EST)
*Lab 9 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:08, 8 October 2014 (EST)
*Lab 10 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 15 October 2014 (EST)
*Lab 11 --[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:31, 22 October 2014 (EST)
*Lab 12

==Individual Assessment==

==='''Lab 1'''===

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 12:45, 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>

'''Your Lab assessment now requires you to find a 2 recent research references on fertilisation or in vitro fertilisation. Paste each reference on your page, as shown in the class. Write below each reference a brief summary of the research article methods and findings. The summary for each need not be more than 3-4 paragraphs in length. This will need to be completed before next weeks laboratory'''.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/25077107 PMID25077107]

<pubmed>25077107</pubmed>

This study was designed to investigate whether the levels of vitamin D is an imperative factor when it comes to the clinical success of implantation and pregnancy rates in infertile women via invitro fertilisation.

'''Method summary'''

A cohort of 173 women were evaluated and selected for this study based on their age, follicle-stimulating hormone levels and their consent to undergo invitro fertilisation. The following study was conducted at Mount Sinai Hospital where proper facilities were available. Blood tests were then conducted for each patient to determine their levels of Vitamin D via the serum 25-hydroxy-vitamin D (25[OH]D) levels. Following the results of the blood test, the cohort were then categorised into two groups which was either vitamin D sufficient (≥ 75 nmol/L) or insufficient ( < 75 nmol/L) based on serum levels of 25(OH)D.

Each patient then underwent IVF cycles whereby standard agonists that contained the active ingredient 0.5 mg/d of buserelin acetate in conjunction with cetrolix acetate as the standard antagonist were used to control the length of the luteal phase and estradiol levels. The length and dose of the treatment were varied for each individual based on their demographic data. Serial transvaginal ultrasonograpy and serum lutenizing hormone assays were then used to check ovarian response. When 3 or more dominant follicles (≥ 17 mm) were produced, 10 000 IU of human chorionic gonadotropin was added to enhance nuclear maturation. Oocyte retrieval was then conducted via transvaginal ultrasound whereby it was fertilised and the resulting embryo was transferred 3-5 days post-fertilisation. The rate of pregnancy per IVF cycle was then used as the primary outcome for this study whereby the visibility of the intrauterine sac of the embryo determined implantation.

'''Results summary'''

Out of the 182 patients that participated in this study, it was found that only 173 patients could continue on with this trial as they satisfied the criteria, however only 162 were fit for embryo transfer. Following the results from the blood test, it was noted that 53.8% of patients had insufficient levels of 25(OH)D and 45.1% had sufficient amounts. It was discovered that 71.8% of those with sufficient levels of 25(OH)D were more likely to proceed with embryo transfer on day 5 compared to 58.9% (p = 0.054) of those assigned to the ‘insufficient 25(OH)D’ category. Other factors such as oocyte retrieval and frequency of intracytoplasmic sperm injection were fairly similar in both groups. The study revealed that there was a higher clinical pregnancy rate per IVF cycle for those assigned to the sufficient 25(OH)D level category by 52.5% compared to those with insufficient amounts of 25(OH)D which was 34.7% (p < 0.001). Similarly, there was a significant clinical pregnancy rate per embryo transfer of 54.7% in comparison to 37.9% in woman belonging to the sufficient and insufficient category respectively. It was also noted that the implantation rate was greater in the sufficient category compared to the insufficient group, however the difference was only minimal (p= 0.6). Overall, the results suggest that serum 25(OH)D levels may be a predictor of clinical pregnancy.

'''Reference:'''[http://www.ncbi.nlm.nih.gov/pubmed/24672163 PMID24672163]

<pubmed>24672163</pubmed>

The process of achieving pregnancy via invitro fertilisation needs to be monitored and controlled with respect to the demographics of the individual in order to achieve a successful outcome. This study focuses on predicting the value of β-human chorionic gonadotrophin (β-HCG) that can lead to clinical success.

'''Method summary'''

Data analysis was taken from 171 female patients using the statistical package for social sciences program whereby all IVF cycles were monitored. The cycles that showed fresh multi-cell embryos (day 3) or blastocysts (day 5) were deemed fit for the trial and were the ones that were further used in this study. Serum β-HCG concentrations were then taken 14 days after the embryo was transferred whereby a second test was done on day 16 only if the first test revealed a positive β-HCG result. This was done to predict values that could enable doctors to evaluate a healthy intrauterine pregnancy or a problematic ectopic pregnancy. After 6-7 weeks of pregnancy, ultrasounds were conducted to check cardiac activity as well as the amount of gestational sacs. This was then repeated at 12 weeks of pregnancy to ensure there was no chance of abortion.

A continuing pregnancy was defined as one that continued for at least 12 weeks of gestation and showed signs of proper cardiac function. On the other hand, those pregnancies that were abnormal had dropped levels of β-HCG concentrations and led to empty gestational sacs that showed no embryonic cardiac function. As a measuring tool for detecting levels of β-HCG, Chemiluminescent microparticle immunoassays were used whereby the measuring range established was between 0.0-15,000 mIU/mL. HCG levels above 10 IU/L signified early pregnancy.

'''Results Summary'''

Out of the 171 patients that participated in this study, only 139 were included due to the missing data on the levels of β-HCG concentrations at day 14 and 16 post embryonic transfer. In total there were 39 abnormal pregnancies that involved ectopic pregnancy, abortions and biochemical pregnancies (sufficient HCG levels detected but no visible gestational sac). Overall the patients were categorised into two groups which were patients with ‘ongoing pregnancy’ (n=100) and ‘without ongoing pregnancy’ (n=39). The Mann-Whitney test (statistical testing) was then used to compare the levels of β-HCG levels in both groups. It was found that the group with ongoing pregnancy had a median serum β-HCG level of 600 mIU/ml, whereas the other group had a median serum β-HCG level of 178 mIU/ml. This indicated a significant difference of P < 0.05 when comparing the two groups. It was also found that when serum β-HCG levels reached 347 mIU/ml, there was a 73.6% chance that the pregnancy was ongoing. Furthermore, there was no definite correlation established between age and the rate of ongoing pregnancy as both categories had patients of similar age groups with a combined range of 23-41 year old patients. Overall, the study revealed that early serum β-HCG is a potential predictor of successful outcomes in invitro fertilisation.

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 19:11, 6 October 2014 (EST) These are relevant references and your descriptions/abstracts are good (5/5).

===Lab 2===

[[File:Phase-contrast images of embryos at different developmental stages via neogenin expression.png|300px]]

Phase-contrast images of embryos at different developmental stages via neogenin expression.<ref><pubmed>25013897</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0101989 PLos One]</ref>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 16:17, 21 August 2014 (EST) This is all correct. The image is very large (4.8 MB), perhaps a small version could have been uploaded. You can adjust the resolution and size in most image editing programs. (5/5)

<references/>

===Lab 3===

'''Parathyroid gland'''

<pubmed>22808183</pubmed>
<pubmed>22649358</pubmed>
<pubmed>21881196</pubmed>
<pubmed>21904825</pubmed>

'''Thymus'''

<pubmed>21733645</pubmed>
<pubmed>20836742</pubmed>
<pubmed>21263742</pubmed>
<pubmed>512270</pubmed>

'''Pancreas'''

<pubmed>22761699</pubmed>
<pubmed>22893718</pubmed>
<pubmed>24496309</pubmed>
<pubmed>24595965</pubmed>
<pubmed>23822675</pubmed>
<pubmed>22968764</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===

'''1. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

'''Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1'''

Glioblastoma multiforme (GBM) is known to belong to a very life threatening form of brain cancer. Research is currently focused on finding treatments regarding such abnormalities, such as the application of neuronal stem cells in reducing the population of tumours, however there were many problems that occurred with such treatment. Recently, Human umbilical cord blood derived stem cells (hUCBSC) has been extensively used as they are useful mesenchymal stem cells that are easy to isolate and are more available. GBM is caused by the overexpression of cyclin D1 and its subsequent binding to Cdk 4/Cdk 6 which defines the rate limiting step required for the cell to progress further on to the cell cycle from the G1 phase. In order to stop this over expression, scientists have used hUCBSC to inhibit the cell from progressing on with the cell cycle.

When (hUCBSC) were cultured with U251 and 5310 cells, flow cytometry technology revealed that the cells underwent G1 arrest showing an increase in the G0-G1/S phase ratio. There was also a 54% reduction in levels of cyclin D1 when hUCBSC was cultured with U251 in comparison to the control. Immunoprecipiation revealed that hUCBSC treated cells when immuno blotted with Cdk 4 and Cdk 6 antibodies, down regulated expression of both Cdk 4 and Cdk 6. Western blot also showed the same down regulating pattern of the individual expression and genes which confirmed that there was cell cycle arrest, thus preventing tumours from forming.

As such, this study helps researchers to grasp the foundation of using hUCBSC as a treatment for glioblastoma and to further build on such research. Since it is evident that hUCBSC is effective in reducing cyclin D1 expression; analysing glioblastomal hierarchy will aid in providing the missing links needed to create the clinical treatment.

<pubmed>21455311</pubmed>

'''2. There are a number of developmental vascular "shunts" present in the embryo, that are closed postnatally. Identify these shunts and their anatomical location.'''

Three major vascular shunts include:

• '''Ductus venosus''' - is a shunt of oxygenated blood from umbilical vein to IVC, bypassing the liver. The ductus venosus constricts and closes soon after birth and becomes the ligamentum venosum

• '''Foramen ovale''' - is a flap valve in the atrial septum between the right and left atrium that shunts highly oxygenated blood . The remnant of the foramen ovale is known as the fossa ovalis.

• '''Ductus arteriosus''' - is a shunt from the descending aorta to the left pulmonary artery near the bifurcation of the pulmonary trunk. Permanent closure takes 4-6 weeks by fibrosis, and the remnant is referred to as the ligamentum arteriosum.

===Lab 5===

'''Select an abnormality of either gastrointestinal or respiratory development and write a brief description of developmental causes(s) for this abnormality. Your answer should be added to your own student page, be brief (2-3 paragraphs) and referenced.'''

'''Midgut volvulus'''

The embryonic development of the midgut has a number of steps which ensures its proper formation. These include the viability of the superior mesenteric artery to divide the midgut into the cephalad (pre-arterial region) and caudad (post-arterial region). <ref><pubmed>15378215</pubmed></ref>During the fourth gestational week, the gastrointestinal system is composed of a centrally positioned linear tube in the abdomen. At approximately 6 weeks of gestational age, the midgut undergoes a process of U-shaped herniation causing the two portions of the midguts to face the opposite directions in relation to the superior mesenteric artery. From this moment, a number of rotation events occur to ensure the complete development of the gastrointestinal tract as it becomes set in the posterior abdominal wall.<ref><pubmed>7277164</pubmed></ref>

In some cases malrotations can occur during the developmental process of the midgut which involves the complete twisting of the midgut in relation to the axis of the superior mesenteric artery. In extreme cases this can lead to midgut volvulus which results in a narrowed mesenteric base that can obstruct the passage of blood and lead to tissue necrosis. Other complications resulting from midgut volvulus include intestinal ischaemia, peritonitis, mucosal necrosis and sepsis which can eventually lead to death if left untreated. <ref><pubmed>14655161</pubmed></ref>

Malrotation is known to occur within 1 in 500 live births and out of those who develop midgut volvusos, 68-71% are neonates. <ref><pubmed>22217896</pubmed></ref>Although the actual cause of malrotation is unknown, researchers have made links to congenital syndromes such as Down syndrome and the VACTERL. It is also hypothesized that any embryonic interference during the normal patterns of rotation and fetal development can lead to midgut volvulus. Treatment of midgut volvulus is dependent on when the disease is diagnosed. <ref><pubmed>18800265</pubmed></ref>Normally a sigmoidoscopy is carried out as well as the Ladd procedure to resect dead gastrointestinal tissues. Transduodenal bands of ladd may also be divided to widen the mesenteric pedicle and prevent obstruction of blood flow. <ref><pubmed>22208840</pubmed></ref>Overall, research is still being conducted on the specific causes of malrotation and other numerous treatments.

<references/>

===Lab 6===

Group work

===Lab 7===

'''1.Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

'''Novel genes upregulated when NOTCH signaling is disrupted during hypothalamic development.'''

It is known that the hypothalamus first develops from the ventral region of the diencephalon and signaling mechanisms such as the sonic hedgehog and bone morphogenic protein pathways are responsible for pattern arrangement. Neurogenesis is the key process required to ensure proper hypothalamus development which relies on many signaling pathways to produce neurons and glia. The Notch signaling pathway is currently known to inhibit neuronal differentiation and preserve neural progenitor identity. As a result of various studies and research, the combined theory has been implemented in this study to determine the effect of downregulating Notch signaling pathways in its effect on hypothalamic development.

Results show that when Notch signaling is inactivated, novel genes such as Dll1, Hes5, Hey1 and Ascl1 are upregulated in the rostral hypothalamus, subsequently leading to the early formation of hypothalamic neurons. This is also seen when embryos that are treated with DAPT (a chemical which inhibits cell differentiation mechanisms regulated by the Notch pathway) had an overexpression of cells differentiated into neurons in a clustered formation. This was compared to the control embryos which had differentiated cells in a scattered arrangement. As such, this research showed that Notch is a powerful signaling mechanism that is used to inhibit cell differentiation in order to control the number of cells differentiated into neurons or glia. This modulating ability of the Notch pathway is imperative in the early developing hypothalamus as it controls expression of cells and hence prevents any form of defects that can be harmful both prenatally and postnatally. Further research needs to be conducted on the Notch pathway to provide procedures where its mechanism can be used to resolve defects in the embryo and hence ensure proper hypothalamic development.

<pubmed>24360028</pubmed>

'''2.Identify the embryonic layers and tissues that contribute to the developing teeth.'''

'''Odontoblasts''' - neural crest-derived mesenchymal cells which establish the outer dental pulp. It differentiates via the enamel epithelium and releases dentin from dentinogenesis.

'''Ameloblasts''' - are derived from oral epithelium tissue of ectodermal origin and make up the inner enamel. They make pre-ameloblasts and produce enamel.

'''Periodontal ligament''' – is comprised of connective tissues which holds the tooth in place in the alveolar bone. It also encloses the cementum coating of the tooth root.

===Lab 8===

'''1. Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs)'''

'''Embryonic development of the ovary'''

The Gonads are known to be formed from the combination of primitive germ cells, adjacent mesenchyme and the mesothelium of the posterior abdominal wall. It isn’t until fifth week of embryonic development that the formation of Gonads occurs. The primordial germ cells first migrate from the embryonic yolk sac towards the hindgut along the dorsal mesentery. These cells then travel to the mesenchyme forming genital ridges positioned medially to the mesonephros by the sixth week of development. Coelomic epithelium and the mesonephros cells also proliferate at this stage. These cells then incorporate into the primary sex cords in which the process is driven by the genes stella, fragilis, and BMP-4 before the seventh week of embryonic development.<ref><pubmed>23409002</pubmed></ref>

The gonads are known to be indifferent until the sixth embryonic week as the gonads appear the same, however sex differentiation based on sex chromosomes determine the sex of the Gonad (XX for female and XY for males). The indifferent gonads are situated well inside the Wolffian body and are comprised of an inner medulla and outer cortex which contains precursors for ovarian stroma and parenchyma respectively.<ref><pubmed>3712511</pubmed></ref> In embryos consisting of XX sex chromosomes, the cortex of the indifferent gonad differentiates into an ovary meanwhile the medulla regresses by week eight of embryonic development. However, the sex cords leads to the formation of rete ovarii which is a complex of tubules and cords that arises from the mesonephros.

Another important event that occurs during the sixth week of development is the formation of the mullerian ducts which are responsible for female gonad formation and prevention of male gonad development. The established XX genotype of the female embryo prevents testosterone from being produced and hence causes the regression of the mesonephric duct since this form is only needed for male gonad expression. Also since there is no production of anti-mullarian hormone, the paramesonephric duct is able to be maintained driving female gonad expression. As of 10 weeks of development, ovaries first become recognizable and the growth of female external genitalia begins to occur.

[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]

<references/>

''' 2.Include an image from the historic genital embryology section of the online notes in your description.'''

[[File:Gray1112.jpg|400px]]

Figure 1. Longitudinal Section of Ovary of Cat Embryo of 9.4 cm long

===Lab 9===

'''Group project 1'''

The introduction was written quite well as it explains what the respiratory system is about and the origin of its development. It also briefly highlights the difference between the embryonic and fetal stage which is important in enabling the viewers to have an understanding on what the project will be focusing on. I also like how the group distinguished between the two zones of the respiratory tract and adequately described the features and function of each. The content in the lung development stages clearly relates to the topic and underlines fetal development. The group briefly mentioned the key features in each stage instead of pasting a whole lot of information; this makes it easier for viewers to understand. Overall the content relates to the learning objectives of embryology and the level of research is good as exemplified under ‘Current Research and Findings’ and ‘abnormalities’ (many forms of diseases described). The project however could benefit from having a ‘Glossary’ list so that viewers can understand some uncommon words.

The images under introduction and the image used for Meconium aspiration syndrome have not been referenced properly as there is missing information such as ((Template: Student Image)), description, copyright information and proper references for some. The image used under the ‘current research and findings’ subheading is a good example for the group to copy the referencing style. It is also vital that the group adds a brief description of what the image illustrates as a caption to help viewers understand the relation of the content and image (this is seen in the image under ‘surfactant’). More images could be added such as in the ‘lung development stage’ and under abnormalities. If images for lung development stages aren’t easily accessible, it is perhaps a good idea to draw them. The table format used for ‘lung development stages’ makes it easy for the viewers to navigate which is a good feature used in the project.

In terms of referencing, there are many in-cite references missing such as in the ‘introduction’ and in ‘lung development stages’. It is important to have these references formatted correctly under the one ‘references’ subheading. There seems to be many ‘references’ subheadings making it harder for viewers to navigate. Some references are shown as ‘ </li> which needs to be fixed right away. Overall, the content seems well written, formatted and concise making it easy to understand. However the problems related to referencing needs to be corrected as this is inconsistent throughout the project.

'''Group project 2'''

The introduction is well addressed as it sufficiently describes what the renal system is about and its function. Not to mention its anatomical structure as well as the difference between the embryonic and fetal stages of development. This differentiation enables viewers to understand what the content will be focused on, which is fetal development. Also, it helps focus the viewer’s attention on how the project will be divided as the group mentions abnormalities in the last paragraph. Overall the introduction has the right amount of information from each subheading and is very easy to comprehend.

There isn’t any information under ‘historic findings’. If there are any difficulties in finding some historic findings, members of the group can go to pubmed and on the side will be dates such as 1920 that could contain key historical events when renal is entered on search. The use of a development timeline was great as they outlined the major events that occur in a concise manner. Although, I believe a glossary is needed for words like ‘metanephros’ since the viewers would not know what that is. The content under current research models is interesting and correctly describes what the studies were about. Overall, the content used in the project was relating to the topic (fetal development of the kidney) and clearly showed extensive research. I really like how the group divided the different parts of the renal system as well as describing their anatomical positions. The abnormalities listed are also interesting and very easy to understand. I’m hoping to see information under the Horseshoe kidney disease.

In terms of images, there should be an image under introduction perhaps having all features of the renal system. Most images are missing the ‘student template’ aspect of the referencing and needs to be added right away. Other aspects such as description, copyright and referencing were correct. I also like the use of captions to describe what the images are about, however some are missing on the page such as the one under ‘anatomical position’ and ‘urethra’. The image used for the ‘development of the kidney’ should be removed from the page as it isn’t permissible. It should be replaced with an image relating to the content and have all the correct copyright and referencing information. Overall, I like the number of images used and its significance to the renal system. They accurately relate to the content of the project.

There is use of in-cite referencing which is good, however some references are just listed and should be placed under the proper ‘references’ subheading such as the ones under ‘ureter’ and ‘renal agenesis’. Some references in the ‘references’ list are used over again and can be fixed by combining it under one reference number. To make the project even more appealing, the group could format the information under ‘developmental timeline’ or even ’historic findings’ in a table. Overall, I think this project is great and by making edits based on the peer-reviews received could enhance their project.

'''Group project 3'''

The introduction is good as it accurately describes what the GIT system is about and the anatomical positions of the features in this system. It also briefly highlights the development stages at embryonic and fetal stages, however ‘embryonic development’ should be mentioned in a little more detail to understand how far in development the fetal stage begins. I also think the introduction should include a sentence or two describing how abnormalities in such organs can lead to these diseases. Basically a bit from each major subheading should be incorporated including current research as an introduction is a summary of the whole page. As for the ‘timeline’, it would’ve been more appropriate to place the timelines under each section, e.g foregut timeline under the ‘foregut’ subheading. This is because viewers would be confused on why there is so much difference in development in one section of the page. A glossary list should be incorporated in a separate subheading to define some of these words such as hematopoiesis so that viewers can fully grasp the information.

The information under recent findings is quite interesting and relatable to the content which is GIT fetal development. However, I believe more findings could be incorporated under this subheading. The information under each organ of the three ‘guts’ are quite detailed in fetal development which is good and shouldn’t be too difficult for the viewers to understand. However, I believe the group could include information on the function of these organs as well. The structure of the information under ‘guts’ does not flow in the sense that the midgut includes features and structure whereas the other ‘guts’ do not. The innvervation and bloody supply of the hindgut should be incorporated in a paragraph instead of being listed like that. All the deformities should be places under one subheading to make it easier for viewers to navigate. The abnormalities were also concise and related to the topic. Overall, the content is relating to the topic of the project and addresses key points. It also shows good amount of research, however there seems to be too much information in some parts which could be reduced a bit. The project needs a coherent flow of the structure.

As for images, there needs to be an image under introduction which includes all features of the GIT tract. There are a lot of potential images missing under each subheading except for the ‘midgut’ section. This shows that there has been one person working on this section or one section being focused on in comparison the others. The information used to reference the images is missing in some images such as the ‘Human- fetal week 10 sagittal plane D.jpg’ (although this is uploaded from a different user so this is understandable. However images such a ‘GIT 2.jpg’ need more information including ‘student template’ as well as the reference where the image idea may have come from. Also, if this is a hand-drawn image then please state this as one member did in ‘Week 11 midgut herniation.png’. Overall, I enjoy the use of self-drawn images as it makes it easier to show what the content is saying without going through the stress of looking for an image online that doesn’t relate to the content. However more images definitely need to be added. The use of captions is also good and indicates what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘Liver, Gallbladder and Bile Duct’ (the [6],[7] should be placed next to the text not above the text. The use of a ‘references’ subheading is good the same references have been combined into one number showing that the group knows how to make the references set out. The use of a table in formatting the ‘Percentage of Foetuses Herniated’ is great and shows more that the group has done research. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 4'''

The project doesn’t have an introduction yet; however information such as what the genital system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of genital development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. As for system development, I can see how there is dot-point description above the table which summarises the same thing. This structure is a bit confusing for me. I believe if the information was summarised into paragraphs and then tabulated it would make more sense. It’s best to format all that information into that table. The use of a table is a great way for the viewers to differentiate between the two sexes and understand the information more easily. I hope to see the table filled out completely soon. A glossary subheading should also be placed on the project page and have keywords defined to make viewers completely understand the content.

As for current findings, the information again is in dot points which should be paragraphed instead. However, the current findings are indeed interesting and the right amount of information is used to describe them in both sexes. The content under historic findings such as the ‘female genital development’ doesn’t show any historical events. There are no dates which show when something related was discovered. The ‘male genital development’ however shows dates and discoveries. In my opinion, if this information were tabulated rather than paragraphed, it’d be easier for viewers to navigate and understand. There is a good amount of detail under the abnormalities which relates to the key topic and is easy to understand. Overall, the content is relatable to the genital development of the fetus and underlines all the keys points. However, if this information were paragraphed in some areas and mentioned above, it would make the content easier to navigate and comprehend.

In terms of images, there are many places where images are missing such as introduction, system development and current models. I believe there needs to be more images on this page that relate to the content to make it more appealing and understandable to the viewers. The image called ‘File:Flow Diagram of Fetal Development of External Genitalia.pptx’ isn’t permissible and needs to be removed. The use of a hand drawn image on the testes is great, however there is information missing on referencing, student template and copyright laws. On the other hand, there are some images which correctly follow the uploading picture procedures such as the image on the ‘abnormalities of the vagina’; group members should follow this procedure. Captions should be added to each image to address what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘system development’. The use of a ‘references’ subheading is good, the same references have been combined into one number showing that the group knows how to make the references set out. However reference 20 and 21 are the same, please fix this. Also there are references under each subheading which should be placed all under one ‘references’ subheading. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 5'''

The introduction is a great summary of what the project page will discuss making sure to highlight every aspect. However, the introduction should also mention more about the integumentary system listing all the organs involved, their function, anatomical position and the difference between the embryonic and fetal stages of integumentary development. The content presented on the page is fantastic. All information under the subheadings looks complete and has key information related to the topic. I like how the timeline is divided into each organ making it easy to understand and navigate. The use of the table to format the information is a brilliant idea and has been presented beautifully with images in each textbox. Also the content under current research is relating to the topic and shows extensive research. The use of the purple background is appealing to the viewer highlighting its significance. I do however believe that the information under ‘historic findings’ should be formatted into a table to make it easier to navigate. The content under ‘abnormalities’ has the right amount of information and clearly relates to the key topic of the project.

In terms of images, I believe a satisfactory amount of images have been used which clearly describes the content. However, some images are missing the all the copyright information needed as well as the description, references and student template such as those in the ‘development overview’ table. This should be added right away to ensure these images do not get deleted. The use of captions on these pictures is important to highlight what the image is referring to and this is present in the page. Although, images could be added under current research as this section looks like it could use more images. Great job on the images under abnormalities, they accurately relate to the content mentioned.

There are some incite references missing such as in the development overview. I’m not sure if the references listed below are supposed to the references for it, however all references should be placed under one ‘references’ subheading. The same references have been combined into one number showing that the group knows how to make the references set out. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections. Overall, this is a great project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 7'''

The introduction is great as it mentions the features of the neural system, their anatomical positions and highlights the key events in the embryonic and fetal stages of development. The last paragraph of the introduction clearly addresses how the page will be divided and what the viewers are to expect which is good. The content under all subheadings are relating to the key topic and are formatted appropriately. I really like the image used under the subheading ‘Development during fetal period’ as it presents a diagrammatic representation of the content mentioned. The use of a table to briefly describe the events that occur at certain periods of fetal development is really helpful in grasping the main details. Some information is missing such as in ‘spinal cord development’, ‘Meninges development’, ‘future research’ and some ‘abnormalities’. This should be added right away. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the neural system and view dates on the side that may contain key findings. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

In terms of images, there are still many potential spaces for images such as under ‘introduction’, ‘current research’ and some ‘abnormalities’. The images used under ‘Development during fetal period’ are great and relate to the content. All images have correct description, referencing, copyright issues and ‘student template’, which shows that members of the group have followed correct ‘uploading image’ procedures. The images however need a caption to describe what the image is showing.

There needs to be more use of incite referencing such as in the ‘introduction’, ‘brain development’ and ‘abnormalities’. There is a huge list of references under ‘current research models and findings’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. References 7 and 8 are the same reference under the ‘references’ subheading and need to be combined into one number. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

'''Group project 8'''

The project doesn’t have an introduction yet; however information such as what the Musculoskeletal system is about, the features of the system as well as the difference between the embryonic and fetal stages of development should be mentioned. Not to mention a brief summary of each key subheading such as abnormalities under introduction e.g. any deformations in the fetal stages of musculoskeletal development can result in to such and such abnormalities which will be addressed. This will help the viewer’s understand what the project will be going through. I like the ‘making gains’ subheading as it adds humour to the page and engages the viewers. The general timeline needs information including what events take place at certain phases of fetal development. This could be present in a table to make the information more clear. It’s good that the project has information on the embryonic development so that the viewers can understand how the fetus arises to that point in development (fetal period).
All of the content seems to relate to the key topic and is appropriately paragraphed. However much of the content is still missing such as in ‘recent findings’ and ‘introduction’. More information could be added under the associated ‘trimesters’ and ‘abnormalities’. There are no historic findings which is great to have on your page for viewer’s fascination into the group project. Members could search on pubmed about the musculoskeletal system and view dates on the side that may contain key findings for historical events. Also a glossary list should be added to help viewers understand the content more instead of just being confused at some sections.

There are no images on this page and definitely needs to be added with the appropriate information such as the description, referencing, copyright issues and ‘student template’. If images are not readily available, it is best to draw them. Also captions should be added on the page to state what the images are showing. As for referencing, there are some sections which shows incite referencing such as in the content under ‘Molecular and Cellular regulation of fetal myogenesis’ and some that don’t have any like in ‘tendon development’. There needs to be references in all sections. There is a huge list of references under ‘abnormalities’ which need to be placed all under one ‘references subheading’; similarly to any other reference list on the page. Number 15 of the reference list has an error in it and needs to be fixed right away. Overall, this is a working progress and if the group makes edits based on the peer-reviews received, this could enhance their project.

===Lab 10===

'''Identify a recent research paper on sensory development (not hearing) and write a brief summary (several paragraphs) of the research methods and findings. Include at the end a link to the relevant wiki sensory notes page.'''

'''''TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction.'''''

A major feature of the olfactory region is the olfactory bulb which contains mitral cells that serve to relay olfactory messages via sensory neurons of the olfactory epithelium to the piriform cortex of the brain. Within the granular cells and glomerular layers are interneurons which control the message output via synaptic linkages between mitral and tufted cell projection neurons. These interneurons continue to grow postnatally via neural stem cells located in the dorsolateral ganglionic eminence (dLGE) which consists of the subventricular zone and subependymal zone. When neuroblasts migrate to the dLGE, this stimulates dLGE-derived interneuron progenitors to migrate radially in the growing bulbs where they mature into the granular or glomerular cell layer. There has been research showing how teashirt zinc finger family member 1 (TSHZ1) is vital for the development of the olfactory bulb. In mice, it was found that olfactory bulb neuroblast differentiation required Tshz1 expression or else a large proportion of interneurons of the granular cell layer will not be present and radial migration of neuroblasts will be impaired. The basis of the previous studies was then replicated in humans suffering from congenital aural atresia that had TSHZ1 loss-of-function mutations.

Coronal sections 500-μm in size was obtained from the subjects which then underwent Nissl staining with cholineacetyl transferase histochemistry to observe the change in patterns of normal and abnormal olfactory development. In some parts of the experiment, mice were used as subjects to observe how congenital aural atresia may also affect them. In situ hybridization was used to investigate this effect on mice whereby Tshz1 positive and negative gene transcripts were obtained and amplified using polymerase chain reaction (PCR). Primers of the targeted gene and splicing enzymes were used to make sure the correct transcripts were produced.

Through immunoflourenscing and immunohistology, it was found that Tshz1 mutation lead to an abnormal distribution and differentiation of granule cell neurons of the developing olfactory bulb. Green fluoresce protein was integrated in the Tshz1 locus in both Tshz1+ and Tshz1- subjects. Through immunostaining of olfactory bulbs, it was shown that there was a consistent outer granule cell ring distribution of GFP+ cells in comparison to the unevenly distributed GFP+ cell located in the inner granule cell layer. DAPI staining revealed that the structure of the olfactory bulb in Tshz1 positive subjects were more layered and structure compared to deformed structure seen in Tshz1 mutants. The granule cell and external plexiform layers were indistinguishable and the glomerular layer had multilayers, thereby showing the abnormality in Tshz1 mutants.

Microarray hybridization was used to sort out gene expression in Tshz1 positive and negative subjects. Out of all the gene transcripts profiled, it was noted that the most significantly changed transcripts was Prokr2. Expression of PK2 was also downregulated in the rostral migratory stream of the subjects. Prokr2 expression was therefore examined in the developing olfactory bulb of Tshz1 positive and mutant mice using in situ hybridization. It was found that Tshz1 mRNA expression was seen in both the outer granule cell layer and the inner layers of the olfactory bulb mainly consisting of immature cells. Prokr2 expression was observed only in the inner layers of the OB in Tshz1 positive subjects and in mutants, Prokr2 expression was greatly downregulated. Overall, it was established that Tshz1 is needed to control the expression of Prokr2 which radially migrates neuroblasts. In addition, the PK2 family and its associated receptor are imperative factors required for normal olfactory bulb development.

<pubmed>24487590</pubmed>

'''Wiki link: https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Smell_Development'''

==Lab 11==

2014 Group Project 6

2014-10-24T07:11:36Z

Z3418837: /* Thymus */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

The endocrine system consists of a number of organs that influence the development, growth, metabolism, electrolyte balance, reproduction and homeostasis of the human body through their release of hormones into the blood stream. Hormones can exert both a direct influence on target organs (for example the pituitary gland) as well as stimulating or inhibiting the release of hormones from other organs (e.g. hypothalamus) as endocrine organs are highly intertwined with each other<ref><pubmed>15706790</pubmed></ref>.
The following page explains the key stages of development of endocrine organs in the human fetus, relevant developmental abnormalities as well as some current research findings.

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

[[File:Keith1902 fig167.jpg|200px|thumb|right|Schematic of a developing pineal gland in week 6 of gestation]] [[File:Pineal-body.jpg|170px|thumb|right|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.

'''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>
*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).

'''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>

{| align="center" style="text-align:centre"
|-
| [[File:Primary brain vesicles.jpg|frame|right|middle|180x150px|Primary brain vesicles]]||[[File:Fetal pineal gland 01.jpg|frame|right|middle|180x150px|Fetal pineal gland at the end of the first trimester of development.]]||[[File:Week 6 embryonic development of CNS.jpg|frame|right|middle|180x150px|Week 6 embryonic development of CNS]]||[[File:Week 11 fetal development of CNS.jpg|frame|right|middle|180x150px|Week 11 fetal development of CNS]]
|}

''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>
|}

===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|This image illustrates the location of nuclei in the hypothalamus]]

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.

'''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:'''
[[File:Hypothalamus histology 001.jpg|250x|thumb|right|Image 2. Histological cross-section of adult monkey hypothalamus depicting two major nuclei]]
* Week 9- The hypophyseal placode changes shape as it is pulled upwards, towards the overlying neuroepithelium, to form Rathke's pouch.
* Week 18- By mid-gestation, this simple epithelial invagination separates from the underlying ectoderm to form the definitive Rathke's pouch with lumen.
[[File:Stage 22 image 057.jpg|200x|thumb|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 <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|centre|thumb|Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28]]

''Table 2. 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
|}

===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===

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

*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]]

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

* Week 8 - By week 8 embryological development, the pituitary gland is fully formed and begins functioning as a control center 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'''

''Table 3. 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'''

''Table 4. 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 !! Neuronal Origin !! Function
|-
| Oxytocin || 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 || 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===

*'''Ectopic Posterior Pituitary:'''
This is an abnormal pituitary development disorder that results from improper migration of the posterior pituitary from the neural tissue that initially forms an invagination at the floor of the third ventricle. This results in the posterior pituitary lobe developing and maturing at the level of the median eminence or in line with the pituitary stalk rather than sitting further down in the cella turcica. Consequently, the releasing factors secreted from the hypothalamus that normally migrate down the portal circulation towards the anterior pituitary can only target their destination using the general vasculature. This leads to growth hormone deficiency and in some cases panhypopituitarism.<ref name =di Iorgi N. • Secco A. • Napoli F. • Calandra E. • Rossi A. • Maghnie M> di Iorgi N. • Secco A. • Napoli F. • Calandra E. • Rossi A. • Maghnie M, 2009, Developmental Abnormalities of the Posterior Pituitary Gland, Endocrine Involvement in Developmental Syndromes: 14(2009); 83-94, http://www.karger.com/Article/FullText/207479></ref>

*'''Hypopituitarism:'''
This is a disorder that results from abnormal production of pituitary hormones like growth hormone, luteinizing hormone, vasopressin and oxytocin. If there are insufficient levels of fetal production of these hormones, there are many postnatal effects. The infant would have irregularities in bone growth, urinary system development and brain growth and would show retinal dysfunction. This is because the pituitary gland plays a pivotal role in the hypothalamic-pituitary axis in maintaining proper body balance and organ growth. <ref name =Webb EA1, AlMutair A, Kelberman D, Bacchelli C, Chanudet E, Lescai F, Andoniadou CL, Banyan A, Alsawaid A, Alrifai MT, Alahmesh MA, Balwi M, Mousavy-Gharavy SN, Lukovic B, Burke D, McCabe MJ, Kasia T, Kleta R, Stupka E, Beales PL, Thompson DA, Chong WK, Alkuraya FS, Martinez-Barbera JP, Sowden JC, Dattani MT> Webb EA1, AlMutair A, Kelberman D, Bacchelli C, Chanudet E, Lescai F, Andoniadou CL, Banyan A, Alsawaid A, Alrifai MT, Alahmesh MA, Balwi M, Mousavy-Gharavy SN, Lukovic B, Burke D, McCabe MJ, Kasia T, Kleta R, Stupka E, Beales PL, Thompson DA, Chong WK, Alkuraya FS, Martinez-Barbera JP, Sowden JC, Dattani MT. (2013). ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies. Brain, 136(10), 3096-3105, http://www.ncbi.nlm.nih.gov/pubmed/24022475></ref>

==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:'''
* Week 7-8- Terminal differentiation of thyroid gland occurs and involves the onset of the gland function
* Week 7-9- This is the '''Pre-colloid''' stage where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* Week 10-11- Is the '''Beginning colloid''' stage and involves the polarisation of the TFC precursors. This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* Week 12- '''Progressive follicular''' growth occurs. 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- Fetal thyroid hormone synthesis occurs. Prior to this, the fetus receives vital maternal thyroid hormones via the placenta

''Table 5. 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:''[[File:Hypothyroidism.jpg|300px|right|thumb|This image compares a normal thyroid gland (a) anatomy with a hypothyroidism thyroid gland (b)]]

{| 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'''

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>

'''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 6. Summarises the 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.
[[File:Stage 22 image 168.jpg|350px|thumb|right|This image shows the 54 - 56th week of thymus development]]

'''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 7. Summarises the 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.

'''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 8. summarises the 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>

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

*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 8. summarises the 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===

'''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:'''

[[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'''

*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 9. summarises the 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/>

2014 Group Project 6

2014-10-24T05:46:09Z

Z3418837: /* Abnormalities */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

The endocrine system consists of a number of organs that influence the development, growth, metabolism, electrolyte balance, reproduction and homeostasis of the human body through their release of hormones into the blood stream. Hormones can exert both a direct influence on target organs (for example the pituitary gland) as well as stimulating or inhibiting the release of hormones from other organs (e.g. hypothalamus) as endocrine organs are highly intertwined with each other<ref><pubmed>15706790</pubmed></ref>.
The following page explains the key stages of development of endocrine organs in the human fetus, relevant developmental abnormalities as well as some current research findings.

==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.

[[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>

''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>
|}

===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]]

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.

[[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

''Table 2. 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]]

===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===

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

*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]]

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

* Week 8 - By week 8 embryological development, the pituitary gland is fully formed and begins functioning as a control center 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'''

''Table 3. 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'''

''Table 4. 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 !! Neuronal Origin !! Function
|-
| Oxytocin || 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 || 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===

*'''Ectopic Posterior Pituitary:'''
This is an abnormal pituitary development disorder that results from improper migration of the posterior pituitary from the neural tissue that initially forms an invagination at the floor of the third ventricle. This results in the posterior pituitary lobe developing and maturing at the level of the median eminence or in line with the pituitary stalk rather than sitting further down in the cella turcica. Consequently, the releasing factors secreted from the hypothalamus that normally migrate down the portal circulation towards the anterior pituitary can only target their destination using the general vasculature. This leads to growth hormone deficiency and in some cases panhypopituitarism.<ref name =di Iorgi N. • Secco A. • Napoli F. • Calandra E. • Rossi A. • Maghnie M> di Iorgi N. • Secco A. • Napoli F. • Calandra E. • Rossi A. • Maghnie M, 2009, Developmental Abnormalities of the Posterior Pituitary Gland, Endocrine Involvement in Developmental Syndromes: 14(2009); 83-94, http://www.karger.com/Article/FullText/207479></ref>

*'''Hypopituitarism:'''
This is a disorder that results from abnormal production of pituitary hormones like growth hormone, luteinizing hormone, vasopressin and oxytocin. If there are insufficient levels of fetal production of these hormones, there are many postnatal effects. The infant would have irregularities in bone growth, urinary system development and brain growth and would show retinal dysfunction. This is because the pituitary gland plays a pivotal role in the hypothalamic-pituitary axis in maintaining proper body balance and organ growth. <ref name =Webb EA1, AlMutair A, Kelberman D, Bacchelli C, Chanudet E, Lescai F, Andoniadou CL, Banyan A, Alsawaid A, Alrifai MT, Alahmesh MA, Balwi M, Mousavy-Gharavy SN, Lukovic B, Burke D, McCabe MJ, Kasia T, Kleta R, Stupka E, Beales PL, Thompson DA, Chong WK, Alkuraya FS, Martinez-Barbera JP, Sowden JC, Dattani MT> Webb EA1, AlMutair A, Kelberman D, Bacchelli C, Chanudet E, Lescai F, Andoniadou CL, Banyan A, Alsawaid A, Alrifai MT, Alahmesh MA, Balwi M, Mousavy-Gharavy SN, Lukovic B, Burke D, McCabe MJ, Kasia T, Kleta R, Stupka E, Beales PL, Thompson DA, Chong WK, Alkuraya FS, Martinez-Barbera JP, Sowden JC, Dattani MT. (2013). ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies. Brain, 136(10), 3096-3105, http://www.ncbi.nlm.nih.gov/pubmed/24022475></ref>

==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:'''
* Week 7-8- Terminal differentiation of thyroid gland occurs and involves the onset of the gland function
* Week 7-9- This is the '''Pre-colloid''' stage where the thyroid gland contains strands of compact unpolarised Thyroid Follicular Cell (TFC) precursors
* Week 10-11- Is the '''Beginning colloid''' stage and involves the polarisation of the TFC precursors. This gives the first appearance of small thyroid follicles (the eventual functional unit of the gland)
* Week 12- '''Progressive follicular''' growth occurs. 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- Fetal thyroid hormone synthesis occurs. Prior to this, the fetus receives vital maternal thyroid hormones via the placenta

''Table 5. 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:''[[File:Hypothyroidism.jpg|300px|right|thumb|This image compares a normal thyroid gland (a) anatomy with a hypothyroidism thyroid gland (b)]]

{| 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'''

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>

'''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 6. Summarises the 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.
[[File:Stage 22 image 168.jpg|200px|thumb|right|This image shows the 54 - 56th week of thymus development]]

'''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 7. Summarises the 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.

'''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 8. summarises the 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>

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

*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 8. summarises the 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===

'''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:'''

[[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'''

*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 9. summarises the 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/>

2014 Group Project 6

2014-10-24T04:43:34Z

Z3418837: /* Fetal development */

{{ANAT2341Project2014header}}
=The Endocrine System=

==Introduction==

The endocrine system consists of a number of organs that influence the development, growth, metabolism, electrolyte balance, reproduction and homeostasis of the human body through their release of hormones into the blood stream. Hormones can exert both a direct influence on target organs (for example the pituitary gland) as well as stimulating or inhibiting the release of hormones from other organs (e.g. hypothalamus) as endocrine organs are highly intertwined with each other<ref><pubmed>15706790</pubmed></ref>.
The following page explains the key stages of development of endocrine organs in the human fetus, relevant developmental abnormalities as well as some current research findings.

==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===

'''*Ectopic Posterior Pituitary:
'''
This is an abnormal pituitary development disorder that results from improper migration of the posterior pituitary from the neural tissue that initially forms an invagination at the floor of the third ventricle. This results in the posterior pituitary lobe developing and maturing at the level of the median eminence or in line with the pituitary stalk rather than sitting further down in the cella turcica. <ref name =di Iorgi N. • Secco A. • Napoli F. • Calandra E. • Rossi A. • Maghnie M> di Iorgi N. • Secco A. • Napoli F. • Calandra E. • Rossi A. • Maghnie M, 2009, Developmental Abnormalities of the Posterior Pituitary Gland, Endocrine Involvement in Developmental Syndromes: 14(2009); 83-94, http://www.karger.com/Article/FullText/207479></ref>

'''*Hypopituitarism:
'''
This is a disorder that results from abnormal production of pituitary hormones like growth hormone, luteinizing hormone, vasopressin and oxytocin. If there are insufficient levels of fetal production of these hormones, there are many postnatal effects. The infant would have irregularities in bone growth, urinary system development and brain growth and would show retinal dysfunction. This is because the pituitary gland plays a pivotal role in the hypothalamic-pituitary axis in maintaining proper body balance and organ growth. <ref name =Webb EA1, AlMutair A, Kelberman D, Bacchelli C, Chanudet E, Lescai F, Andoniadou CL, Banyan A, Alsawaid A, Alrifai MT, Alahmesh MA, Balwi M, Mousavy-Gharavy SN, Lukovic B, Burke D, McCabe MJ, Kasia T, Kleta R, Stupka E, Beales PL, Thompson DA, Chong WK, Alkuraya FS, Martinez-Barbera JP, Sowden JC, Dattani MT> Webb EA1, AlMutair A, Kelberman D, Bacchelli C, Chanudet E, Lescai F, Andoniadou CL, Banyan A, Alsawaid A, Alrifai MT, Alahmesh MA, Balwi M, Mousavy-Gharavy SN, Lukovic B, Burke D, McCabe MJ, Kasia T, Kleta R, Stupka E, Beales PL, Thompson DA, Chong WK, Alkuraya FS, Martinez-Barbera JP, Sowden JC, Dattani MT. (2013). ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies. Brain, 136(10), 3096-3105, http://www.ncbi.nlm.nih.gov/pubmed/24022475></ref>

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

{| 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'''

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.
[[File:Stage 22 image 168.jpg|200px|thumb|right|This image shows the 54 - 56th week of thymus development]]
'''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/>

2014 Group Project 6

2014-10-24T04:23:45Z

Z3418837: /* Thyroid */

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

{| 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'''

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/>

2014 Group Project 6

2014-10-24T03:35:39Z

Z3418837: /* Hypothalamus */

{{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===

'''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:Placenta accreta.jpg

2014-10-24T03:19:35Z

Z3418837: /* Placenta accreta */

==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}}

File:Placenta schematic.jpg

2014-10-24T03:18:55Z

Z3418837: /* Diagramatic representation of the human placenta */

==Diagramatic representation of the human placenta==
This image indicates the different components of the mature placenta; fetal placenta, decidua, chorionic villous, intervillous space and maternal spiral arteries that supply the fetus.

==Reference==
<pubmed>25071761</pubmed>

==Copyright==

© 2014 Faas, Spaans and De Vos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms

{{Template:Student Image}}

File:Cushing's syndrome.jpg

2014-10-24T03:18:15Z

Z3418837: /* Clinical manifestations of Cushing’s Syndrome */

==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}}

File:Annular pancreas.jpg

2014-10-24T03:17:38Z

Z3418837: /* Annular pancreas */

==Graphical illustration of Annular pancreas==
Figure 4: (a) Annular pancreas might be formed when the left ventral pancreatic anlage persists, and the right ventral pancreatic anlage does not rotate around the duodenum. The two ventral anlagen encircle the duodenum.

==Reference==

<pubmed>22567291</pubmed>

==Copyright==

Copyright © 2011 Hiroyuki Tadokoro et al. This is an open access article distributed under 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}}

File:Annular pancreas.jpg

2014-10-24T03:16:38Z

Z3418837:

==Annular pancreas==
Figure 4: (a) Annular pancreas might be formed when the left ventral pancreatic anlage persists, and the right ventral pancreatic anlage does not rotate around the duodenum. The two ventral anlagen encircle the duodenum.

==Reference==

<pubmed>22567291</pubmed>

==Copyright==

Copyright © 2011 Hiroyuki Tadokoro et al. This is an open access article distributed under 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}}

File:Ratio of alpha & beta cells at different phases of fetal development.png

2014-10-24T03:16:07Z

Z3418837: /* Ratio of alpha & beta cells at different phases of fetal development */

==Ratio of alpha and beta cells at different phases of fetal development==
'''Image shows the development of the islet of langerhans and the ratio of alpha & beta cells at different phases of fetal development.'''

FIGURE 4: Islet formation in the neonatal pancreas.
A: Increased ratio of alpha-cells to beta-cells in the neonatal pancreas. The difference was significant at all time points compared to the adult (8-mo) as a control. B: Frequency of alpha-, beta-, and exocrine-cell proliferation. Both alpha- and beta-cell proliferation at P1 was significantly increased compared to P21. C: Endocrine-cells coated with a layer of extracellular matrix (P1). Immunohistochemical staining for Insulin (green), glucagon (red) and collagen IV (yellow) is shown. Note that intra-islet blood vessels are also associated with the extracellular matrix. Scale bar is 50 µm. D: A fission model of islet formation in the neonatal pancreas. a. Endocrine cells proliferate contiguously, forming branching cord-like structures in the fetal and newborn pancreas. b. Islet formation in the neonatal pancreas may occur by fission of elongated structures composed of beta-cells and surrounding alpha-cells. The fission process appears to be random, producing islets of different size. c. Each islet is subsequently coated with a layer of extracellular matrix that stabilizes the structure. This process of islet formation may also result in small isolated clusters of pancreatic endocrine cells that persist even in the adult pancreas. d. Beta-cell mass expansion within an islet leads to an alpha-cell ratio of 5–10%.

==Reference==

<pubmed>19893748</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007739 PLos One]

==Copyright==

© 2009 Miller et al. 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}}

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 12:34, 11 October 2014 (EST) Please avoid using an ampersand in the file names. I have also added additional categories to your uploaded image, it is not part of the final assessment.

[[Category:Human]][[Category:Pancreas]][[Category:Endocrine]]

File:Ratio of alpha & beta cells at different phases of fetal development.png

2014-10-24T03:14:03Z

Z3418837:

==Ratio of alpha & beta cells at different phases of fetal development==
'''Image shows the development of the islet of langerhans and the ratio of alpha & beta cells at different phases of fetal development.'''

FIGURE 4: Islet formation in the neonatal pancreas.
A: Increased ratio of alpha-cells to beta-cells in the neonatal pancreas. The difference was significant at all time points compared to the adult (8-mo) as a control. B: Frequency of alpha-, beta-, and exocrine-cell proliferation. Both alpha- and beta-cell proliferation at P1 was significantly increased compared to P21. C: Endocrine-cells coated with a layer of extracellular matrix (P1). Immunohistochemical staining for Insulin (green), glucagon (red) and collagen IV (yellow) is shown. Note that intra-islet blood vessels are also associated with the extracellular matrix. Scale bar is 50 µm. D: A fission model of islet formation in the neonatal pancreas. a. Endocrine cells proliferate contiguously, forming branching cord-like structures in the fetal and newborn pancreas. b. Islet formation in the neonatal pancreas may occur by fission of elongated structures composed of beta-cells and surrounding alpha-cells. The fission process appears to be random, producing islets of different size. c. Each islet is subsequently coated with a layer of extracellular matrix that stabilizes the structure. This process of islet formation may also result in small isolated clusters of pancreatic endocrine cells that persist even in the adult pancreas. d. Beta-cell mass expansion within an islet leads to an alpha-cell ratio of 5–10%.

==Reference==

<pubmed>19893748</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007739 PLos One]

==Copyright==

© 2009 Miller et al. 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}}

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 12:34, 11 October 2014 (EST) Please avoid using an ampersand in the file names. I have also added additional categories to your uploaded image, it is not part of the final assessment.

[[Category:Human]][[Category:Pancreas]][[Category:Endocrine]]

File:Histopathology of the thymus with hyperplasia.jpg

2014-10-24T03:12:59Z

Z3418837:

==Histopathology of the thymus with hyperplasia==

This image shows the histopathology of the thymus with hyperplasia and thymoma.

(A) S1PL+/+ thymus: A broad thymic cortex is densely packed with thymic lymphocytes (lower panel) (B) S1PL−/− thymus: The hypoplastic cortex is very thin and hypocellular due to severe cortical lymphoid depletion and apoptosis. At higher magnification (lower panel) the remaining cells in the thymic cortex include vacuolated stromal/epithelial cells and smaller numbers of granulocytes, macrophages, lymphocytes, and apoptotic cells. In contrast, the markedly expanded and '''hypercellular thymic medulla of S1PL−/− mice contains numerous mature lymphocytes as well as vacuolated stromal/epithelial cells''', macrophages, and histiocytes (lower panel). (C) S1PLH/H thymus: The cortex contains minimally decreased numbers of lymphocytes while there is a minimal expansion of the medulla by increased numbers of lymphocytes (D) S1PLH/− thymus: Thinning of the thymic cortex is accompanied by mild expansion of the medulla due primarily to increased numbers of lymphocytes (lower panel). H&E stain.

==Reference==
<pubmed>19119317</pubmed>

==Copyright==
Copyright Vogel et al. 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}}

File:Development of the pancreas during fetal development.jpg

2014-10-24T03:12:41Z

Z3418837:

==Development of the pancreas during fetal development==

Figure 1.

Normal development of the pancreas. The ventral pancreatic anlage is initially paired, with the left lobe subsequently disappearing during development. The ventral pancreatic anlage fuses side by side with the dorsal anlage.

==Reference==

<pubmed>22567291</pubmed>

==Copyright==

Copyright © 2011 Hiroyuki Tadokoro et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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File:Thymic Epithelial Cell Development and Function.png

2014-10-24T03:11:56Z

Z3418837:

==Thymic Epithelial Cell Development and Function==

'''Image shows Thymic Epithelial Cell Development and Function in fetal period'''

FIGURE 4: Continued expression of Isl1 and Foxg1 in the ventral third pouch endoderm/thymus rudiment at E11.5.
Parasagittal sections of E11.5 embryos hybridized with Foxn1 (A, E), Nkx2-5 (B, F), Isl1 (C, G) and Foxg1 (D, H) probes. Ventral is on the left and anterior is up. Arrow heads in A–D indicate the third pouch. Scale bar represents 500 (A–D) and 100 µm (E–H).

==Reference==

<pubmed>22087235</pubmed>

==Copyright==

© 2011 Wei, Condie. 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}}

File:Active parathyroid hormone assay cartoon.png

2014-10-24T03:11:22Z

Z3418837:

==Active parathyroid hormone assay cartoon==

FIGURE 6: This figure shows the chemical structure of parathyroid hormone and how the hormone is activated (oxidised) Basic principles of the new assay system for detection of intact and real intact PTH in human samples.

==Reference===
<pubmed>22792251</pubmed>

==Copyright==

© 2012 Hocher et al. 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}}

File:Parathyroid position in mouse embryo.jpg

2014-10-24T03:10:31Z

Z3418837: /* Parathyroid position in mouse embryo */

==Parathyroid position in mouse embryo==

Figure 1. The position of the parathyroid glands are seen in the mouse embryo.

Mig12 expression analysis during embryonic development. (A) Whole mount in situ hybridization on E11.5 mouse embryo showing expression in the central nervous system and in the developing limbs (blue signal, a). Coronal and sagittal sections of E14.5 entire mouse embryos (white signal) (b). (B) Details of coronal (a, b, c, d, h) and sagittal (e, f, g, i) sections of E14.5 mouse embryos. Strong Mig12 expression (red signal) is observed in isthmal (a), pontine (a, b, e) and medulla oblongata (c) neuroepithelia, and it is maintained throughout the entire region of the spinal cord central canal (d). Expression is also observed in dorsal root ganglia (d). Mig12 transcript is detected in the telencephalon at the level of the ventricular zone (f). Signal is also present in other organs: in the perichondrium of the digits (g); in the thyroid (th) '''and parathyroid (pth) glands''' (h), and in the phallic part of the urogenital sinus (i). Abbreviations: CB, cerebellum; ccn, central canal neuroepithelium; drg, dorsal root ganglia; IS, isthmus; isn, isthmal neuroepithelium; M, medulla oblongata; mn, medulla oblongata neuroepithelium; P, pons; pc, perichondrium; pnn, pontine neuroepithelium; pth, parathyroid glands; SC, spinal cord; T, telencephalon; th, thyroid gland; us, urogenital sinus; vz, ventricular zone.

==Reference==

<pubmed>PMC385223</pubmed>

==Copyright==

© 2004 Berti et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

{{Template:Student Image}}

File:Parathyroid position in mouse embryo.jpg

2014-10-24T03:09:20Z

Z3418837:

==Parathyroid position in mouse embryo==

Figure 1. The position of the parathyroid glands are seen in the mouse embryo.

Mig12 expression analysis during embryonic development. (A) Whole mount in situ hybridization on E11.5 mouse embryo showing expression in the central nervous system and in the developing limbs (blue signal, a). Coronal and sagittal sections of E14.5 entire mouse embryos (white signal) (b). (B) Details of coronal (a, b, c, d, h) and sagittal (e, f, g, i) sections of E14.5 mouse embryos. Strong Mig12 expression (red signal) is observed in isthmal (a), pontine (a, b, e) and medulla oblongata (c) neuroepithelia, and it is maintained throughout the entire region of the spinal cord central canal (d). Expression is also observed in dorsal root ganglia (d). Mig12 transcript is detected in the telencephalon at the level of the ventricular zone (f). Signal is also present in other organs: in the perichondrium of the digits (g); in the thyroid (th) '''and parathyroid (pth) glands''' (h), and in the phallic part of the urogenital sinus (i). Abbreviations: CB, cerebellum; ccn, central canal neuroepithelium; drg, dorsal root ganglia; IS, isthmus; isn, isthmal neuroepithelium; M, medulla oblongata; mn, medulla oblongata neuroepithelium; P, pons; pc, perichondrium; pnn, pontine neuroepithelium; pth, parathyroid glands; SC, spinal cord; T, telencephalon; th, thyroid gland; us, urogenital sinus; vz, ventricular zone.

'''Reference'''

<pubmed>PMC385223</pubmed>

'''Copyright'''

© 2004 Berti et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

{{Template:Student Image}}

File:Anterior Pituitary Hormones.jpg

2014-10-24T03:06:46Z

Z3418837:

==Graphical illustration of gonadotrope and thyrotrope development==

This student-drawn diagram is adapted from a diagram found in the research report Gonadotrope and thyrotrope development in the human and mouse anterior pituitary gland published in the Developmental Biology journal. It illustrates the fetal timeline of anterior pituitary hormone precursor cells and synthesis. It shows that by week 14 there are Gonadotroph Secreting Unit (GSC) precursor cells for Luteinizing hormone (LH), follicle-stimulating hormone (FSH) and other GSU production which proliferate and are not fully differentiated. By week 19 the LH, FSH and thyroid-stimulating hormone (TSH) secreting cells exist independently and do not proliferate. The diagram also shows how these cells migrate within the anterior pituitary gland in a rostro-caudal fashion.

This image is adapted from:<ref name =Caroline Pope, Judy R. McNeilly, Shiona Coutts, Mike Millar, Richard A. Anderson, Alan S. McNeilly>Caroline Pope, Judy R. McNeilly, Shiona Coutts, Mike Millar, Richard A. Anderson, Alan S. McNeilly, 2006, "'Gonadotrope and thyrotrope development in the human and mouse anterior pituitary gland"', Developmental Biology: 297(1); 172-181, http://www.sciencedirect.com/science/article/pii/S0012160606007755></ref>

==References==
<references/>

==Copyright==

Beginning six months after publication, I z3414648 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

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File:ThyroidDevelopment.png

2014-10-24T02:58:25Z

Z3418837:

==Graphical representation of the endodermal and mesodermal contribution of the thyroid gland==
This image summarises the endodermal and mesodermal contribution to the development of the thyroid gland. The progenitor cells are from anterior endoderm and receives buds from left and right endodermal buds covered in mesoderm.

==References==
<pubmed>21364918</pubmed>

==Copyright==
Copyright: © 2011 Carre et al. 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}}

File:Pituitary Development.jpg

2014-10-24T02:55:51Z

Z3418837:

==Cartoon image of the human pituitary gland anatomy==

A cartoon image of the human pituitary gland anatomy showing the Anterior Pituitary (AP) and Posterior Pituitary (NP) separated by the Marginal Zone (MZ). The MZ is surrounded by dilated Rathke's remnant's cysts in orange and labelled RC on the H&E staining image.

==References==
<pubmed>19283075</pubmed>

==Copyright==
© 2009 Garcia-Lavandeira et al. 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}}

File:Development of hypothalamus.jpg

2014-10-24T02:50:24Z

Z3418837:

==Stages of hypothalamus development==

Stages of hypothalamus development: a) Week 6 b) Week 9 c) Week 18 d) Weeks 19-28

Image adapted from <ref name=Rizzot>K. Rizzot, ‘Organ recital in a dish’, Regenerative Medicine: 2011, 280, pp.44-46,
http://www.nature.com/nature/journal/v480/n7375/full/480044a.html</ref>

==References==
<references/>

==Copyright==
Beginning six months after publication, I z3418698 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}}

z3418698

File:Primary brain vesicles.jpg

2014-10-24T02:45:09Z

Z3418837:

== Graphical illustration of primary brain vesicles==

This image shows the primary brain vesicles on day 30 of embryonic development of CNS.

Adapted from <ref name= PMID10852851><pubmed>10852851</pubmed></ref>

==References==
<references/>

==Copyright ==
Beginning six months after publication, I z3418698 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}}

z3418698

File:Week 6 embryonic development of CNS.jpg

2014-10-24T02:43:04Z

Z3418837:

==Week 6 embryonic development of CNS and emergence of pineal evagination.==

This image shows the structural processes of the CNS that occur in Week 6.

This image is adapted from:<ref name=Pansky>B. Pansky, '''‘The Diencephalon, second vesicle’''' Review of Medical Embryology:2011, http://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-153-the-diencephalon-second-vesicle</ref>

==References==

<references/>

==Copyright==

Beginning six months after publication, I z3418698 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}}

z3418698

File:Week 11 fetal development of CNS.jpg

2014-10-24T02:42:57Z

Z3418837:

==Fetal development of the CNS during week 11==

This image shows the structural processes of the CNS that occur in Week 11.

This image is adapted from:<ref name=Pansky>B. Pansky, '''‘The Diencephalon, second vesicle’''' Review of Medical Embryology:2011, http://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-153-the-diencephalon-second-vesicle</ref>

==References==

<references/>

==Copyright==

Beginning six months after publication, I z3418698 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}}

z3418698

File:Week 11 fetal development of CNS.jpg

2014-10-24T02:38:25Z

Z3418837:

==Fetal development of the CNS during week 11==

This image shows the structural processes of the CNS that occur in Week 11.

This image is adapted from:<ref name=Pansky>B. Pansky, '''‘The Diencephalon, second vesicle’''' Review of Medical Embryology:201, http://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-153-the-diencephalon-second-vesicle</ref>

==References==

<references/>

==Copyright==

Beginning six months after publication, I z3418698 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}}

z3418698

File:Week 11 fetal development of CNS.jpg

2014-10-24T02:37:01Z

Z3418837:

==Fetal development of the CNS during week 11==

This image shows the structural processes of the CNS that occur in Week 11.

This image is adapted from:<ref name=Pansky>B. Pansky, '''‘The Diencephalon, second vesicle’''' Review of Medical Embryology:201, http://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-153-the-diencephalon-second-vesicle</ref>

<references/>

==References==

B. Pansky, '''‘The Diencephalon, second vesicle’''' Review of Medical Embryology:201, http://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-153-the-diencephalon-second-vesicle

==Copyright==

Beginning six months after publication, I z3418698 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}}

z3418698

2014 Group Project 6

2014-10-23T22:36:16Z

Z3418837: /* Thymus */

{{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'''

*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:Histopathology of the thymus with hyperplasia.jpg

2014-10-23T14:55:04Z

Z3418837: /* Reference */

Histopathology of Thymus.

This image shows the histopathology of the thymus with hyperplasia and thymoma.

(A) S1PL+/+ thymus: A broad thymic cortex is densely packed with thymic lymphocytes (lower panel) (B) S1PL−/− thymus: The hypoplastic cortex is very thin and hypocellular due to severe cortical lymphoid depletion and apoptosis. At higher magnification (lower panel) the remaining cells in the thymic cortex include vacuolated stromal/epithelial cells and smaller numbers of granulocytes, macrophages, lymphocytes, and apoptotic cells. In contrast, the markedly expanded and '''hypercellular thymic medulla of S1PL−/− mice contains numerous mature lymphocytes as well as vacuolated stromal/epithelial cells''', macrophages, and histiocytes (lower panel). (C) S1PLH/H thymus: The cortex contains minimally decreased numbers of lymphocytes while there is a minimal expansion of the medulla by increased numbers of lymphocytes (D) S1PLH/− thymus: Thinning of the thymic cortex is accompanied by mild expansion of the medulla due primarily to increased numbers of lymphocytes (lower panel). H&E stain.

==Reference==
<pubmed>19119317</pubmed>

==Copyright==
Copyright Vogel et al. 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}}

File:Histopathology of the thymus with hyperplasia.jpg

2014-10-23T14:44:19Z

Z3418837:

Histopathology of Thymus.

This image shows the histopathology of the thymus with hyperplasia and thymoma.

(A) S1PL+/+ thymus: A broad thymic cortex is densely packed with thymic lymphocytes (lower panel) (B) S1PL−/− thymus: The hypoplastic cortex is very thin and hypocellular due to severe cortical lymphoid depletion and apoptosis. At higher magnification (lower panel) the remaining cells in the thymic cortex include vacuolated stromal/epithelial cells and smaller numbers of granulocytes, macrophages, lymphocytes, and apoptotic cells. In contrast, the markedly expanded and '''hypercellular thymic medulla of S1PL−/− mice contains numerous mature lymphocytes as well as vacuolated stromal/epithelial cells''', macrophages, and histiocytes (lower panel). (C) S1PLH/H thymus: The cortex contains minimally decreased numbers of lymphocytes while there is a minimal expansion of the medulla by increased numbers of lymphocytes (D) S1PLH/− thymus: Thinning of the thymic cortex is accompanied by mild expansion of the medulla due primarily to increased numbers of lymphocytes (lower panel). H&E stain.

==Reference==
<pubmed>2606024</pubmed>
==Copyright==
Copyright Vogel et al. 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}}

File:Histopathology of the thymus with hyperplasia.jpg

2014-10-23T14:40:51Z

Z3418837:

2014 Group Project 6

2014-10-23T14:08:46Z

Z3418837: /* 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
|}

{| 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>

'''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'''

*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/>

2014 Group Project 6

2014-10-23T14:04:53Z

Z3418837: /* Introduction */

{{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 fetal vasopressin plays a role in the adaptation to stress caused by the birth process by redistribution of the foetal blood flow.

'''Timeline'''

[[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]]

'''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>

==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'''

*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/>

2014 Group Project 6

2014-10-23T09:01:29Z

Z3418837: /* 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===

'''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>

==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

2014-10-23T08:28:58Z

Z3418837: /* 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.[[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>

==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

2014-10-23T08:23:46Z

Z3418837: /* 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> [[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]]

*'''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>

==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

2014-10-23T08:19:12Z

Z3418837: /* 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> [[File:Cushing's syndrome.jpg|200px|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'''

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

2014-10-23T06:39:30Z

Z3418837: /* Recent Findings */

{{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>

==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

2014-10-23T06:30:42Z

Z3418837: /* Recent Findings */

{{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>

==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><pubmed>24757681</pubmed></ref>

=References=

<references/>

2014 Group Project 6

2014-10-23T06:21:07Z

Z3418837: /* 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 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>

==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/>