Embryology - User contributions [en-gb]

User:Z3416697

2014-11-04T12:13:59Z

Z3416697: /* Lab attendance week 12 */

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:45, 6 August 2014 (EST)
==lab attendance==
Lab 1
http://www.ncbi.nlm.nih.gov/pubmed

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

<pubmed>2508416</pubmed>

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==Lab Assessment 1==
===ARTICLE 1===
<pubmed>25071849</pubmed>

In Vitro Fertilization (IVF) is a popular method of Assisted Reproduction which allows for fertilization to occur under optimal conditions (which may not be achieved in those that are having trouble conceiving), with monitored hormone levels and calculated growth of the embryo so as to maximize implantation, and ideally, successful pregnancy. This research article endeavors to assess the different variables available in IVF to determine which method yields the most successful amount of pregnancies. The variables in question are whether the embryo should be fresh (within a hours of fertilization), or frozen-thawed (embryo frozen a few days after fertilization and thawed when the mother is ready to receive an embryo). Another variable considered is the developmental stage at which the embryo is implanted; some embryos are implanted at the cleavage stage (hours after fertilization) and others are implanted at the blastocyst stage (5 days after fertilization), this study also considered implants at the cleavage stage extended blastocyst stage however it did not clarify what this term means, and I was unable to find elsewhere what this means.

This study observed IVF cycles of 1891 women at the Wuhan Union Hospital between January and December of 2012. Of the 1891 women observed, 1150 had fresh embryo transfers and 741 had frozen thawed embryo transfers. Of the Fresh embryo transfers 993 were implanted at the cleavage stage (799 of them women were less than 35 years old and 194 were greater than or equal to 35 years old), and 157 were implanted at the blastocyst stage (131 were less than 35 years old, 26 greater than or equal to 35 years old). Of the 741 women with frozen thawed embryo transfers, 212 were implanted at the cleavage stage of embryonic development (159 women were less than 35 and 53 were greater than or equal to 35), 137 were implanted at the cleavage stage extended blastocyst stage (111 were less than 35, 26 were greater than or equal to 35) and 328 were implanted at the blastocyst stage (276 were less than 35, 52 were greater than or equal to 35). All of these women underwent traditional methods of IVF- that is they were initially treated with Gonadotropin Releasing Hormone to stimulate follicular development. When two or more follicles were greater than 18mm Human Chorionic Gonadotropin was injected to assist follicular maturation. 24-26 hours later the ova were collected (Ovum Pick Up/OPU) and 4-6 hours after OPU IVF or Intracytoplasmic Sperm Injection (ICSI) were performed on the ova. The embryos were assessed by morphology and rate of development and at day three they are transferred onto a blastocyst medium and cultured for 2-3 days until it forms a blastocyst. The blastocysts are socred according to the Gardner standard and usually 1-2 good embryos are implanted. The remaining viable embryos are cryopreserved via vitrification and may be used if the current IVF cycle is unsuccessful. The Estrogen and Progesterone levels are monitored and regulated throughout the process according to the characteristics of the patient. Clinical pregnancy was defined by the presence of a gestational sac with or without a heart beat 30 days after implantation.

From this experiment it was found that there was a greater amount of successful pregnancies in women less than 35 years old resulting from implantation of fresh embryos at the cleavage stage (52.7% success) as opposed to the blastocyst stage (35.88%). There was no statistically significant differences clinically between the two types of implantation [ie- multiple pregnancies, abortion or ectopic pregnancy]. There were also a significantly higher number of pregnancies in the cleavage stage [41.24%] vs the blastocyst stage [26.92%]. However, this was not that case for those whom has frozen-thawed embryo transfers, as there was generally a much greater success rate for pregnancy in those who had blastocyst stage transfers than those who had cleavage stage transfers. Furthermore, there is a significantly greater pregnancy rate between in fresh embryo transfers compared to frozen thawed embryo transfers at the cleavage stage. Overall, there was a greater incidence of clinical pregnancy resulting from fresh cleavage stage embryo transfers compared to any other type of transfer [ie fresh blastocyst stage, frozen thawed cleavage stage and frozen thawed blastocyst stage]. These researchers concluded that this type of implantation should be used under normal conditions, and other methods should only be considered if the mother is of compromised health (eg has Ovarian Hyper Stimulation Syndrome), in which case as fresh blastocyst stage embryo is used.

===ARTICLE 2===
<pubmed>25017405 </pubmed>
This article aimed to assess the success rate of clinical pregnancy of women at differing age groups whom have undergone assisted reproductive methods such as In-Vitro Fertilzation and Intracytoplasmic Sperm Injection. Based on previous literature it was expected that the success rate would decline as the woman ages, as typically the most successful IVF cycles are seen in women whom are 25-30 years old. Also based on natural conception rates, spontaneous conception rates begin to decrease around 31-35 years old, and women tend to have difficulty conceiving around the ages of 35-39. General fecundabilty (probability of released ovum becoming fertilized and resulting in a successful pregnancy in one menstrual cycle) tend t decrease as the woman reaches menopause (around the early fifties) and at 5-10 years prior to this (40-44 years old), half of the women have reduced reproductive capacity.

This study observed 2,900 women undergoing IVF at the KK Women and Children’s hospital, of which yielded 3,412 fresh IVF cycles. The women were classifies into sub groups based only on age [< 30 years; 30–35 years; 36–37 years; 38 years; 39 years; 40–44 years; and ≥ 45 years]. The IVF cycles were monitored and the average number of occytes, average duration of stimulation and fertilization rates were observed. Furthermore, the number of cycles until successful embryo transfer, clinically successfully pregnancy rates, miscarriage rates and multiple pregnancy rates were also reported.
In this study, most of the patients undergoing IVF were between the ages of 30-35 and 36-37, and the least amount of patients belonged to the ≥ 45 years group. Of these, it was found that there was a 15% miscarriage rate in those younger than 30 years old, but this figure doubled to 30% at the age of 38 and among women aged 40-44, the miscarriage rate was as high as 55%. Only half of the women aged greater than 45 reached embryo transfer, and of those, none proceeded to successful clinical pregnancy. Furthermore, compared to other age groups, these women had the lowest amount of oocytes collected and the lowest fertilization rate with only 50% of oocytes proceeding to fertilization, compared to 95% in women less than 30 years old. However, it was found that there was no differences in mean duration of ovarian stimulation prior to ovum collection based on age. Finally, it was found that there was a general decreasing trend of successful clinical pregnancies as age increased in women undergoing IVF, as the rate of live births was highest in women who were less than 30 years old. The occurence of multiple births was highest in this age group also.

Overall it was found that the age of the woman undoubtedly has an effect on the reproductive capacity of a woman undergoing IVF. The researchers hypothesized that the general decreased success of an aging woman may be due to decreasing ovarian reserve, poorer oocyte quality, lower embryo implantation rates, altered hormonal environment resulting in ovulatory dysfunction and uterine problems. Male factors were also considered to be causative.

--[[User:Z8600021|Mark Hill]] These papers are suitable for the assessment exercise and you have included an appropriate summary. (5/5)

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==Lab Assessment 2==
[[File:Mutation of Gene Wt1 Causes Aberrant Gonadal Development.jpeg|300px]]

Mutation of Gene Wt1 Causes Aberrant Gonadal Development<ref><pubmed>23497137 </pubmed>| [http://www.biomedcentral.com/1741-7007/11/22/figure/F1]</ref>

<references/>

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:08, 20 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] This is a relevant image. I have fixed a few formatting issues in the associated file information, don't include the .jpeg in the figure legend, see the image page history for changes. (5/5)

==Lab Attendance: LAB 2==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:56, 20 August 2014 (EST)
Forgot to do my attendance at the lab of week 3 given by guest Speakers Hayden Homer and Rob Gilchrist about meiosis, oocyte quality and various technologies in assisted reproduction

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==Lab Attendance week 4==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:39, 20 August 2014 (EST)

==Lab three Online Assessment==
Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 20:10, 26 August 2014 (EST)

--[[User:Z8600021|Mark Hill]]These 3 references meet the assessment requirement, it appears that you have just included the references without a description? Your description of genital differentiation is not quite accurate and should be clarified by the future Genital Development Lecture. (4/5)

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==Lab 4 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 27 August 2014 (EST)

==Lab 4 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:23, 2 September 2014 (EST)

<pubmed>25137413</pubmed>

Hepatocellular carcinoma and other degenerative liver diseases often result in hepatic dysfunction and ultimately organ failure. To avoid this otherwise fatal diagnosis, bio-artificial livers and hepatocyte transplantation provides some leg- room whilst waiting on a full-organ transplant. However liver transplants, much like many other organs, are often hard to come by and are usually sensitive to the immune response of the host. As a result, researchers are looking towards stem cells as an answer to this problem. Mesenchymal stem cells derived from the Wharton’s Jelly of the umbilical Chord are often chosen because they have been found to have a slightly higher multipotency and immunogenicity. The umbilical stem cells were selected because they are more primitive compared to other Mesenchymal stem cells and do not express the major histocompatibility complex class II antigens- a key determinant in illiciting an immune response form the host. However, hepatocyte like cells derived from stem cells are not clinically used because they do not express enough functional proteins and do not exhibit a full level of metabolic activity.

This study aimed to identify and observe the transcription factors involved in hepatocyte differentiation from Human umbilical cord Mesenchymal Stem Cells (HuMSCs), they were particularly interested in Hepatocyte Nuclear Factor 4-alpha (HNF-4alpha) which is believed to behave like a “master gene” in driving hepatocyte differentiation and maturation. This study continued to expose the differentiating HuMSCs to excess amounts of HNF-4alpha and hypothesized a significant improvement in the differentiation status of the hepatocyte-like cells, providing a basis for future clinical application of HuMSCs in the treatment and management of liver diseases.

The research initially confirmed that the HuMSCs are of low immunogenicity- a critical issue with organ transplantation. Once this was confirmed, they observed that there was an up-regulation of functional hepatic enzymes once the differentiating hepatocyte-like stem cells were exposed to HNF-4alpha. An important finding they discovered that the time at which the stem cells were exposed to HNF-4alpha were integral in ensuring correct hepatocyte differentiation. Ultimately they concluded that the differentiation of HuMSCs could be improved by exposure to high levels of HNF-4alpha at specific times in the development of hepatocyte-like stem cells, an important discovery for the progression of the therapeutic application of stem cells.

The three shunts which are present in fetal development but are closed postnatally are:

• ductus arteriosis → channel between the pulmonary artery and aorta in the fetus which bypasses the lungs to distribute oxygenated blood from the placenta derived from the mothers circulation.

• ductus venosus → shunts a portion of the left umbilical vein blood flow which would flow directly to the inferior vena cava- allows b=oxygenated blood to bypass the liver.

• foramen ovale → allows passageway of blood from left atrium to right atrium in the fetus.

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==Lab 5 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 3 September 2014 (EST)

==Lab 5 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:10, 16 September 2014 (EST)

Congenital Lobar emphysema (CLE) is a condition of the respiratory system which results in hyperinflation of one or more pulmonary lobes and is usually diagnosed postnatally, usually in the neonatal period- however there have been cases where CLE is not diagnosed until 10 years after birth. The clinical symptoms of CLE are often at birth as dyspnea, cyanosis and recurrent respiratory tract infections, as well as generalized neonatal respiratory distress and hyperinflation and hyperaeration of the pulmonary lobes- often seen as visible enlargements or imaged through CT. CLE is a rare disorder affecting only 1 in 20,000 to 30, 000 newborns, and appears to have a slight male predominance [3:1 male to female ratio], although the cause of this gender predilection is not fully understood.

The developmental causes of CLE are often as final result of a number of bronchopulmonary disturbances during development. These result from abnormal interactions between embryonic endodermal and mesodermal components of the lung which may result in abnormalities in airway or alveoli number and size, however the exact pathogenesis of CLE is not able to be determined in approximately half of cases. Another frequently observed cause of CLE is an obstruction of the developing airway, which creates a “ball valve” resulting in an uneven distribution of air- favoring greater airflow to the affected lobe during inspiration than is able to be cleared in expiration- resulting in air trapping. There may also be vascular abnormalities which produce compression, bronchial stenosis, bronchogenic cysts and congenital cytomegaloviral infections observed.

<pubmed>PMC2141574</pubmed>

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==Lab attendance week 8==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 17 September 2014 (EST)

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==Lab Report- week 8==

<pubmed>24753613</pubmed>

This paper aims to identify the correlation between differing levels of androgen exposure during the fetal period on testosterone production from Leydig cells during adulthood. A low level of adult testosterone production in men is related to an increased rate of aging, as well as cardiometabolic syndromes, pro-inflammatory changes, frailty and increased mortality. Due to the impending clinical significance of such study, coupled with the limited understanding of fetal programming of Leydig cells, these researchers endeavored to find the influences of fetal exposure to androgens on the production of testosterone later in life. This paper hypothesizes that fetal programming of Leydig pro-genitor cells by exposure to androgens has a direct correlation to androgen production during puberty and adulthood, and further hypothesized that exposure to lower levels of androgens may result in the development of testosterone- dependent disorders such as male infertility.

Based on murine models, it was found that Leydig cells (interstitial cells of the testis which do not develop until puberty) are present in the fetal period as pro-genitor, or ‘stem’ cells, and manipulation of the transcription factors involved in the production and regulation of these stem cells can affect the behavior of adult testosterone production, an example of such a transcription factor is COUP-TFII. To briefly outline the findings of this study, it was initially identified that adult Leydig cells were derived from stem cells which were under COUP-TF11 transcriptional control. Once this was established, the researchers identified that these stem cells possessed androgen receptors, and that experimental reduction of androgens to these stem cells in the fetal period resulted in a reduced stem cell population in adulthood and subsequently adult Leydig cell failure. Another component of this study was to identify possible mechanisms where there would naturally be decreased or aberrant androgen exposure in the fetal period and hypothesized that it may primarily be due to altered histone methylation (an epigenetic event) at the gene promoter for steroidogeneic acute regulatory protein (H3K27me3). Ultimately these studies were done in the hopes of understanding the causes and fetal influences of reduced testosterone production in humans, which can have an impact on the development of diseases such as testosterone-dependent cardio-metabolic disorders, and even mortality in humans.

'''Identify the embryonic layers and tissues that contribute to the development of teeth'''

* ''Odontobolasts'': These cells originate from the neural crest mesenchyme and differentiate under enamel epithelium influence. These cells have functions in dentiogenesis and secretes predentin which will ultimately calcify to dent.

*''Ameloblasts'': derived from the oral epithelium of the ectoderm- function to deposit tooth enamel after the initial production of dentin by odonotoblasts. Form the outer layer of tooth.

* ''Periodontal Ligament'': specialised connective tissue which develops from the dental sac of the tooth. Acts as an anchor for the tooth.

==lab Attendance WEEK 9==
==lab report week 9==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)
<pubmed>24741072</pubmed>

This paper endeavoured to provide an extensive overview of mammalian ovary development, drawing comparisons of human ovary development to that of sheep, mice and cattle. Whilst there are time differences between these mammalian species, it appears that structurally the development of the ovary is very similar provides a relevant model for human ovarian development. The ovary initially begins as a thickening of the coelomic epithelium on the medial aspect of the mesonephros. The mesonephros, which acts as a transient kidney in mammals, contributes to the tubules and cells in the ovary as it develops and regresses in females.

Primordial germ cells (PGCs) are an important key feature of ovigenesis. PGC’s, which originate from the endoderm of the yolk sac, migrate through the developing hindgut and along the dorsal mesentery and ultimately enter the developing gonads. This process occurs in days 7-11 in mouse, 17-21 in sheep and 18-31 in cattle. Once in the gonadal region, the PGC’s begin to proliferate. The KIT ligand plays an important role in germ cell proliferation and survival, as well as extracellular matrix proteins such as fibronectin. PGC’s being stem cells are multipotent in nature, and this is maintained by the expression of transcription factors such as OCT4, whose activity ceases at the initiation of meiosis in the ovary.

The ovarian role in sexual differentiation was often seen as the “less active” pathway, comparative to testis development in males. The process of gonadal sexual differentiation commences at day 12 of mice, 32 in sheep and 40 in cattle (still within the embryonic period of humans). Ovary and ovigerous cord formation, which is not dependent on the SRY gene, occurs at a relatively delayed time course and does not begin to emerge until day 40 of sheep. Upon sexual differentiation, there are at least 5 cell types recorded- ovarian surface epithelium, endothelial cells which form blood vessels, Mesenchymal cells, pre-granulosa cells and PGCs. Recent study also indicates that there are Gonadal Ridge Epithelial-Like (GREL) cells present at sexual differentiation which progress to form the genital ridge from the surface epithelium of the mesonephros. It was found that these GREL cells give rise to ovarian epithelium, and re involved in the initial establishment of germ-cell-pre-granulosa cell complexes. At this point, oogonia and pre-granulosa cells are distinct and are separated by remnants of smooth endoplasmic reticulum- indicative of steroid producing cells. Fetal sheep from as early as day 35 of gestation can produce hormones such as progesterone and androstenedione.

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==Lab attendance week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)

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==Lab assessment week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 00:56, 15 October 2014 (EST)
'''Group 1'''
This project is extremely well done. I found the overall layout of your work to be easy to read and succinct. It captured my attention throughout the entirety of the project and was engaging with the use of bullet points. I thought your use of diagrams was great in aiding the understanding of this topic, however I thought that more diagrams or pictures could be added in order to help the reader visualize exactly what’s going on. I thought that te developmental timeline was a great idea, however could benefit from some more images or diagrams to assist in understanding the developmental stages. I thought the historic findings sections was especially well done as it appears well researched and thoroughly informative. The abnormalities was also well done, however again could benefit from the addition of a few more diagrams.

I think that with the addition of more drawings needs to be some attention to detail when referencing and stating copyright. I’ve noticed that some pictures lack copyright and some don’t have a description, making it difficult to understand the context of the picture and to envisage how it relates to the content. Whilst this is mostly self explanatory- I think that because this is an informative piece it pays to spoon-feed us a bit. Also, your referencing could use a bit of a tidy, but that can easily be fixed before submission. I think that overall this has great potential to be a wonderful project and I look forward to seeing it at its completion!

'''Group 2'''
I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

'''Group 3'''
Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

'''Group 5'''
Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once.

I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

'''Group 6'''
Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

'''Group 7'''
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.
The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.
The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing.
Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

'''Group 8'''
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

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==Lab Attendance week 11==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:43, 15 October 2014 (EST)
<pubmed>23904336</pubmed>

==Lab attendance week 12==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:51, 22 October 2014 (EST)
<pubmed>25347858 </pubmed>

Stem cells usage in the fabrication of bioartificial organs is increasingly becoming a trending area of medical research due to its potential use as an alternative to live organ transplants, which have issues in donor scarcity and host rejection. This paper concerns the differentiation of induced pluripotent stem cells (iPSCs) to produce the phenotypes of lung epithelial cells, specifically the expression of Nkx2.1+lung/thyroid progenitor cells. A major issue regarding respiratory stem cell applications is that normal pulmonary function usually exists at very low oxygen tensions of 1-5%, whilst in-vitro differentiations of iPSC’s generally occur at room-air oxygen tension, which is about 20%. This study strives to identify the variances in stem cell quality when differentiation was carried out at oxygen tensions of 5% and 20% respectively. Briefly, this was done by testing the expression of Nkx2.1, a transcription factor which is involved in early lung development in the embryo and subsequently acts as a marker when determining the success of stem cell differentiation to lung tissue. Other transcription factors involved in early organogenesis such as Foxa2 and Sox17 were also tested.

To briefly outline the methods utilized in this study- pluripotent stem cells were obtained from mouse embryonic fibroblasts and were routinely maintained on an antibiotic inactivated basic murine stem cell medium. The oxygen tension differences were able to be created via a cell culture incubator. After the stem cells were cultured, they were generated into endodermal lung progenitors which utilized a step-wise differentiation protocol, performed at oxygen tensions of 5% and 20% respectively. The stem cell-derived lung progenitors were then left to mature for 10 days, and then tested by immunocytochemistry for differences in transcription factor expression based on the oxygen tensions they were exposed to.

Overall the results of the study found a positive result for stem cells exposed to lower oxygen tensions. It was observed that embryoid bodies (the first step in a differentiation protocol for pluripotent stem cells) were more efficiently formed at oxygen tensions of 5% compared to oxygen tensions of 20%. Furthermore, when comparing the inductions of the stem cells into the definitive endoderm it was found that there was a much higher level of the transcription factors involved in lung cell development at oxygen tensions of 5% compared to 20%. The transcription factors tested were Nkx2.1, Foxa2 and Sox17- all of which had elevated levels at a lower oxygen tension environment. Thus, we can conclude based on this study that stem cell differentiations are actually more effective at lower oxygen tensions- a result which is fortuitous when looking to develop stem cell cultures to be used in pulmonary environments, which naturally have lower oxygen tensions.

==Lab Attendance week 13==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 29 October 2014 (EST)

User:Z3416697

2014-11-02T12:52:06Z

Z3416697: /* Lab attendance week 12 */

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:45, 6 August 2014 (EST)
==lab attendance==
Lab 1
http://www.ncbi.nlm.nih.gov/pubmed

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

<pubmed>2508416</pubmed>

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==Lab Assessment 1==
===ARTICLE 1===
<pubmed>25071849</pubmed>

In Vitro Fertilization (IVF) is a popular method of Assisted Reproduction which allows for fertilization to occur under optimal conditions (which may not be achieved in those that are having trouble conceiving), with monitored hormone levels and calculated growth of the embryo so as to maximize implantation, and ideally, successful pregnancy. This research article endeavors to assess the different variables available in IVF to determine which method yields the most successful amount of pregnancies. The variables in question are whether the embryo should be fresh (within a hours of fertilization), or frozen-thawed (embryo frozen a few days after fertilization and thawed when the mother is ready to receive an embryo). Another variable considered is the developmental stage at which the embryo is implanted; some embryos are implanted at the cleavage stage (hours after fertilization) and others are implanted at the blastocyst stage (5 days after fertilization), this study also considered implants at the cleavage stage extended blastocyst stage however it did not clarify what this term means, and I was unable to find elsewhere what this means.

This study observed IVF cycles of 1891 women at the Wuhan Union Hospital between January and December of 2012. Of the 1891 women observed, 1150 had fresh embryo transfers and 741 had frozen thawed embryo transfers. Of the Fresh embryo transfers 993 were implanted at the cleavage stage (799 of them women were less than 35 years old and 194 were greater than or equal to 35 years old), and 157 were implanted at the blastocyst stage (131 were less than 35 years old, 26 greater than or equal to 35 years old). Of the 741 women with frozen thawed embryo transfers, 212 were implanted at the cleavage stage of embryonic development (159 women were less than 35 and 53 were greater than or equal to 35), 137 were implanted at the cleavage stage extended blastocyst stage (111 were less than 35, 26 were greater than or equal to 35) and 328 were implanted at the blastocyst stage (276 were less than 35, 52 were greater than or equal to 35). All of these women underwent traditional methods of IVF- that is they were initially treated with Gonadotropin Releasing Hormone to stimulate follicular development. When two or more follicles were greater than 18mm Human Chorionic Gonadotropin was injected to assist follicular maturation. 24-26 hours later the ova were collected (Ovum Pick Up/OPU) and 4-6 hours after OPU IVF or Intracytoplasmic Sperm Injection (ICSI) were performed on the ova. The embryos were assessed by morphology and rate of development and at day three they are transferred onto a blastocyst medium and cultured for 2-3 days until it forms a blastocyst. The blastocysts are socred according to the Gardner standard and usually 1-2 good embryos are implanted. The remaining viable embryos are cryopreserved via vitrification and may be used if the current IVF cycle is unsuccessful. The Estrogen and Progesterone levels are monitored and regulated throughout the process according to the characteristics of the patient. Clinical pregnancy was defined by the presence of a gestational sac with or without a heart beat 30 days after implantation.

From this experiment it was found that there was a greater amount of successful pregnancies in women less than 35 years old resulting from implantation of fresh embryos at the cleavage stage (52.7% success) as opposed to the blastocyst stage (35.88%). There was no statistically significant differences clinically between the two types of implantation [ie- multiple pregnancies, abortion or ectopic pregnancy]. There were also a significantly higher number of pregnancies in the cleavage stage [41.24%] vs the blastocyst stage [26.92%]. However, this was not that case for those whom has frozen-thawed embryo transfers, as there was generally a much greater success rate for pregnancy in those who had blastocyst stage transfers than those who had cleavage stage transfers. Furthermore, there is a significantly greater pregnancy rate between in fresh embryo transfers compared to frozen thawed embryo transfers at the cleavage stage. Overall, there was a greater incidence of clinical pregnancy resulting from fresh cleavage stage embryo transfers compared to any other type of transfer [ie fresh blastocyst stage, frozen thawed cleavage stage and frozen thawed blastocyst stage]. These researchers concluded that this type of implantation should be used under normal conditions, and other methods should only be considered if the mother is of compromised health (eg has Ovarian Hyper Stimulation Syndrome), in which case as fresh blastocyst stage embryo is used.

===ARTICLE 2===
<pubmed>25017405 </pubmed>
This article aimed to assess the success rate of clinical pregnancy of women at differing age groups whom have undergone assisted reproductive methods such as In-Vitro Fertilzation and Intracytoplasmic Sperm Injection. Based on previous literature it was expected that the success rate would decline as the woman ages, as typically the most successful IVF cycles are seen in women whom are 25-30 years old. Also based on natural conception rates, spontaneous conception rates begin to decrease around 31-35 years old, and women tend to have difficulty conceiving around the ages of 35-39. General fecundabilty (probability of released ovum becoming fertilized and resulting in a successful pregnancy in one menstrual cycle) tend t decrease as the woman reaches menopause (around the early fifties) and at 5-10 years prior to this (40-44 years old), half of the women have reduced reproductive capacity.

This study observed 2,900 women undergoing IVF at the KK Women and Children’s hospital, of which yielded 3,412 fresh IVF cycles. The women were classifies into sub groups based only on age [< 30 years; 30–35 years; 36–37 years; 38 years; 39 years; 40–44 years; and ≥ 45 years]. The IVF cycles were monitored and the average number of occytes, average duration of stimulation and fertilization rates were observed. Furthermore, the number of cycles until successful embryo transfer, clinically successfully pregnancy rates, miscarriage rates and multiple pregnancy rates were also reported.
In this study, most of the patients undergoing IVF were between the ages of 30-35 and 36-37, and the least amount of patients belonged to the ≥ 45 years group. Of these, it was found that there was a 15% miscarriage rate in those younger than 30 years old, but this figure doubled to 30% at the age of 38 and among women aged 40-44, the miscarriage rate was as high as 55%. Only half of the women aged greater than 45 reached embryo transfer, and of those, none proceeded to successful clinical pregnancy. Furthermore, compared to other age groups, these women had the lowest amount of oocytes collected and the lowest fertilization rate with only 50% of oocytes proceeding to fertilization, compared to 95% in women less than 30 years old. However, it was found that there was no differences in mean duration of ovarian stimulation prior to ovum collection based on age. Finally, it was found that there was a general decreasing trend of successful clinical pregnancies as age increased in women undergoing IVF, as the rate of live births was highest in women who were less than 30 years old. The occurence of multiple births was highest in this age group also.

Overall it was found that the age of the woman undoubtedly has an effect on the reproductive capacity of a woman undergoing IVF. The researchers hypothesized that the general decreased success of an aging woman may be due to decreasing ovarian reserve, poorer oocyte quality, lower embryo implantation rates, altered hormonal environment resulting in ovulatory dysfunction and uterine problems. Male factors were also considered to be causative.

--[[User:Z8600021|Mark Hill]] These papers are suitable for the assessment exercise and you have included an appropriate summary. (5/5)

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==Lab Assessment 2==
[[File:Mutation of Gene Wt1 Causes Aberrant Gonadal Development.jpeg|300px]]

Mutation of Gene Wt1 Causes Aberrant Gonadal Development<ref><pubmed>23497137 </pubmed>| [http://www.biomedcentral.com/1741-7007/11/22/figure/F1]</ref>

<references/>

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:08, 20 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] This is a relevant image. I have fixed a few formatting issues in the associated file information, don't include the .jpeg in the figure legend, see the image page history for changes. (5/5)

==Lab Attendance: LAB 2==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:56, 20 August 2014 (EST)
Forgot to do my attendance at the lab of week 3 given by guest Speakers Hayden Homer and Rob Gilchrist about meiosis, oocyte quality and various technologies in assisted reproduction

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==Lab Attendance week 4==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:39, 20 August 2014 (EST)

==Lab three Online Assessment==
Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 20:10, 26 August 2014 (EST)

--[[User:Z8600021|Mark Hill]]These 3 references meet the assessment requirement, it appears that you have just included the references without a description? Your description of genital differentiation is not quite accurate and should be clarified by the future Genital Development Lecture. (4/5)

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==Lab 4 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 27 August 2014 (EST)

==Lab 4 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:23, 2 September 2014 (EST)

<pubmed>25137413</pubmed>

Hepatocellular carcinoma and other degenerative liver diseases often result in hepatic dysfunction and ultimately organ failure. To avoid this otherwise fatal diagnosis, bio-artificial livers and hepatocyte transplantation provides some leg- room whilst waiting on a full-organ transplant. However liver transplants, much like many other organs, are often hard to come by and are usually sensitive to the immune response of the host. As a result, researchers are looking towards stem cells as an answer to this problem. Mesenchymal stem cells derived from the Wharton’s Jelly of the umbilical Chord are often chosen because they have been found to have a slightly higher multipotency and immunogenicity. The umbilical stem cells were selected because they are more primitive compared to other Mesenchymal stem cells and do not express the major histocompatibility complex class II antigens- a key determinant in illiciting an immune response form the host. However, hepatocyte like cells derived from stem cells are not clinically used because they do not express enough functional proteins and do not exhibit a full level of metabolic activity.

This study aimed to identify and observe the transcription factors involved in hepatocyte differentiation from Human umbilical cord Mesenchymal Stem Cells (HuMSCs), they were particularly interested in Hepatocyte Nuclear Factor 4-alpha (HNF-4alpha) which is believed to behave like a “master gene” in driving hepatocyte differentiation and maturation. This study continued to expose the differentiating HuMSCs to excess amounts of HNF-4alpha and hypothesized a significant improvement in the differentiation status of the hepatocyte-like cells, providing a basis for future clinical application of HuMSCs in the treatment and management of liver diseases.

The research initially confirmed that the HuMSCs are of low immunogenicity- a critical issue with organ transplantation. Once this was confirmed, they observed that there was an up-regulation of functional hepatic enzymes once the differentiating hepatocyte-like stem cells were exposed to HNF-4alpha. An important finding they discovered that the time at which the stem cells were exposed to HNF-4alpha were integral in ensuring correct hepatocyte differentiation. Ultimately they concluded that the differentiation of HuMSCs could be improved by exposure to high levels of HNF-4alpha at specific times in the development of hepatocyte-like stem cells, an important discovery for the progression of the therapeutic application of stem cells.

The three shunts which are present in fetal development but are closed postnatally are:

• ductus arteriosis → channel between the pulmonary artery and aorta in the fetus which bypasses the lungs to distribute oxygenated blood from the placenta derived from the mothers circulation.

• ductus venosus → shunts a portion of the left umbilical vein blood flow which would flow directly to the inferior vena cava- allows b=oxygenated blood to bypass the liver.

• foramen ovale → allows passageway of blood from left atrium to right atrium in the fetus.

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==Lab 5 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 3 September 2014 (EST)

==Lab 5 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:10, 16 September 2014 (EST)

Congenital Lobar emphysema (CLE) is a condition of the respiratory system which results in hyperinflation of one or more pulmonary lobes and is usually diagnosed postnatally, usually in the neonatal period- however there have been cases where CLE is not diagnosed until 10 years after birth. The clinical symptoms of CLE are often at birth as dyspnea, cyanosis and recurrent respiratory tract infections, as well as generalized neonatal respiratory distress and hyperinflation and hyperaeration of the pulmonary lobes- often seen as visible enlargements or imaged through CT. CLE is a rare disorder affecting only 1 in 20,000 to 30, 000 newborns, and appears to have a slight male predominance [3:1 male to female ratio], although the cause of this gender predilection is not fully understood.

The developmental causes of CLE are often as final result of a number of bronchopulmonary disturbances during development. These result from abnormal interactions between embryonic endodermal and mesodermal components of the lung which may result in abnormalities in airway or alveoli number and size, however the exact pathogenesis of CLE is not able to be determined in approximately half of cases. Another frequently observed cause of CLE is an obstruction of the developing airway, which creates a “ball valve” resulting in an uneven distribution of air- favoring greater airflow to the affected lobe during inspiration than is able to be cleared in expiration- resulting in air trapping. There may also be vascular abnormalities which produce compression, bronchial stenosis, bronchogenic cysts and congenital cytomegaloviral infections observed.

<pubmed>PMC2141574</pubmed>

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==Lab attendance week 8==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 17 September 2014 (EST)

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==Lab Report- week 8==

<pubmed>24753613</pubmed>

This paper aims to identify the correlation between differing levels of androgen exposure during the fetal period on testosterone production from Leydig cells during adulthood. A low level of adult testosterone production in men is related to an increased rate of aging, as well as cardiometabolic syndromes, pro-inflammatory changes, frailty and increased mortality. Due to the impending clinical significance of such study, coupled with the limited understanding of fetal programming of Leydig cells, these researchers endeavored to find the influences of fetal exposure to androgens on the production of testosterone later in life. This paper hypothesizes that fetal programming of Leydig pro-genitor cells by exposure to androgens has a direct correlation to androgen production during puberty and adulthood, and further hypothesized that exposure to lower levels of androgens may result in the development of testosterone- dependent disorders such as male infertility.

Based on murine models, it was found that Leydig cells (interstitial cells of the testis which do not develop until puberty) are present in the fetal period as pro-genitor, or ‘stem’ cells, and manipulation of the transcription factors involved in the production and regulation of these stem cells can affect the behavior of adult testosterone production, an example of such a transcription factor is COUP-TFII. To briefly outline the findings of this study, it was initially identified that adult Leydig cells were derived from stem cells which were under COUP-TF11 transcriptional control. Once this was established, the researchers identified that these stem cells possessed androgen receptors, and that experimental reduction of androgens to these stem cells in the fetal period resulted in a reduced stem cell population in adulthood and subsequently adult Leydig cell failure. Another component of this study was to identify possible mechanisms where there would naturally be decreased or aberrant androgen exposure in the fetal period and hypothesized that it may primarily be due to altered histone methylation (an epigenetic event) at the gene promoter for steroidogeneic acute regulatory protein (H3K27me3). Ultimately these studies were done in the hopes of understanding the causes and fetal influences of reduced testosterone production in humans, which can have an impact on the development of diseases such as testosterone-dependent cardio-metabolic disorders, and even mortality in humans.

'''Identify the embryonic layers and tissues that contribute to the development of teeth'''

* ''Odontobolasts'': These cells originate from the neural crest mesenchyme and differentiate under enamel epithelium influence. These cells have functions in dentiogenesis and secretes predentin which will ultimately calcify to dent.

*''Ameloblasts'': derived from the oral epithelium of the ectoderm- function to deposit tooth enamel after the initial production of dentin by odonotoblasts. Form the outer layer of tooth.

* ''Periodontal Ligament'': specialised connective tissue which develops from the dental sac of the tooth. Acts as an anchor for the tooth.

==lab Attendance WEEK 9==
==lab report week 9==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)
<pubmed>24741072</pubmed>

This paper endeavoured to provide an extensive overview of mammalian ovary development, drawing comparisons of human ovary development to that of sheep, mice and cattle. Whilst there are time differences between these mammalian species, it appears that structurally the development of the ovary is very similar provides a relevant model for human ovarian development. The ovary initially begins as a thickening of the coelomic epithelium on the medial aspect of the mesonephros. The mesonephros, which acts as a transient kidney in mammals, contributes to the tubules and cells in the ovary as it develops and regresses in females.

Primordial germ cells (PGCs) are an important key feature of ovigenesis. PGC’s, which originate from the endoderm of the yolk sac, migrate through the developing hindgut and along the dorsal mesentery and ultimately enter the developing gonads. This process occurs in days 7-11 in mouse, 17-21 in sheep and 18-31 in cattle. Once in the gonadal region, the PGC’s begin to proliferate. The KIT ligand plays an important role in germ cell proliferation and survival, as well as extracellular matrix proteins such as fibronectin. PGC’s being stem cells are multipotent in nature, and this is maintained by the expression of transcription factors such as OCT4, whose activity ceases at the initiation of meiosis in the ovary.

The ovarian role in sexual differentiation was often seen as the “less active” pathway, comparative to testis development in males. The process of gonadal sexual differentiation commences at day 12 of mice, 32 in sheep and 40 in cattle (still within the embryonic period of humans). Ovary and ovigerous cord formation, which is not dependent on the SRY gene, occurs at a relatively delayed time course and does not begin to emerge until day 40 of sheep. Upon sexual differentiation, there are at least 5 cell types recorded- ovarian surface epithelium, endothelial cells which form blood vessels, Mesenchymal cells, pre-granulosa cells and PGCs. Recent study also indicates that there are Gonadal Ridge Epithelial-Like (GREL) cells present at sexual differentiation which progress to form the genital ridge from the surface epithelium of the mesonephros. It was found that these GREL cells give rise to ovarian epithelium, and re involved in the initial establishment of germ-cell-pre-granulosa cell complexes. At this point, oogonia and pre-granulosa cells are distinct and are separated by remnants of smooth endoplasmic reticulum- indicative of steroid producing cells. Fetal sheep from as early as day 35 of gestation can produce hormones such as progesterone and androstenedione.

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==Lab attendance week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)

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==Lab assessment week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 00:56, 15 October 2014 (EST)
'''Group 1'''
This project is extremely well done. I found the overall layout of your work to be easy to read and succinct. It captured my attention throughout the entirety of the project and was engaging with the use of bullet points. I thought your use of diagrams was great in aiding the understanding of this topic, however I thought that more diagrams or pictures could be added in order to help the reader visualize exactly what’s going on. I thought that te developmental timeline was a great idea, however could benefit from some more images or diagrams to assist in understanding the developmental stages. I thought the historic findings sections was especially well done as it appears well researched and thoroughly informative. The abnormalities was also well done, however again could benefit from the addition of a few more diagrams.

I think that with the addition of more drawings needs to be some attention to detail when referencing and stating copyright. I’ve noticed that some pictures lack copyright and some don’t have a description, making it difficult to understand the context of the picture and to envisage how it relates to the content. Whilst this is mostly self explanatory- I think that because this is an informative piece it pays to spoon-feed us a bit. Also, your referencing could use a bit of a tidy, but that can easily be fixed before submission. I think that overall this has great potential to be a wonderful project and I look forward to seeing it at its completion!

'''Group 2'''
I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

'''Group 3'''
Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

'''Group 5'''
Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once.

I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

'''Group 6'''
Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

'''Group 7'''
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.
The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.
The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing.
Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

'''Group 8'''
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

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==Lab Attendance week 11==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:43, 15 October 2014 (EST)
<pubmed>23904336</pubmed>

==Lab attendance week 12==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:51, 22 October 2014 (EST)
<pubmed>25347858 </pubmed>

This paper was exploring the role that the oxygen tension of the atmospheric environment plays when creating lung/thyroid progenitor cells from Induced Pluripotent Stem Cells (iPSCs) and Embryonic Stem Cells (ESCs). Despite in vitro iPSC production occurring at room-air oxygen tensions of 20%, normal pulmonary development occurs at low oxygen tensions (around 1-5%). Lung bioengineering can have a multitude of applications medically, and tissue engineering has great curative and preventative potential and provides an alternative to whole organ transplants, which have issues with donor scarcity and host rejection. The multipotent nature of iPSCs, ie their ability to differentiate to many specific cell types within the organ, make iPSCs a suitable cell source for lung recellularization.

To briefly outline the methods undertaken by this study- pluripotency was induced into mouse embryonic fibroblasts and were maintained on a feeder layer of mitomycin-inactivated mouse embryonic fibroblasts in murine embryonic stem cell medium. These stem cells were maintained in oxygen tensions 20% and 5% CO2. Embryoid bodies were then forms and finally endodermal lung progenitors were generated from the pluripotent stem cells via a three step process – 1) induction of definitive endoderm, 2) anteriorization of endoder, and 3) generation of lung progenitors- which occurred at oxygen tensions of both 5% and 20%. The progenitors were then left to mature and were then analyzed to observe the discrepancies noted from differing oxygen tensions.

Ultimately, it was found that oxygen is involved in the generation of epithelial lung cell lineages from pluripotent stem cells. It was also found that Nkx2 and Foxa2, important transcription factors involved in the development of epithelial lung cells, are upregulated in low oxygen conditions. Despite this, lower oxygen tensions have been found to cause variety among stem cell lineages, and so it is integral to factor oxygen presence when developing stem cell lineages.

==Lab Attendance week 13==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 29 October 2014 (EST)

User:Z3416697

2014-11-02T11:52:46Z

Z3416697: /* lab report week 9 */

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:45, 6 August 2014 (EST)
==lab attendance==
Lab 1
http://www.ncbi.nlm.nih.gov/pubmed

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

<pubmed>2508416</pubmed>

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==Lab Assessment 1==
===ARTICLE 1===
<pubmed>25071849</pubmed>

In Vitro Fertilization (IVF) is a popular method of Assisted Reproduction which allows for fertilization to occur under optimal conditions (which may not be achieved in those that are having trouble conceiving), with monitored hormone levels and calculated growth of the embryo so as to maximize implantation, and ideally, successful pregnancy. This research article endeavors to assess the different variables available in IVF to determine which method yields the most successful amount of pregnancies. The variables in question are whether the embryo should be fresh (within a hours of fertilization), or frozen-thawed (embryo frozen a few days after fertilization and thawed when the mother is ready to receive an embryo). Another variable considered is the developmental stage at which the embryo is implanted; some embryos are implanted at the cleavage stage (hours after fertilization) and others are implanted at the blastocyst stage (5 days after fertilization), this study also considered implants at the cleavage stage extended blastocyst stage however it did not clarify what this term means, and I was unable to find elsewhere what this means.

This study observed IVF cycles of 1891 women at the Wuhan Union Hospital between January and December of 2012. Of the 1891 women observed, 1150 had fresh embryo transfers and 741 had frozen thawed embryo transfers. Of the Fresh embryo transfers 993 were implanted at the cleavage stage (799 of them women were less than 35 years old and 194 were greater than or equal to 35 years old), and 157 were implanted at the blastocyst stage (131 were less than 35 years old, 26 greater than or equal to 35 years old). Of the 741 women with frozen thawed embryo transfers, 212 were implanted at the cleavage stage of embryonic development (159 women were less than 35 and 53 were greater than or equal to 35), 137 were implanted at the cleavage stage extended blastocyst stage (111 were less than 35, 26 were greater than or equal to 35) and 328 were implanted at the blastocyst stage (276 were less than 35, 52 were greater than or equal to 35). All of these women underwent traditional methods of IVF- that is they were initially treated with Gonadotropin Releasing Hormone to stimulate follicular development. When two or more follicles were greater than 18mm Human Chorionic Gonadotropin was injected to assist follicular maturation. 24-26 hours later the ova were collected (Ovum Pick Up/OPU) and 4-6 hours after OPU IVF or Intracytoplasmic Sperm Injection (ICSI) were performed on the ova. The embryos were assessed by morphology and rate of development and at day three they are transferred onto a blastocyst medium and cultured for 2-3 days until it forms a blastocyst. The blastocysts are socred according to the Gardner standard and usually 1-2 good embryos are implanted. The remaining viable embryos are cryopreserved via vitrification and may be used if the current IVF cycle is unsuccessful. The Estrogen and Progesterone levels are monitored and regulated throughout the process according to the characteristics of the patient. Clinical pregnancy was defined by the presence of a gestational sac with or without a heart beat 30 days after implantation.

From this experiment it was found that there was a greater amount of successful pregnancies in women less than 35 years old resulting from implantation of fresh embryos at the cleavage stage (52.7% success) as opposed to the blastocyst stage (35.88%). There was no statistically significant differences clinically between the two types of implantation [ie- multiple pregnancies, abortion or ectopic pregnancy]. There were also a significantly higher number of pregnancies in the cleavage stage [41.24%] vs the blastocyst stage [26.92%]. However, this was not that case for those whom has frozen-thawed embryo transfers, as there was generally a much greater success rate for pregnancy in those who had blastocyst stage transfers than those who had cleavage stage transfers. Furthermore, there is a significantly greater pregnancy rate between in fresh embryo transfers compared to frozen thawed embryo transfers at the cleavage stage. Overall, there was a greater incidence of clinical pregnancy resulting from fresh cleavage stage embryo transfers compared to any other type of transfer [ie fresh blastocyst stage, frozen thawed cleavage stage and frozen thawed blastocyst stage]. These researchers concluded that this type of implantation should be used under normal conditions, and other methods should only be considered if the mother is of compromised health (eg has Ovarian Hyper Stimulation Syndrome), in which case as fresh blastocyst stage embryo is used.

===ARTICLE 2===
<pubmed>25017405 </pubmed>
This article aimed to assess the success rate of clinical pregnancy of women at differing age groups whom have undergone assisted reproductive methods such as In-Vitro Fertilzation and Intracytoplasmic Sperm Injection. Based on previous literature it was expected that the success rate would decline as the woman ages, as typically the most successful IVF cycles are seen in women whom are 25-30 years old. Also based on natural conception rates, spontaneous conception rates begin to decrease around 31-35 years old, and women tend to have difficulty conceiving around the ages of 35-39. General fecundabilty (probability of released ovum becoming fertilized and resulting in a successful pregnancy in one menstrual cycle) tend t decrease as the woman reaches menopause (around the early fifties) and at 5-10 years prior to this (40-44 years old), half of the women have reduced reproductive capacity.

This study observed 2,900 women undergoing IVF at the KK Women and Children’s hospital, of which yielded 3,412 fresh IVF cycles. The women were classifies into sub groups based only on age [< 30 years; 30–35 years; 36–37 years; 38 years; 39 years; 40–44 years; and ≥ 45 years]. The IVF cycles were monitored and the average number of occytes, average duration of stimulation and fertilization rates were observed. Furthermore, the number of cycles until successful embryo transfer, clinically successfully pregnancy rates, miscarriage rates and multiple pregnancy rates were also reported.
In this study, most of the patients undergoing IVF were between the ages of 30-35 and 36-37, and the least amount of patients belonged to the ≥ 45 years group. Of these, it was found that there was a 15% miscarriage rate in those younger than 30 years old, but this figure doubled to 30% at the age of 38 and among women aged 40-44, the miscarriage rate was as high as 55%. Only half of the women aged greater than 45 reached embryo transfer, and of those, none proceeded to successful clinical pregnancy. Furthermore, compared to other age groups, these women had the lowest amount of oocytes collected and the lowest fertilization rate with only 50% of oocytes proceeding to fertilization, compared to 95% in women less than 30 years old. However, it was found that there was no differences in mean duration of ovarian stimulation prior to ovum collection based on age. Finally, it was found that there was a general decreasing trend of successful clinical pregnancies as age increased in women undergoing IVF, as the rate of live births was highest in women who were less than 30 years old. The occurence of multiple births was highest in this age group also.

Overall it was found that the age of the woman undoubtedly has an effect on the reproductive capacity of a woman undergoing IVF. The researchers hypothesized that the general decreased success of an aging woman may be due to decreasing ovarian reserve, poorer oocyte quality, lower embryo implantation rates, altered hormonal environment resulting in ovulatory dysfunction and uterine problems. Male factors were also considered to be causative.

--[[User:Z8600021|Mark Hill]] These papers are suitable for the assessment exercise and you have included an appropriate summary. (5/5)

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==Lab Assessment 2==
[[File:Mutation of Gene Wt1 Causes Aberrant Gonadal Development.jpeg|300px]]

Mutation of Gene Wt1 Causes Aberrant Gonadal Development<ref><pubmed>23497137 </pubmed>| [http://www.biomedcentral.com/1741-7007/11/22/figure/F1]</ref>

<references/>

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:08, 20 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] This is a relevant image. I have fixed a few formatting issues in the associated file information, don't include the .jpeg in the figure legend, see the image page history for changes. (5/5)

==Lab Attendance: LAB 2==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:56, 20 August 2014 (EST)
Forgot to do my attendance at the lab of week 3 given by guest Speakers Hayden Homer and Rob Gilchrist about meiosis, oocyte quality and various technologies in assisted reproduction

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==Lab Attendance week 4==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:39, 20 August 2014 (EST)

==Lab three Online Assessment==
Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 20:10, 26 August 2014 (EST)

--[[User:Z8600021|Mark Hill]]These 3 references meet the assessment requirement, it appears that you have just included the references without a description? Your description of genital differentiation is not quite accurate and should be clarified by the future Genital Development Lecture. (4/5)

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==Lab 4 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 27 August 2014 (EST)

==Lab 4 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:23, 2 September 2014 (EST)

<pubmed>25137413</pubmed>

Hepatocellular carcinoma and other degenerative liver diseases often result in hepatic dysfunction and ultimately organ failure. To avoid this otherwise fatal diagnosis, bio-artificial livers and hepatocyte transplantation provides some leg- room whilst waiting on a full-organ transplant. However liver transplants, much like many other organs, are often hard to come by and are usually sensitive to the immune response of the host. As a result, researchers are looking towards stem cells as an answer to this problem. Mesenchymal stem cells derived from the Wharton’s Jelly of the umbilical Chord are often chosen because they have been found to have a slightly higher multipotency and immunogenicity. The umbilical stem cells were selected because they are more primitive compared to other Mesenchymal stem cells and do not express the major histocompatibility complex class II antigens- a key determinant in illiciting an immune response form the host. However, hepatocyte like cells derived from stem cells are not clinically used because they do not express enough functional proteins and do not exhibit a full level of metabolic activity.

This study aimed to identify and observe the transcription factors involved in hepatocyte differentiation from Human umbilical cord Mesenchymal Stem Cells (HuMSCs), they were particularly interested in Hepatocyte Nuclear Factor 4-alpha (HNF-4alpha) which is believed to behave like a “master gene” in driving hepatocyte differentiation and maturation. This study continued to expose the differentiating HuMSCs to excess amounts of HNF-4alpha and hypothesized a significant improvement in the differentiation status of the hepatocyte-like cells, providing a basis for future clinical application of HuMSCs in the treatment and management of liver diseases.

The research initially confirmed that the HuMSCs are of low immunogenicity- a critical issue with organ transplantation. Once this was confirmed, they observed that there was an up-regulation of functional hepatic enzymes once the differentiating hepatocyte-like stem cells were exposed to HNF-4alpha. An important finding they discovered that the time at which the stem cells were exposed to HNF-4alpha were integral in ensuring correct hepatocyte differentiation. Ultimately they concluded that the differentiation of HuMSCs could be improved by exposure to high levels of HNF-4alpha at specific times in the development of hepatocyte-like stem cells, an important discovery for the progression of the therapeutic application of stem cells.

The three shunts which are present in fetal development but are closed postnatally are:

• ductus arteriosis → channel between the pulmonary artery and aorta in the fetus which bypasses the lungs to distribute oxygenated blood from the placenta derived from the mothers circulation.

• ductus venosus → shunts a portion of the left umbilical vein blood flow which would flow directly to the inferior vena cava- allows b=oxygenated blood to bypass the liver.

• foramen ovale → allows passageway of blood from left atrium to right atrium in the fetus.

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==Lab 5 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 3 September 2014 (EST)

==Lab 5 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:10, 16 September 2014 (EST)

Congenital Lobar emphysema (CLE) is a condition of the respiratory system which results in hyperinflation of one or more pulmonary lobes and is usually diagnosed postnatally, usually in the neonatal period- however there have been cases where CLE is not diagnosed until 10 years after birth. The clinical symptoms of CLE are often at birth as dyspnea, cyanosis and recurrent respiratory tract infections, as well as generalized neonatal respiratory distress and hyperinflation and hyperaeration of the pulmonary lobes- often seen as visible enlargements or imaged through CT. CLE is a rare disorder affecting only 1 in 20,000 to 30, 000 newborns, and appears to have a slight male predominance [3:1 male to female ratio], although the cause of this gender predilection is not fully understood.

The developmental causes of CLE are often as final result of a number of bronchopulmonary disturbances during development. These result from abnormal interactions between embryonic endodermal and mesodermal components of the lung which may result in abnormalities in airway or alveoli number and size, however the exact pathogenesis of CLE is not able to be determined in approximately half of cases. Another frequently observed cause of CLE is an obstruction of the developing airway, which creates a “ball valve” resulting in an uneven distribution of air- favoring greater airflow to the affected lobe during inspiration than is able to be cleared in expiration- resulting in air trapping. There may also be vascular abnormalities which produce compression, bronchial stenosis, bronchogenic cysts and congenital cytomegaloviral infections observed.

<pubmed>PMC2141574</pubmed>

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==Lab attendance week 8==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 17 September 2014 (EST)

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==Lab Report- week 8==

<pubmed>24753613</pubmed>

This paper aims to identify the correlation between differing levels of androgen exposure during the fetal period on testosterone production from Leydig cells during adulthood. A low level of adult testosterone production in men is related to an increased rate of aging, as well as cardiometabolic syndromes, pro-inflammatory changes, frailty and increased mortality. Due to the impending clinical significance of such study, coupled with the limited understanding of fetal programming of Leydig cells, these researchers endeavored to find the influences of fetal exposure to androgens on the production of testosterone later in life. This paper hypothesizes that fetal programming of Leydig pro-genitor cells by exposure to androgens has a direct correlation to androgen production during puberty and adulthood, and further hypothesized that exposure to lower levels of androgens may result in the development of testosterone- dependent disorders such as male infertility.

Based on murine models, it was found that Leydig cells (interstitial cells of the testis which do not develop until puberty) are present in the fetal period as pro-genitor, or ‘stem’ cells, and manipulation of the transcription factors involved in the production and regulation of these stem cells can affect the behavior of adult testosterone production, an example of such a transcription factor is COUP-TFII. To briefly outline the findings of this study, it was initially identified that adult Leydig cells were derived from stem cells which were under COUP-TF11 transcriptional control. Once this was established, the researchers identified that these stem cells possessed androgen receptors, and that experimental reduction of androgens to these stem cells in the fetal period resulted in a reduced stem cell population in adulthood and subsequently adult Leydig cell failure. Another component of this study was to identify possible mechanisms where there would naturally be decreased or aberrant androgen exposure in the fetal period and hypothesized that it may primarily be due to altered histone methylation (an epigenetic event) at the gene promoter for steroidogeneic acute regulatory protein (H3K27me3). Ultimately these studies were done in the hopes of understanding the causes and fetal influences of reduced testosterone production in humans, which can have an impact on the development of diseases such as testosterone-dependent cardio-metabolic disorders, and even mortality in humans.

'''Identify the embryonic layers and tissues that contribute to the development of teeth'''

* ''Odontobolasts'': These cells originate from the neural crest mesenchyme and differentiate under enamel epithelium influence. These cells have functions in dentiogenesis and secretes predentin which will ultimately calcify to dent.

*''Ameloblasts'': derived from the oral epithelium of the ectoderm- function to deposit tooth enamel after the initial production of dentin by odonotoblasts. Form the outer layer of tooth.

* ''Periodontal Ligament'': specialised connective tissue which develops from the dental sac of the tooth. Acts as an anchor for the tooth.

==lab Attendance WEEK 9==
==lab report week 9==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)
<pubmed>24741072</pubmed>

This paper endeavoured to provide an extensive overview of mammalian ovary development, drawing comparisons of human ovary development to that of sheep, mice and cattle. Whilst there are time differences between these mammalian species, it appears that structurally the development of the ovary is very similar provides a relevant model for human ovarian development. The ovary initially begins as a thickening of the coelomic epithelium on the medial aspect of the mesonephros. The mesonephros, which acts as a transient kidney in mammals, contributes to the tubules and cells in the ovary as it develops and regresses in females.

Primordial germ cells (PGCs) are an important key feature of ovigenesis. PGC’s, which originate from the endoderm of the yolk sac, migrate through the developing hindgut and along the dorsal mesentery and ultimately enter the developing gonads. This process occurs in days 7-11 in mouse, 17-21 in sheep and 18-31 in cattle. Once in the gonadal region, the PGC’s begin to proliferate. The KIT ligand plays an important role in germ cell proliferation and survival, as well as extracellular matrix proteins such as fibronectin. PGC’s being stem cells are multipotent in nature, and this is maintained by the expression of transcription factors such as OCT4, whose activity ceases at the initiation of meiosis in the ovary.

The ovarian role in sexual differentiation was often seen as the “less active” pathway, comparative to testis development in males. The process of gonadal sexual differentiation commences at day 12 of mice, 32 in sheep and 40 in cattle (still within the embryonic period of humans). Ovary and ovigerous cord formation, which is not dependent on the SRY gene, occurs at a relatively delayed time course and does not begin to emerge until day 40 of sheep. Upon sexual differentiation, there are at least 5 cell types recorded- ovarian surface epithelium, endothelial cells which form blood vessels, Mesenchymal cells, pre-granulosa cells and PGCs. Recent study also indicates that there are Gonadal Ridge Epithelial-Like (GREL) cells present at sexual differentiation which progress to form the genital ridge from the surface epithelium of the mesonephros. It was found that these GREL cells give rise to ovarian epithelium, and re involved in the initial establishment of germ-cell-pre-granulosa cell complexes. At this point, oogonia and pre-granulosa cells are distinct and are separated by remnants of smooth endoplasmic reticulum- indicative of steroid producing cells. Fetal sheep from as early as day 35 of gestation can produce hormones such as progesterone and androstenedione.

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==Lab attendance week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)

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==Lab assessment week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 00:56, 15 October 2014 (EST)
'''Group 1'''
This project is extremely well done. I found the overall layout of your work to be easy to read and succinct. It captured my attention throughout the entirety of the project and was engaging with the use of bullet points. I thought your use of diagrams was great in aiding the understanding of this topic, however I thought that more diagrams or pictures could be added in order to help the reader visualize exactly what’s going on. I thought that te developmental timeline was a great idea, however could benefit from some more images or diagrams to assist in understanding the developmental stages. I thought the historic findings sections was especially well done as it appears well researched and thoroughly informative. The abnormalities was also well done, however again could benefit from the addition of a few more diagrams.

I think that with the addition of more drawings needs to be some attention to detail when referencing and stating copyright. I’ve noticed that some pictures lack copyright and some don’t have a description, making it difficult to understand the context of the picture and to envisage how it relates to the content. Whilst this is mostly self explanatory- I think that because this is an informative piece it pays to spoon-feed us a bit. Also, your referencing could use a bit of a tidy, but that can easily be fixed before submission. I think that overall this has great potential to be a wonderful project and I look forward to seeing it at its completion!

'''Group 2'''
I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

'''Group 3'''
Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

'''Group 5'''
Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once.

I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

'''Group 6'''
Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

'''Group 7'''
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.
The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.
The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing.
Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

'''Group 8'''
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

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==Lab Attendance week 11==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:43, 15 October 2014 (EST)
<pubmed>23904336</pubmed>

==Lab attendance week 12==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:51, 22 October 2014 (EST)
<pubmed>25345934 </pubmed>

==Lab Attendance week 13==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 29 October 2014 (EST)

User:Z3416697

2014-11-02T05:42:09Z

Z3416697:

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:45, 6 August 2014 (EST)
==lab attendance==
Lab 1
http://www.ncbi.nlm.nih.gov/pubmed

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

<pubmed>2508416</pubmed>

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==Lab Assessment 1==
===ARTICLE 1===
<pubmed>25071849</pubmed>

In Vitro Fertilization (IVF) is a popular method of Assisted Reproduction which allows for fertilization to occur under optimal conditions (which may not be achieved in those that are having trouble conceiving), with monitored hormone levels and calculated growth of the embryo so as to maximize implantation, and ideally, successful pregnancy. This research article endeavors to assess the different variables available in IVF to determine which method yields the most successful amount of pregnancies. The variables in question are whether the embryo should be fresh (within a hours of fertilization), or frozen-thawed (embryo frozen a few days after fertilization and thawed when the mother is ready to receive an embryo). Another variable considered is the developmental stage at which the embryo is implanted; some embryos are implanted at the cleavage stage (hours after fertilization) and others are implanted at the blastocyst stage (5 days after fertilization), this study also considered implants at the cleavage stage extended blastocyst stage however it did not clarify what this term means, and I was unable to find elsewhere what this means.

This study observed IVF cycles of 1891 women at the Wuhan Union Hospital between January and December of 2012. Of the 1891 women observed, 1150 had fresh embryo transfers and 741 had frozen thawed embryo transfers. Of the Fresh embryo transfers 993 were implanted at the cleavage stage (799 of them women were less than 35 years old and 194 were greater than or equal to 35 years old), and 157 were implanted at the blastocyst stage (131 were less than 35 years old, 26 greater than or equal to 35 years old). Of the 741 women with frozen thawed embryo transfers, 212 were implanted at the cleavage stage of embryonic development (159 women were less than 35 and 53 were greater than or equal to 35), 137 were implanted at the cleavage stage extended blastocyst stage (111 were less than 35, 26 were greater than or equal to 35) and 328 were implanted at the blastocyst stage (276 were less than 35, 52 were greater than or equal to 35). All of these women underwent traditional methods of IVF- that is they were initially treated with Gonadotropin Releasing Hormone to stimulate follicular development. When two or more follicles were greater than 18mm Human Chorionic Gonadotropin was injected to assist follicular maturation. 24-26 hours later the ova were collected (Ovum Pick Up/OPU) and 4-6 hours after OPU IVF or Intracytoplasmic Sperm Injection (ICSI) were performed on the ova. The embryos were assessed by morphology and rate of development and at day three they are transferred onto a blastocyst medium and cultured for 2-3 days until it forms a blastocyst. The blastocysts are socred according to the Gardner standard and usually 1-2 good embryos are implanted. The remaining viable embryos are cryopreserved via vitrification and may be used if the current IVF cycle is unsuccessful. The Estrogen and Progesterone levels are monitored and regulated throughout the process according to the characteristics of the patient. Clinical pregnancy was defined by the presence of a gestational sac with or without a heart beat 30 days after implantation.

From this experiment it was found that there was a greater amount of successful pregnancies in women less than 35 years old resulting from implantation of fresh embryos at the cleavage stage (52.7% success) as opposed to the blastocyst stage (35.88%). There was no statistically significant differences clinically between the two types of implantation [ie- multiple pregnancies, abortion or ectopic pregnancy]. There were also a significantly higher number of pregnancies in the cleavage stage [41.24%] vs the blastocyst stage [26.92%]. However, this was not that case for those whom has frozen-thawed embryo transfers, as there was generally a much greater success rate for pregnancy in those who had blastocyst stage transfers than those who had cleavage stage transfers. Furthermore, there is a significantly greater pregnancy rate between in fresh embryo transfers compared to frozen thawed embryo transfers at the cleavage stage. Overall, there was a greater incidence of clinical pregnancy resulting from fresh cleavage stage embryo transfers compared to any other type of transfer [ie fresh blastocyst stage, frozen thawed cleavage stage and frozen thawed blastocyst stage]. These researchers concluded that this type of implantation should be used under normal conditions, and other methods should only be considered if the mother is of compromised health (eg has Ovarian Hyper Stimulation Syndrome), in which case as fresh blastocyst stage embryo is used.

===ARTICLE 2===
<pubmed>25017405 </pubmed>
This article aimed to assess the success rate of clinical pregnancy of women at differing age groups whom have undergone assisted reproductive methods such as In-Vitro Fertilzation and Intracytoplasmic Sperm Injection. Based on previous literature it was expected that the success rate would decline as the woman ages, as typically the most successful IVF cycles are seen in women whom are 25-30 years old. Also based on natural conception rates, spontaneous conception rates begin to decrease around 31-35 years old, and women tend to have difficulty conceiving around the ages of 35-39. General fecundabilty (probability of released ovum becoming fertilized and resulting in a successful pregnancy in one menstrual cycle) tend t decrease as the woman reaches menopause (around the early fifties) and at 5-10 years prior to this (40-44 years old), half of the women have reduced reproductive capacity.

This study observed 2,900 women undergoing IVF at the KK Women and Children’s hospital, of which yielded 3,412 fresh IVF cycles. The women were classifies into sub groups based only on age [< 30 years; 30–35 years; 36–37 years; 38 years; 39 years; 40–44 years; and ≥ 45 years]. The IVF cycles were monitored and the average number of occytes, average duration of stimulation and fertilization rates were observed. Furthermore, the number of cycles until successful embryo transfer, clinically successfully pregnancy rates, miscarriage rates and multiple pregnancy rates were also reported.
In this study, most of the patients undergoing IVF were between the ages of 30-35 and 36-37, and the least amount of patients belonged to the ≥ 45 years group. Of these, it was found that there was a 15% miscarriage rate in those younger than 30 years old, but this figure doubled to 30% at the age of 38 and among women aged 40-44, the miscarriage rate was as high as 55%. Only half of the women aged greater than 45 reached embryo transfer, and of those, none proceeded to successful clinical pregnancy. Furthermore, compared to other age groups, these women had the lowest amount of oocytes collected and the lowest fertilization rate with only 50% of oocytes proceeding to fertilization, compared to 95% in women less than 30 years old. However, it was found that there was no differences in mean duration of ovarian stimulation prior to ovum collection based on age. Finally, it was found that there was a general decreasing trend of successful clinical pregnancies as age increased in women undergoing IVF, as the rate of live births was highest in women who were less than 30 years old. The occurence of multiple births was highest in this age group also.

Overall it was found that the age of the woman undoubtedly has an effect on the reproductive capacity of a woman undergoing IVF. The researchers hypothesized that the general decreased success of an aging woman may be due to decreasing ovarian reserve, poorer oocyte quality, lower embryo implantation rates, altered hormonal environment resulting in ovulatory dysfunction and uterine problems. Male factors were also considered to be causative.

--[[User:Z8600021|Mark Hill]] These papers are suitable for the assessment exercise and you have included an appropriate summary. (5/5)

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==Lab Assessment 2==
[[File:Mutation of Gene Wt1 Causes Aberrant Gonadal Development.jpeg|300px]]

Mutation of Gene Wt1 Causes Aberrant Gonadal Development<ref><pubmed>23497137 </pubmed>| [http://www.biomedcentral.com/1741-7007/11/22/figure/F1]</ref>

<references/>

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:08, 20 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] This is a relevant image. I have fixed a few formatting issues in the associated file information, don't include the .jpeg in the figure legend, see the image page history for changes. (5/5)

==Lab Attendance: LAB 2==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:56, 20 August 2014 (EST)
Forgot to do my attendance at the lab of week 3 given by guest Speakers Hayden Homer and Rob Gilchrist about meiosis, oocyte quality and various technologies in assisted reproduction

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==Lab Attendance week 4==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:39, 20 August 2014 (EST)

==Lab three Online Assessment==
Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 20:10, 26 August 2014 (EST)

--[[User:Z8600021|Mark Hill]]These 3 references meet the assessment requirement, it appears that you have just included the references without a description? Your description of genital differentiation is not quite accurate and should be clarified by the future Genital Development Lecture. (4/5)

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==Lab 4 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 27 August 2014 (EST)

==Lab 4 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:23, 2 September 2014 (EST)

<pubmed>25137413</pubmed>

Hepatocellular carcinoma and other degenerative liver diseases often result in hepatic dysfunction and ultimately organ failure. To avoid this otherwise fatal diagnosis, bio-artificial livers and hepatocyte transplantation provides some leg- room whilst waiting on a full-organ transplant. However liver transplants, much like many other organs, are often hard to come by and are usually sensitive to the immune response of the host. As a result, researchers are looking towards stem cells as an answer to this problem. Mesenchymal stem cells derived from the Wharton’s Jelly of the umbilical Chord are often chosen because they have been found to have a slightly higher multipotency and immunogenicity. The umbilical stem cells were selected because they are more primitive compared to other Mesenchymal stem cells and do not express the major histocompatibility complex class II antigens- a key determinant in illiciting an immune response form the host. However, hepatocyte like cells derived from stem cells are not clinically used because they do not express enough functional proteins and do not exhibit a full level of metabolic activity.

This study aimed to identify and observe the transcription factors involved in hepatocyte differentiation from Human umbilical cord Mesenchymal Stem Cells (HuMSCs), they were particularly interested in Hepatocyte Nuclear Factor 4-alpha (HNF-4alpha) which is believed to behave like a “master gene” in driving hepatocyte differentiation and maturation. This study continued to expose the differentiating HuMSCs to excess amounts of HNF-4alpha and hypothesized a significant improvement in the differentiation status of the hepatocyte-like cells, providing a basis for future clinical application of HuMSCs in the treatment and management of liver diseases.

The research initially confirmed that the HuMSCs are of low immunogenicity- a critical issue with organ transplantation. Once this was confirmed, they observed that there was an up-regulation of functional hepatic enzymes once the differentiating hepatocyte-like stem cells were exposed to HNF-4alpha. An important finding they discovered that the time at which the stem cells were exposed to HNF-4alpha were integral in ensuring correct hepatocyte differentiation. Ultimately they concluded that the differentiation of HuMSCs could be improved by exposure to high levels of HNF-4alpha at specific times in the development of hepatocyte-like stem cells, an important discovery for the progression of the therapeutic application of stem cells.

The three shunts which are present in fetal development but are closed postnatally are:

• ductus arteriosis → channel between the pulmonary artery and aorta in the fetus which bypasses the lungs to distribute oxygenated blood from the placenta derived from the mothers circulation.

• ductus venosus → shunts a portion of the left umbilical vein blood flow which would flow directly to the inferior vena cava- allows b=oxygenated blood to bypass the liver.

• foramen ovale → allows passageway of blood from left atrium to right atrium in the fetus.

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==Lab 5 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 3 September 2014 (EST)

==Lab 5 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:10, 16 September 2014 (EST)

Congenital Lobar emphysema (CLE) is a condition of the respiratory system which results in hyperinflation of one or more pulmonary lobes and is usually diagnosed postnatally, usually in the neonatal period- however there have been cases where CLE is not diagnosed until 10 years after birth. The clinical symptoms of CLE are often at birth as dyspnea, cyanosis and recurrent respiratory tract infections, as well as generalized neonatal respiratory distress and hyperinflation and hyperaeration of the pulmonary lobes- often seen as visible enlargements or imaged through CT. CLE is a rare disorder affecting only 1 in 20,000 to 30, 000 newborns, and appears to have a slight male predominance [3:1 male to female ratio], although the cause of this gender predilection is not fully understood.

The developmental causes of CLE are often as final result of a number of bronchopulmonary disturbances during development. These result from abnormal interactions between embryonic endodermal and mesodermal components of the lung which may result in abnormalities in airway or alveoli number and size, however the exact pathogenesis of CLE is not able to be determined in approximately half of cases. Another frequently observed cause of CLE is an obstruction of the developing airway, which creates a “ball valve” resulting in an uneven distribution of air- favoring greater airflow to the affected lobe during inspiration than is able to be cleared in expiration- resulting in air trapping. There may also be vascular abnormalities which produce compression, bronchial stenosis, bronchogenic cysts and congenital cytomegaloviral infections observed.

<pubmed>PMC2141574</pubmed>

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==Lab attendance week 8==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 17 September 2014 (EST)

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==Lab Report- week 8==

<pubmed>24753613</pubmed>

This paper aims to identify the correlation between differing levels of androgen exposure during the fetal period on testosterone production from Leydig cells during adulthood. A low level of adult testosterone production in men is related to an increased rate of aging, as well as cardiometabolic syndromes, pro-inflammatory changes, frailty and increased mortality. Due to the impending clinical significance of such study, coupled with the limited understanding of fetal programming of Leydig cells, these researchers endeavored to find the influences of fetal exposure to androgens on the production of testosterone later in life. This paper hypothesizes that fetal programming of Leydig pro-genitor cells by exposure to androgens has a direct correlation to androgen production during puberty and adulthood, and further hypothesized that exposure to lower levels of androgens may result in the development of testosterone- dependent disorders such as male infertility.

Based on murine models, it was found that Leydig cells (interstitial cells of the testis which do not develop until puberty) are present in the fetal period as pro-genitor, or ‘stem’ cells, and manipulation of the transcription factors involved in the production and regulation of these stem cells can affect the behavior of adult testosterone production, an example of such a transcription factor is COUP-TFII. To briefly outline the findings of this study, it was initially identified that adult Leydig cells were derived from stem cells which were under COUP-TF11 transcriptional control. Once this was established, the researchers identified that these stem cells possessed androgen receptors, and that experimental reduction of androgens to these stem cells in the fetal period resulted in a reduced stem cell population in adulthood and subsequently adult Leydig cell failure. Another component of this study was to identify possible mechanisms where there would naturally be decreased or aberrant androgen exposure in the fetal period and hypothesized that it may primarily be due to altered histone methylation (an epigenetic event) at the gene promoter for steroidogeneic acute regulatory protein (H3K27me3). Ultimately these studies were done in the hopes of understanding the causes and fetal influences of reduced testosterone production in humans, which can have an impact on the development of diseases such as testosterone-dependent cardio-metabolic disorders, and even mortality in humans.

'''Identify the embryonic layers and tissues that contribute to the development of teeth'''

* ''Odontobolasts'': These cells originate from the neural crest mesenchyme and differentiate under enamel epithelium influence. These cells have functions in dentiogenesis and secretes predentin which will ultimately calcify to dent.

*''Ameloblasts'': derived from the oral epithelium of the ectoderm- function to deposit tooth enamel after the initial production of dentin by odonotoblasts. Form the outer layer of tooth.

* ''Periodontal Ligament'': specialised connective tissue which develops from the dental sac of the tooth. Acts as an anchor for the tooth.

==lab Attendance WEEK 9==
==lab report week 9==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)
<pubmed>24741072</pubmed>
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==Lab attendance week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)

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==Lab assessment week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 00:56, 15 October 2014 (EST)
'''Group 1'''
This project is extremely well done. I found the overall layout of your work to be easy to read and succinct. It captured my attention throughout the entirety of the project and was engaging with the use of bullet points. I thought your use of diagrams was great in aiding the understanding of this topic, however I thought that more diagrams or pictures could be added in order to help the reader visualize exactly what’s going on. I thought that te developmental timeline was a great idea, however could benefit from some more images or diagrams to assist in understanding the developmental stages. I thought the historic findings sections was especially well done as it appears well researched and thoroughly informative. The abnormalities was also well done, however again could benefit from the addition of a few more diagrams.

I think that with the addition of more drawings needs to be some attention to detail when referencing and stating copyright. I’ve noticed that some pictures lack copyright and some don’t have a description, making it difficult to understand the context of the picture and to envisage how it relates to the content. Whilst this is mostly self explanatory- I think that because this is an informative piece it pays to spoon-feed us a bit. Also, your referencing could use a bit of a tidy, but that can easily be fixed before submission. I think that overall this has great potential to be a wonderful project and I look forward to seeing it at its completion!

'''Group 2'''
I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

'''Group 3'''
Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

'''Group 5'''
Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once.

I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

'''Group 6'''
Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

'''Group 7'''
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.
The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.
The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing.
Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

'''Group 8'''
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

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==Lab Attendance week 11==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:43, 15 October 2014 (EST)
<pubmed>23904336</pubmed>

==Lab attendance week 12==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:51, 22 October 2014 (EST)
<pubmed>25345934 </pubmed>

==Lab Attendance week 13==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 29 October 2014 (EST)

User:Z3416697

2014-11-02T05:12:10Z

Z3416697:

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:45, 6 August 2014 (EST)
==lab attendance==
Lab 1
http://www.ncbi.nlm.nih.gov/pubmed

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

<pubmed>2508416</pubmed>

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==Lab Assessment 1==
===ARTICLE 1===
<pubmed>25071849</pubmed>

In Vitro Fertilization (IVF) is a popular method of Assisted Reproduction which allows for fertilization to occur under optimal conditions (which may not be achieved in those that are having trouble conceiving), with monitored hormone levels and calculated growth of the embryo so as to maximize implantation, and ideally, successful pregnancy. This research article endeavors to assess the different variables available in IVF to determine which method yields the most successful amount of pregnancies. The variables in question are whether the embryo should be fresh (within a hours of fertilization), or frozen-thawed (embryo frozen a few days after fertilization and thawed when the mother is ready to receive an embryo). Another variable considered is the developmental stage at which the embryo is implanted; some embryos are implanted at the cleavage stage (hours after fertilization) and others are implanted at the blastocyst stage (5 days after fertilization), this study also considered implants at the cleavage stage extended blastocyst stage however it did not clarify what this term means, and I was unable to find elsewhere what this means.

This study observed IVF cycles of 1891 women at the Wuhan Union Hospital between January and December of 2012. Of the 1891 women observed, 1150 had fresh embryo transfers and 741 had frozen thawed embryo transfers. Of the Fresh embryo transfers 993 were implanted at the cleavage stage (799 of them women were less than 35 years old and 194 were greater than or equal to 35 years old), and 157 were implanted at the blastocyst stage (131 were less than 35 years old, 26 greater than or equal to 35 years old). Of the 741 women with frozen thawed embryo transfers, 212 were implanted at the cleavage stage of embryonic development (159 women were less than 35 and 53 were greater than or equal to 35), 137 were implanted at the cleavage stage extended blastocyst stage (111 were less than 35, 26 were greater than or equal to 35) and 328 were implanted at the blastocyst stage (276 were less than 35, 52 were greater than or equal to 35). All of these women underwent traditional methods of IVF- that is they were initially treated with Gonadotropin Releasing Hormone to stimulate follicular development. When two or more follicles were greater than 18mm Human Chorionic Gonadotropin was injected to assist follicular maturation. 24-26 hours later the ova were collected (Ovum Pick Up/OPU) and 4-6 hours after OPU IVF or Intracytoplasmic Sperm Injection (ICSI) were performed on the ova. The embryos were assessed by morphology and rate of development and at day three they are transferred onto a blastocyst medium and cultured for 2-3 days until it forms a blastocyst. The blastocysts are socred according to the Gardner standard and usually 1-2 good embryos are implanted. The remaining viable embryos are cryopreserved via vitrification and may be used if the current IVF cycle is unsuccessful. The Estrogen and Progesterone levels are monitored and regulated throughout the process according to the characteristics of the patient. Clinical pregnancy was defined by the presence of a gestational sac with or without a heart beat 30 days after implantation.

From this experiment it was found that there was a greater amount of successful pregnancies in women less than 35 years old resulting from implantation of fresh embryos at the cleavage stage (52.7% success) as opposed to the blastocyst stage (35.88%). There was no statistically significant differences clinically between the two types of implantation [ie- multiple pregnancies, abortion or ectopic pregnancy]. There were also a significantly higher number of pregnancies in the cleavage stage [41.24%] vs the blastocyst stage [26.92%]. However, this was not that case for those whom has frozen-thawed embryo transfers, as there was generally a much greater success rate for pregnancy in those who had blastocyst stage transfers than those who had cleavage stage transfers. Furthermore, there is a significantly greater pregnancy rate between in fresh embryo transfers compared to frozen thawed embryo transfers at the cleavage stage. Overall, there was a greater incidence of clinical pregnancy resulting from fresh cleavage stage embryo transfers compared to any other type of transfer [ie fresh blastocyst stage, frozen thawed cleavage stage and frozen thawed blastocyst stage]. These researchers concluded that this type of implantation should be used under normal conditions, and other methods should only be considered if the mother is of compromised health (eg has Ovarian Hyper Stimulation Syndrome), in which case as fresh blastocyst stage embryo is used.

===ARTICLE 2===
<pubmed>25017405 </pubmed>
This article aimed to assess the success rate of clinical pregnancy of women at differing age groups whom have undergone assisted reproductive methods such as In-Vitro Fertilzation and Intracytoplasmic Sperm Injection. Based on previous literature it was expected that the success rate would decline as the woman ages, as typically the most successful IVF cycles are seen in women whom are 25-30 years old. Also based on natural conception rates, spontaneous conception rates begin to decrease around 31-35 years old, and women tend to have difficulty conceiving around the ages of 35-39. General fecundabilty (probability of released ovum becoming fertilized and resulting in a successful pregnancy in one menstrual cycle) tend t decrease as the woman reaches menopause (around the early fifties) and at 5-10 years prior to this (40-44 years old), half of the women have reduced reproductive capacity.

This study observed 2,900 women undergoing IVF at the KK Women and Children’s hospital, of which yielded 3,412 fresh IVF cycles. The women were classifies into sub groups based only on age [< 30 years; 30–35 years; 36–37 years; 38 years; 39 years; 40–44 years; and ≥ 45 years]. The IVF cycles were monitored and the average number of occytes, average duration of stimulation and fertilization rates were observed. Furthermore, the number of cycles until successful embryo transfer, clinically successfully pregnancy rates, miscarriage rates and multiple pregnancy rates were also reported.
In this study, most of the patients undergoing IVF were between the ages of 30-35 and 36-37, and the least amount of patients belonged to the ≥ 45 years group. Of these, it was found that there was a 15% miscarriage rate in those younger than 30 years old, but this figure doubled to 30% at the age of 38 and among women aged 40-44, the miscarriage rate was as high as 55%. Only half of the women aged greater than 45 reached embryo transfer, and of those, none proceeded to successful clinical pregnancy. Furthermore, compared to other age groups, these women had the lowest amount of oocytes collected and the lowest fertilization rate with only 50% of oocytes proceeding to fertilization, compared to 95% in women less than 30 years old. However, it was found that there was no differences in mean duration of ovarian stimulation prior to ovum collection based on age. Finally, it was found that there was a general decreasing trend of successful clinical pregnancies as age increased in women undergoing IVF, as the rate of live births was highest in women who were less than 30 years old. The occurence of multiple births was highest in this age group also.

Overall it was found that the age of the woman undoubtedly has an effect on the reproductive capacity of a woman undergoing IVF. The researchers hypothesized that the general decreased success of an aging woman may be due to decreasing ovarian reserve, poorer oocyte quality, lower embryo implantation rates, altered hormonal environment resulting in ovulatory dysfunction and uterine problems. Male factors were also considered to be causative.

--[[User:Z8600021|Mark Hill]] These papers are suitable for the assessment exercise and you have included an appropriate summary. (5/5)

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==Lab Assessment 2==
[[File:Mutation of Gene Wt1 Causes Aberrant Gonadal Development.jpeg|300px]]

Mutation of Gene Wt1 Causes Aberrant Gonadal Development<ref><pubmed>23497137 </pubmed>| [http://www.biomedcentral.com/1741-7007/11/22/figure/F1]</ref>

<references/>

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:08, 20 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] This is a relevant image. I have fixed a few formatting issues in the associated file information, don't include the .jpeg in the figure legend, see the image page history for changes. (5/5)

==Lab Attendance: LAB 2==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:56, 20 August 2014 (EST)
Forgot to do my attendance at the lab of week 3 given by guest Speakers Hayden Homer and Rob Gilchrist about meiosis, oocyte quality and various technologies in assisted reproduction

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==Lab Attendance week 4==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:39, 20 August 2014 (EST)

==Lab three Online Assessment==
Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 20:10, 26 August 2014 (EST)

--[[User:Z8600021|Mark Hill]]These 3 references meet the assessment requirement, it appears that you have just included the references without a description? Your description of genital differentiation is not quite accurate and should be clarified by the future Genital Development Lecture. (4/5)

----

==Lab 4 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 27 August 2014 (EST)

==Lab 4 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:23, 2 September 2014 (EST)

<pubmed>25137413</pubmed>

Hepatocellular carcinoma and other degenerative liver diseases often result in hepatic dysfunction and ultimately organ failure. To avoid this otherwise fatal diagnosis, bio-artificial livers and hepatocyte transplantation provides some leg- room whilst waiting on a full-organ transplant. However liver transplants, much like many other organs, are often hard to come by and are usually sensitive to the immune response of the host. As a result, researchers are looking towards stem cells as an answer to this problem. Mesenchymal stem cells derived from the Wharton’s Jelly of the umbilical Chord are often chosen because they have been found to have a slightly higher multipotency and immunogenicity. The umbilical stem cells were selected because they are more primitive compared to other Mesenchymal stem cells and do not express the major histocompatibility complex class II antigens- a key determinant in illiciting an immune response form the host. However, hepatocyte like cells derived from stem cells are not clinically used because they do not express enough functional proteins and do not exhibit a full level of metabolic activity.

This study aimed to identify and observe the transcription factors involved in hepatocyte differentiation from Human umbilical cord Mesenchymal Stem Cells (HuMSCs), they were particularly interested in Hepatocyte Nuclear Factor 4-alpha (HNF-4alpha) which is believed to behave like a “master gene” in driving hepatocyte differentiation and maturation. This study continued to expose the differentiating HuMSCs to excess amounts of HNF-4alpha and hypothesized a significant improvement in the differentiation status of the hepatocyte-like cells, providing a basis for future clinical application of HuMSCs in the treatment and management of liver diseases.

The research initially confirmed that the HuMSCs are of low immunogenicity- a critical issue with organ transplantation. Once this was confirmed, they observed that there was an up-regulation of functional hepatic enzymes once the differentiating hepatocyte-like stem cells were exposed to HNF-4alpha. An important finding they discovered that the time at which the stem cells were exposed to HNF-4alpha were integral in ensuring correct hepatocyte differentiation. Ultimately they concluded that the differentiation of HuMSCs could be improved by exposure to high levels of HNF-4alpha at specific times in the development of hepatocyte-like stem cells, an important discovery for the progression of the therapeutic application of stem cells.

The three shunts which are present in fetal development but are closed postnatally are:

• ductus arteriosis → channel between the pulmonary artery and aorta in the fetus which bypasses the lungs to distribute oxygenated blood from the placenta derived from the mothers circulation.

• ductus venosus → shunts a portion of the left umbilical vein blood flow which would flow directly to the inferior vena cava- allows b=oxygenated blood to bypass the liver.

• foramen ovale → allows passageway of blood from left atrium to right atrium in the fetus.

----

==Lab 5 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 3 September 2014 (EST)

==Lab 5 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:10, 16 September 2014 (EST)

Congenital Lobar emphysema (CLE) is a condition of the respiratory system which results in hyperinflation of one or more pulmonary lobes and is usually diagnosed postnatally, usually in the neonatal period- however there have been cases where CLE is not diagnosed until 10 years after birth. The clinical symptoms of CLE are often at birth as dyspnea, cyanosis and recurrent respiratory tract infections, as well as generalized neonatal respiratory distress and hyperinflation and hyperaeration of the pulmonary lobes- often seen as visible enlargements or imaged through CT. CLE is a rare disorder affecting only 1 in 20,000 to 30, 000 newborns, and appears to have a slight male predominance [3:1 male to female ratio], although the cause of this gender predilection is not fully understood.

The developmental causes of CLE are often as final result of a number of bronchopulmonary disturbances during development. These result from abnormal interactions between embryonic endodermal and mesodermal components of the lung which may result in abnormalities in airway or alveoli number and size, however the exact pathogenesis of CLE is not able to be determined in approximately half of cases. Another frequently observed cause of CLE is an obstruction of the developing airway, which creates a “ball valve” resulting in an uneven distribution of air- favoring greater airflow to the affected lobe during inspiration than is able to be cleared in expiration- resulting in air trapping. There may also be vascular abnormalities which produce compression, bronchial stenosis, bronchogenic cysts and congenital cytomegaloviral infections observed.

<pubmed>PMC2141574</pubmed>

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==Lab attendance week 8==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 17 September 2014 (EST)

----

==Lab Report- week 8==

<pubmed>24753613</pubmed>

This paper aims to identify the correlation between differing levels of androgen exposure during the fetal period on testosterone production from Leydig cells during adulthood. A low level of adult testosterone production in men is related to an increased rate of aging, as well as cardiometabolic syndromes, pro-inflammatory changes, frailty and increased mortality. Due to the impending clinical significance of such study, coupled with the limited understanding of fetal programming of Leydig cells, these researchers endeavored to find the influences of fetal exposure to androgens on the production of testosterone later in life. This paper hypothesizes that fetal programming of Leydig pro-genitor cells by exposure to androgens has a direct correlation to androgen production during puberty and adulthood, and further hypothesized that exposure to lower levels of androgens may result in the development of testosterone- dependent disorders such as male infertility.

Based on murine models, it was found that Leydig cells (interstitial cells of the testis which do not develop until puberty) are present in the fetal period as pro-genitor, or ‘stem’ cells, and manipulation of the transcription factors involved in the production and regulation of these stem cells can affect the behavior of adult testosterone production, an example of such a transcription factor is COUP-TFII. To briefly outline the findings of this study, it was initially identified that adult Leydig cells were derived from stem cells which were under COUP-TF11 transcriptional control. Once this was established, the researchers identified that these stem cells possessed androgen receptors, and that experimental reduction of androgens to these stem cells in the fetal period resulted in a reduced stem cell population in adulthood and subsequently adult Leydig cell failure. Another component of this study was to identify possible mechanisms where there would naturally be decreased or aberrant androgen exposure in the fetal period and hypothesized that it may primarily be due to altered histone methylation (an epigenetic event) at the gene promoter for steroidogeneic acute regulatory protein (H3K27me3). Ultimately these studies were done in the hopes of understanding the causes and fetal influences of reduced testosterone production in humans, which can have an impact on the development of diseases such as testosterone-dependent cardio-metabolic disorders, and even mortality in humans.

==lab Attendance WEEK 9==
==lab report week 9==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)
<pubmed>24741072</pubmed>
----

==Lab attendance week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)

----

==Lab assessment week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 00:56, 15 October 2014 (EST)
'''Group 1'''
This project is extremely well done. I found the overall layout of your work to be easy to read and succinct. It captured my attention throughout the entirety of the project and was engaging with the use of bullet points. I thought your use of diagrams was great in aiding the understanding of this topic, however I thought that more diagrams or pictures could be added in order to help the reader visualize exactly what’s going on. I thought that te developmental timeline was a great idea, however could benefit from some more images or diagrams to assist in understanding the developmental stages. I thought the historic findings sections was especially well done as it appears well researched and thoroughly informative. The abnormalities was also well done, however again could benefit from the addition of a few more diagrams.

I think that with the addition of more drawings needs to be some attention to detail when referencing and stating copyright. I’ve noticed that some pictures lack copyright and some don’t have a description, making it difficult to understand the context of the picture and to envisage how it relates to the content. Whilst this is mostly self explanatory- I think that because this is an informative piece it pays to spoon-feed us a bit. Also, your referencing could use a bit of a tidy, but that can easily be fixed before submission. I think that overall this has great potential to be a wonderful project and I look forward to seeing it at its completion!

'''Group 2'''
I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

'''Group 3'''
Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

'''Group 5'''
Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once.

I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

'''Group 6'''
Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

'''Group 7'''
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.
The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.
The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing.
Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

'''Group 8'''
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

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==Lab Attendance week 11==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:43, 15 October 2014 (EST)
<pubmed>23904336</pubmed>

==Lab attendance week 12==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:51, 22 October 2014 (EST)
<pubmed>25345934 </pubmed>

==Lab Attendance week 13==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 29 October 2014 (EST)

User:Z3416697

2014-11-01T10:21:12Z

Z3416697:

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:45, 6 August 2014 (EST)
==lab attendance==
Lab 1
http://www.ncbi.nlm.nih.gov/pubmed

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

<pubmed>2508416</pubmed>

----

==Lab Assessment 1==
===ARTICLE 1===
<pubmed>25071849</pubmed>

In Vitro Fertilization (IVF) is a popular method of Assisted Reproduction which allows for fertilization to occur under optimal conditions (which may not be achieved in those that are having trouble conceiving), with monitored hormone levels and calculated growth of the embryo so as to maximize implantation, and ideally, successful pregnancy. This research article endeavors to assess the different variables available in IVF to determine which method yields the most successful amount of pregnancies. The variables in question are whether the embryo should be fresh (within a hours of fertilization), or frozen-thawed (embryo frozen a few days after fertilization and thawed when the mother is ready to receive an embryo). Another variable considered is the developmental stage at which the embryo is implanted; some embryos are implanted at the cleavage stage (hours after fertilization) and others are implanted at the blastocyst stage (5 days after fertilization), this study also considered implants at the cleavage stage extended blastocyst stage however it did not clarify what this term means, and I was unable to find elsewhere what this means.

This study observed IVF cycles of 1891 women at the Wuhan Union Hospital between January and December of 2012. Of the 1891 women observed, 1150 had fresh embryo transfers and 741 had frozen thawed embryo transfers. Of the Fresh embryo transfers 993 were implanted at the cleavage stage (799 of them women were less than 35 years old and 194 were greater than or equal to 35 years old), and 157 were implanted at the blastocyst stage (131 were less than 35 years old, 26 greater than or equal to 35 years old). Of the 741 women with frozen thawed embryo transfers, 212 were implanted at the cleavage stage of embryonic development (159 women were less than 35 and 53 were greater than or equal to 35), 137 were implanted at the cleavage stage extended blastocyst stage (111 were less than 35, 26 were greater than or equal to 35) and 328 were implanted at the blastocyst stage (276 were less than 35, 52 were greater than or equal to 35). All of these women underwent traditional methods of IVF- that is they were initially treated with Gonadotropin Releasing Hormone to stimulate follicular development. When two or more follicles were greater than 18mm Human Chorionic Gonadotropin was injected to assist follicular maturation. 24-26 hours later the ova were collected (Ovum Pick Up/OPU) and 4-6 hours after OPU IVF or Intracytoplasmic Sperm Injection (ICSI) were performed on the ova. The embryos were assessed by morphology and rate of development and at day three they are transferred onto a blastocyst medium and cultured for 2-3 days until it forms a blastocyst. The blastocysts are socred according to the Gardner standard and usually 1-2 good embryos are implanted. The remaining viable embryos are cryopreserved via vitrification and may be used if the current IVF cycle is unsuccessful. The Estrogen and Progesterone levels are monitored and regulated throughout the process according to the characteristics of the patient. Clinical pregnancy was defined by the presence of a gestational sac with or without a heart beat 30 days after implantation.

From this experiment it was found that there was a greater amount of successful pregnancies in women less than 35 years old resulting from implantation of fresh embryos at the cleavage stage (52.7% success) as opposed to the blastocyst stage (35.88%). There was no statistically significant differences clinically between the two types of implantation [ie- multiple pregnancies, abortion or ectopic pregnancy]. There were also a significantly higher number of pregnancies in the cleavage stage [41.24%] vs the blastocyst stage [26.92%]. However, this was not that case for those whom has frozen-thawed embryo transfers, as there was generally a much greater success rate for pregnancy in those who had blastocyst stage transfers than those who had cleavage stage transfers. Furthermore, there is a significantly greater pregnancy rate between in fresh embryo transfers compared to frozen thawed embryo transfers at the cleavage stage. Overall, there was a greater incidence of clinical pregnancy resulting from fresh cleavage stage embryo transfers compared to any other type of transfer [ie fresh blastocyst stage, frozen thawed cleavage stage and frozen thawed blastocyst stage]. These researchers concluded that this type of implantation should be used under normal conditions, and other methods should only be considered if the mother is of compromised health (eg has Ovarian Hyper Stimulation Syndrome), in which case as fresh blastocyst stage embryo is used.

===ARTICLE 2===
<pubmed>25017405 </pubmed>
This article aimed to assess the success rate of clinical pregnancy of women at differing age groups whom have undergone assisted reproductive methods such as In-Vitro Fertilzation and Intracytoplasmic Sperm Injection. Based on previous literature it was expected that the success rate would decline as the woman ages, as typically the most successful IVF cycles are seen in women whom are 25-30 years old. Also based on natural conception rates, spontaneous conception rates begin to decrease around 31-35 years old, and women tend to have difficulty conceiving around the ages of 35-39. General fecundabilty (probability of released ovum becoming fertilized and resulting in a successful pregnancy in one menstrual cycle) tend t decrease as the woman reaches menopause (around the early fifties) and at 5-10 years prior to this (40-44 years old), half of the women have reduced reproductive capacity.

This study observed 2,900 women undergoing IVF at the KK Women and Children’s hospital, of which yielded 3,412 fresh IVF cycles. The women were classifies into sub groups based only on age [< 30 years; 30–35 years; 36–37 years; 38 years; 39 years; 40–44 years; and ≥ 45 years]. The IVF cycles were monitored and the average number of occytes, average duration of stimulation and fertilization rates were observed. Furthermore, the number of cycles until successful embryo transfer, clinically successfully pregnancy rates, miscarriage rates and multiple pregnancy rates were also reported.
In this study, most of the patients undergoing IVF were between the ages of 30-35 and 36-37, and the least amount of patients belonged to the ≥ 45 years group. Of these, it was found that there was a 15% miscarriage rate in those younger than 30 years old, but this figure doubled to 30% at the age of 38 and among women aged 40-44, the miscarriage rate was as high as 55%. Only half of the women aged greater than 45 reached embryo transfer, and of those, none proceeded to successful clinical pregnancy. Furthermore, compared to other age groups, these women had the lowest amount of oocytes collected and the lowest fertilization rate with only 50% of oocytes proceeding to fertilization, compared to 95% in women less than 30 years old. However, it was found that there was no differences in mean duration of ovarian stimulation prior to ovum collection based on age. Finally, it was found that there was a general decreasing trend of successful clinical pregnancies as age increased in women undergoing IVF, as the rate of live births was highest in women who were less than 30 years old. The occurence of multiple births was highest in this age group also.

Overall it was found that the age of the woman undoubtedly has an effect on the reproductive capacity of a woman undergoing IVF. The researchers hypothesized that the general decreased success of an aging woman may be due to decreasing ovarian reserve, poorer oocyte quality, lower embryo implantation rates, altered hormonal environment resulting in ovulatory dysfunction and uterine problems. Male factors were also considered to be causative.

--[[User:Z8600021|Mark Hill]] These papers are suitable for the assessment exercise and you have included an appropriate summary. (5/5)

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==Lab Assessment 2==
[[File:Mutation of Gene Wt1 Causes Aberrant Gonadal Development.jpeg|300px]]

Mutation of Gene Wt1 Causes Aberrant Gonadal Development<ref><pubmed>23497137 </pubmed>| [http://www.biomedcentral.com/1741-7007/11/22/figure/F1]</ref>

<references/>

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:08, 20 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] This is a relevant image. I have fixed a few formatting issues in the associated file information, don't include the .jpeg in the figure legend, see the image page history for changes. (5/5)

==Lab Attendance: LAB 2==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:56, 20 August 2014 (EST)
Forgot to do my attendance at the lab of week 3 given by guest Speakers Hayden Homer and Rob Gilchrist about meiosis, oocyte quality and various technologies in assisted reproduction

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==Lab Attendance week 4==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:39, 20 August 2014 (EST)

==Lab three Online Assessment==
Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 20:10, 26 August 2014 (EST)

--[[User:Z8600021|Mark Hill]]These 3 references meet the assessment requirement, it appears that you have just included the references without a description? Your description of genital differentiation is not quite accurate and should be clarified by the future Genital Development Lecture. (4/5)

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==Lab 4 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 27 August 2014 (EST)

==Lab 4 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:23, 2 September 2014 (EST)

<pubmed>25137413</pubmed>

Hepatocellular carcinoma and other degenerative liver diseases often result in hepatic dysfunction and ultimately organ failure. To avoid this otherwise fatal diagnosis, bio-artificial livers and hepatocyte transplantation provides some leg- room whilst waiting on a full-organ transplant. However liver transplants, much like many other organs, are often hard to come by and are usually sensitive to the immune response of the host. As a result, researchers are looking towards stem cells as an answer to this problem. Mesenchymal stem cells derived from the Wharton’s Jelly of the umbilical Chord are often chosen because they have been found to have a slightly higher multipotency and immunogenicity. The umbilical stem cells were selected because they are more primitive compared to other Mesenchymal stem cells and do not express the major histocompatibility complex class II antigens- a key determinant in illiciting an immune response form the host. However, hepatocyte like cells derived from stem cells are not clinically used because they do not express enough functional proteins and do not exhibit a full level of metabolic activity.

This study aimed to identify and observe the transcription factors involved in hepatocyte differentiation from Human umbilical cord Mesenchymal Stem Cells (HuMSCs), they were particularly interested in Hepatocyte Nuclear Factor 4-alpha (HNF-4alpha) which is believed to behave like a “master gene” in driving hepatocyte differentiation and maturation. This study continued to expose the differentiating HuMSCs to excess amounts of HNF-4alpha and hypothesized a significant improvement in the differentiation status of the hepatocyte-like cells, providing a basis for future clinical application of HuMSCs in the treatment and management of liver diseases.

The research initially confirmed that the HuMSCs are of low immunogenicity- a critical issue with organ transplantation. Once this was confirmed, they observed that there was an up-regulation of functional hepatic enzymes once the differentiating hepatocyte-like stem cells were exposed to HNF-4alpha. An important finding they discovered that the time at which the stem cells were exposed to HNF-4alpha were integral in ensuring correct hepatocyte differentiation. Ultimately they concluded that the differentiation of HuMSCs could be improved by exposure to high levels of HNF-4alpha at specific times in the development of hepatocyte-like stem cells, an important discovery for the progression of the therapeutic application of stem cells.

The three shunts which are present in fetal development but are closed postnatally are:

• ductus arteriosis → channel between the pulmonary artery and aorta in the fetus which bypasses the lungs to distribute oxygenated blood from the placenta derived from the mothers circulation.

• ductus venosus → shunts a portion of the left umbilical vein blood flow which would flow directly to the inferior vena cava- allows b=oxygenated blood to bypass the liver.

• foramen ovale → allows passageway of blood from left atrium to right atrium in the fetus.

----

==Lab 5 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 3 September 2014 (EST)

==Lab 5 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:10, 16 September 2014 (EST)

Congenital Lobar emphysema (CLE) is a condition of the respiratory system which results in hyperinflation of one or more pulmonary lobes and is usually diagnosed postnatally, usually in the neonatal period- however there have been cases where CLE is not diagnosed until 10 years after birth. The clinical symptoms of CLE are often at birth as dyspnea, cyanosis and recurrent respiratory tract infections, as well as generalized neonatal respiratory distress and hyperinflation and hyperaeration of the pulmonary lobes- often seen as visible enlargements or imaged through CT. CLE is a rare disorder affecting only 1 in 20,000 to 30, 000 newborns, and appears to have a slight male predominance [3:1 male to female ratio], although the cause of this gender predilection is not fully understood.

The developmental causes of CLE are often as final result of a number of bronchopulmonary disturbances during development. These result from abnormal interactions between embryonic endodermal and mesodermal components of the lung which may result in abnormalities in airway or alveoli number and size, however the exact pathogenesis of CLE is not able to be determined in approximately half of cases. Another frequently observed cause of CLE is an obstruction of the developing airway, which creates a “ball valve” resulting in an uneven distribution of air- favoring greater airflow to the affected lobe during inspiration than is able to be cleared in expiration- resulting in air trapping. There may also be vascular abnormalities which produce compression, bronchial stenosis, bronchogenic cysts and congenital cytomegaloviral infections observed.

<pubmed>PMC2141574</pubmed>

----

==Lab attendance week 8==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 17 September 2014 (EST)

----

==Lab Report- week 8==

<pubmed>24753613</pubmed>
==lab Attendance WEEK 9==

----

==Lab attendance week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)
==lab report week 9==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)
<pubmed>24741072</pubmed>
----

==Lab assessment week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 00:56, 15 October 2014 (EST)
'''Group 1'''
This project is extremely well done. I found the overall layout of your work to be easy to read and succinct. It captured my attention throughout the entirety of the project and was engaging with the use of bullet points. I thought your use of diagrams was great in aiding the understanding of this topic, however I thought that more diagrams or pictures could be added in order to help the reader visualize exactly what’s going on. I thought that te developmental timeline was a great idea, however could benefit from some more images or diagrams to assist in understanding the developmental stages. I thought the historic findings sections was especially well done as it appears well researched and thoroughly informative. The abnormalities was also well done, however again could benefit from the addition of a few more diagrams.

I think that with the addition of more drawings needs to be some attention to detail when referencing and stating copyright. I’ve noticed that some pictures lack copyright and some don’t have a description, making it difficult to understand the context of the picture and to envisage how it relates to the content. Whilst this is mostly self explanatory- I think that because this is an informative piece it pays to spoon-feed us a bit. Also, your referencing could use a bit of a tidy, but that can easily be fixed before submission. I think that overall this has great potential to be a wonderful project and I look forward to seeing it at its completion!

'''Group 2'''
I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

'''Group 3'''
Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

'''Group 5'''
Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once.

I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

'''Group 6'''
Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

'''Group 7'''
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.
The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.
The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing.
Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

'''Group 8'''
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

----

==Lab Attendance week 11==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:43, 15 October 2014 (EST)
<pubmed>23904336</pubmed>

==Lab attendance week 12==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:51, 22 October 2014 (EST)
<pubmed>25345934 </pubmed>

==Lab Attendance week 13==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 29 October 2014 (EST)

User:Z3416697

2014-11-01T10:13:09Z

Z3416697: /* Lab Report- week 8 */

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:45, 6 August 2014 (EST)
==lab attendance==
Lab 1
http://www.ncbi.nlm.nih.gov/pubmed

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

<pubmed>2508416</pubmed>

----

==Lab Assessment 1==
===ARTICLE 1===
<pubmed>25071849</pubmed>

In Vitro Fertilization (IVF) is a popular method of Assisted Reproduction which allows for fertilization to occur under optimal conditions (which may not be achieved in those that are having trouble conceiving), with monitored hormone levels and calculated growth of the embryo so as to maximize implantation, and ideally, successful pregnancy. This research article endeavors to assess the different variables available in IVF to determine which method yields the most successful amount of pregnancies. The variables in question are whether the embryo should be fresh (within a hours of fertilization), or frozen-thawed (embryo frozen a few days after fertilization and thawed when the mother is ready to receive an embryo). Another variable considered is the developmental stage at which the embryo is implanted; some embryos are implanted at the cleavage stage (hours after fertilization) and others are implanted at the blastocyst stage (5 days after fertilization), this study also considered implants at the cleavage stage extended blastocyst stage however it did not clarify what this term means, and I was unable to find elsewhere what this means.

This study observed IVF cycles of 1891 women at the Wuhan Union Hospital between January and December of 2012. Of the 1891 women observed, 1150 had fresh embryo transfers and 741 had frozen thawed embryo transfers. Of the Fresh embryo transfers 993 were implanted at the cleavage stage (799 of them women were less than 35 years old and 194 were greater than or equal to 35 years old), and 157 were implanted at the blastocyst stage (131 were less than 35 years old, 26 greater than or equal to 35 years old). Of the 741 women with frozen thawed embryo transfers, 212 were implanted at the cleavage stage of embryonic development (159 women were less than 35 and 53 were greater than or equal to 35), 137 were implanted at the cleavage stage extended blastocyst stage (111 were less than 35, 26 were greater than or equal to 35) and 328 were implanted at the blastocyst stage (276 were less than 35, 52 were greater than or equal to 35). All of these women underwent traditional methods of IVF- that is they were initially treated with Gonadotropin Releasing Hormone to stimulate follicular development. When two or more follicles were greater than 18mm Human Chorionic Gonadotropin was injected to assist follicular maturation. 24-26 hours later the ova were collected (Ovum Pick Up/OPU) and 4-6 hours after OPU IVF or Intracytoplasmic Sperm Injection (ICSI) were performed on the ova. The embryos were assessed by morphology and rate of development and at day three they are transferred onto a blastocyst medium and cultured for 2-3 days until it forms a blastocyst. The blastocysts are socred according to the Gardner standard and usually 1-2 good embryos are implanted. The remaining viable embryos are cryopreserved via vitrification and may be used if the current IVF cycle is unsuccessful. The Estrogen and Progesterone levels are monitored and regulated throughout the process according to the characteristics of the patient. Clinical pregnancy was defined by the presence of a gestational sac with or without a heart beat 30 days after implantation.

From this experiment it was found that there was a greater amount of successful pregnancies in women less than 35 years old resulting from implantation of fresh embryos at the cleavage stage (52.7% success) as opposed to the blastocyst stage (35.88%). There was no statistically significant differences clinically between the two types of implantation [ie- multiple pregnancies, abortion or ectopic pregnancy]. There were also a significantly higher number of pregnancies in the cleavage stage [41.24%] vs the blastocyst stage [26.92%]. However, this was not that case for those whom has frozen-thawed embryo transfers, as there was generally a much greater success rate for pregnancy in those who had blastocyst stage transfers than those who had cleavage stage transfers. Furthermore, there is a significantly greater pregnancy rate between in fresh embryo transfers compared to frozen thawed embryo transfers at the cleavage stage. Overall, there was a greater incidence of clinical pregnancy resulting from fresh cleavage stage embryo transfers compared to any other type of transfer [ie fresh blastocyst stage, frozen thawed cleavage stage and frozen thawed blastocyst stage]. These researchers concluded that this type of implantation should be used under normal conditions, and other methods should only be considered if the mother is of compromised health (eg has Ovarian Hyper Stimulation Syndrome), in which case as fresh blastocyst stage embryo is used.

===ARTICLE 2===
<pubmed>25017405 </pubmed>
This article aimed to assess the success rate of clinical pregnancy of women at differing age groups whom have undergone assisted reproductive methods such as In-Vitro Fertilzation and Intracytoplasmic Sperm Injection. Based on previous literature it was expected that the success rate would decline as the woman ages, as typically the most successful IVF cycles are seen in women whom are 25-30 years old. Also based on natural conception rates, spontaneous conception rates begin to decrease around 31-35 years old, and women tend to have difficulty conceiving around the ages of 35-39. General fecundabilty (probability of released ovum becoming fertilized and resulting in a successful pregnancy in one menstrual cycle) tend t decrease as the woman reaches menopause (around the early fifties) and at 5-10 years prior to this (40-44 years old), half of the women have reduced reproductive capacity.

This study observed 2,900 women undergoing IVF at the KK Women and Children’s hospital, of which yielded 3,412 fresh IVF cycles. The women were classifies into sub groups based only on age [< 30 years; 30–35 years; 36–37 years; 38 years; 39 years; 40–44 years; and ≥ 45 years]. The IVF cycles were monitored and the average number of occytes, average duration of stimulation and fertilization rates were observed. Furthermore, the number of cycles until successful embryo transfer, clinically successfully pregnancy rates, miscarriage rates and multiple pregnancy rates were also reported.
In this study, most of the patients undergoing IVF were between the ages of 30-35 and 36-37, and the least amount of patients belonged to the ≥ 45 years group. Of these, it was found that there was a 15% miscarriage rate in those younger than 30 years old, but this figure doubled to 30% at the age of 38 and among women aged 40-44, the miscarriage rate was as high as 55%. Only half of the women aged greater than 45 reached embryo transfer, and of those, none proceeded to successful clinical pregnancy. Furthermore, compared to other age groups, these women had the lowest amount of oocytes collected and the lowest fertilization rate with only 50% of oocytes proceeding to fertilization, compared to 95% in women less than 30 years old. However, it was found that there was no differences in mean duration of ovarian stimulation prior to ovum collection based on age. Finally, it was found that there was a general decreasing trend of successful clinical pregnancies as age increased in women undergoing IVF, as the rate of live births was highest in women who were less than 30 years old. The occurence of multiple births was highest in this age group also.

Overall it was found that the age of the woman undoubtedly has an effect on the reproductive capacity of a woman undergoing IVF. The researchers hypothesized that the general decreased success of an aging woman may be due to decreasing ovarian reserve, poorer oocyte quality, lower embryo implantation rates, altered hormonal environment resulting in ovulatory dysfunction and uterine problems. Male factors were also considered to be causative.

--[[User:Z8600021|Mark Hill]] These papers are suitable for the assessment exercise and you have included an appropriate summary. (5/5)

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==Lab Assessment 2==
[[File:Mutation of Gene Wt1 Causes Aberrant Gonadal Development.jpeg|300px]]

Mutation of Gene Wt1 Causes Aberrant Gonadal Development<ref><pubmed>23497137 </pubmed>| [http://www.biomedcentral.com/1741-7007/11/22/figure/F1]</ref>

<references/>

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:08, 20 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] This is a relevant image. I have fixed a few formatting issues in the associated file information, don't include the .jpeg in the figure legend, see the image page history for changes. (5/5)

==Lab Attendance: LAB 2==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:56, 20 August 2014 (EST)
Forgot to do my attendance at the lab of week 3 given by guest Speakers Hayden Homer and Rob Gilchrist about meiosis, oocyte quality and various technologies in assisted reproduction

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==Lab Attendance week 4==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:39, 20 August 2014 (EST)

==Lab three Online Assessment==
Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 20:10, 26 August 2014 (EST)

--[[User:Z8600021|Mark Hill]]These 3 references meet the assessment requirement, it appears that you have just included the references without a description? Your description of genital differentiation is not quite accurate and should be clarified by the future Genital Development Lecture. (4/5)

----

==Lab 4 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 27 August 2014 (EST)

==Lab 4 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:23, 2 September 2014 (EST)

<pubmed>25137413</pubmed>

Hepatocellular carcinoma and other degenerative liver diseases often result in hepatic dysfunction and ultimately organ failure. To avoid this otherwise fatal diagnosis, bio-artificial livers and hepatocyte transplantation provides some leg- room whilst waiting on a full-organ transplant. However liver transplants, much like many other organs, are often hard to come by and are usually sensitive to the immune response of the host. As a result, researchers are looking towards stem cells as an answer to this problem. Mesenchymal stem cells derived from the Wharton’s Jelly of the umbilical Chord are often chosen because they have been found to have a slightly higher multipotency and immunogenicity. The umbilical stem cells were selected because they are more primitive compared to other Mesenchymal stem cells and do not express the major histocompatibility complex class II antigens- a key determinant in illiciting an immune response form the host. However, hepatocyte like cells derived from stem cells are not clinically used because they do not express enough functional proteins and do not exhibit a full level of metabolic activity.

This study aimed to identify and observe the transcription factors involved in hepatocyte differentiation from Human umbilical cord Mesenchymal Stem Cells (HuMSCs), they were particularly interested in Hepatocyte Nuclear Factor 4-alpha (HNF-4alpha) which is believed to behave like a “master gene” in driving hepatocyte differentiation and maturation. This study continued to expose the differentiating HuMSCs to excess amounts of HNF-4alpha and hypothesized a significant improvement in the differentiation status of the hepatocyte-like cells, providing a basis for future clinical application of HuMSCs in the treatment and management of liver diseases.

The research initially confirmed that the HuMSCs are of low immunogenicity- a critical issue with organ transplantation. Once this was confirmed, they observed that there was an up-regulation of functional hepatic enzymes once the differentiating hepatocyte-like stem cells were exposed to HNF-4alpha. An important finding they discovered that the time at which the stem cells were exposed to HNF-4alpha were integral in ensuring correct hepatocyte differentiation. Ultimately they concluded that the differentiation of HuMSCs could be improved by exposure to high levels of HNF-4alpha at specific times in the development of hepatocyte-like stem cells, an important discovery for the progression of the therapeutic application of stem cells.

The three shunts which are present in fetal development but are closed postnatally are:

• ductus arteriosis → channel between the pulmonary artery and aorta in the fetus which bypasses the lungs to distribute oxygenated blood from the placenta derived from the mothers circulation.

• ductus venosus → shunts a portion of the left umbilical vein blood flow which would flow directly to the inferior vena cava- allows b=oxygenated blood to bypass the liver.

• foramen ovale → allows passageway of blood from left atrium to right atrium in the fetus.

----

==Lab 5 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 3 September 2014 (EST)

==Lab 5 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:10, 16 September 2014 (EST)

Congenital Lobar emphysema (CLE) is a condition of the respiratory system which results in hyperinflation of one or more pulmonary lobes and is usually diagnosed postnatally, usually in the neonatal period- however there have been cases where CLE is not diagnosed until 10 years after birth. The clinical symptoms of CLE are often at birth as dyspnea, cyanosis and recurrent respiratory tract infections, as well as generalized neonatal respiratory distress and hyperinflation and hyperaeration of the pulmonary lobes- often seen as visible enlargements or imaged through CT. CLE is a rare disorder affecting only 1 in 20,000 to 30, 000 newborns, and appears to have a slight male predominance [3:1 male to female ratio], although the cause of this gender predilection is not fully understood.

The developmental causes of CLE are often as final result of a number of bronchopulmonary disturbances during development. These result from abnormal interactions between embryonic endodermal and mesodermal components of the lung which may result in abnormalities in airway or alveoli number and size, however the exact pathogenesis of CLE is not able to be determined in approximately half of cases. Another frequently observed cause of CLE is an obstruction of the developing airway, which creates a “ball valve” resulting in an uneven distribution of air- favoring greater airflow to the affected lobe during inspiration than is able to be cleared in expiration- resulting in air trapping. There may also be vascular abnormalities which produce compression, bronchial stenosis, bronchogenic cysts and congenital cytomegaloviral infections observed.

<pubmed>PMC2141574</pubmed>

----

==Lab attendance week 8==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 17 September 2014 (EST)

----

==Lab Report- week 8==
<pubmed>24741072</pubmed>

==lab Attendance WEEK 9==

----

==Lab attendance week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)
==lab report week 9==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)

----

==Lab assessment week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 00:56, 15 October 2014 (EST)
'''Group 1'''
This project is extremely well done. I found the overall layout of your work to be easy to read and succinct. It captured my attention throughout the entirety of the project and was engaging with the use of bullet points. I thought your use of diagrams was great in aiding the understanding of this topic, however I thought that more diagrams or pictures could be added in order to help the reader visualize exactly what’s going on. I thought that te developmental timeline was a great idea, however could benefit from some more images or diagrams to assist in understanding the developmental stages. I thought the historic findings sections was especially well done as it appears well researched and thoroughly informative. The abnormalities was also well done, however again could benefit from the addition of a few more diagrams.

I think that with the addition of more drawings needs to be some attention to detail when referencing and stating copyright. I’ve noticed that some pictures lack copyright and some don’t have a description, making it difficult to understand the context of the picture and to envisage how it relates to the content. Whilst this is mostly self explanatory- I think that because this is an informative piece it pays to spoon-feed us a bit. Also, your referencing could use a bit of a tidy, but that can easily be fixed before submission. I think that overall this has great potential to be a wonderful project and I look forward to seeing it at its completion!

'''Group 2'''
I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

'''Group 3'''
Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

'''Group 5'''
Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once.

I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

'''Group 6'''
Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

'''Group 7'''
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.
The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.
The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing.
Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

'''Group 8'''
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

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==Lab Attendance week 11==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:43, 15 October 2014 (EST)

==Lab attendance week 12==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:51, 22 October 2014 (EST)

==Lab Attendance week 13==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 29 October 2014 (EST)

User:Z3416697

2014-10-29T00:55:06Z

Z3416697:

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:45, 6 August 2014 (EST)
==lab attendance==
Lab 1
http://www.ncbi.nlm.nih.gov/pubmed

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

<pubmed>2508416</pubmed>

----

==Lab Assessment 1==
===ARTICLE 1===
<pubmed>25071849</pubmed>

In Vitro Fertilization (IVF) is a popular method of Assisted Reproduction which allows for fertilization to occur under optimal conditions (which may not be achieved in those that are having trouble conceiving), with monitored hormone levels and calculated growth of the embryo so as to maximize implantation, and ideally, successful pregnancy. This research article endeavors to assess the different variables available in IVF to determine which method yields the most successful amount of pregnancies. The variables in question are whether the embryo should be fresh (within a hours of fertilization), or frozen-thawed (embryo frozen a few days after fertilization and thawed when the mother is ready to receive an embryo). Another variable considered is the developmental stage at which the embryo is implanted; some embryos are implanted at the cleavage stage (hours after fertilization) and others are implanted at the blastocyst stage (5 days after fertilization), this study also considered implants at the cleavage stage extended blastocyst stage however it did not clarify what this term means, and I was unable to find elsewhere what this means.

This study observed IVF cycles of 1891 women at the Wuhan Union Hospital between January and December of 2012. Of the 1891 women observed, 1150 had fresh embryo transfers and 741 had frozen thawed embryo transfers. Of the Fresh embryo transfers 993 were implanted at the cleavage stage (799 of them women were less than 35 years old and 194 were greater than or equal to 35 years old), and 157 were implanted at the blastocyst stage (131 were less than 35 years old, 26 greater than or equal to 35 years old). Of the 741 women with frozen thawed embryo transfers, 212 were implanted at the cleavage stage of embryonic development (159 women were less than 35 and 53 were greater than or equal to 35), 137 were implanted at the cleavage stage extended blastocyst stage (111 were less than 35, 26 were greater than or equal to 35) and 328 were implanted at the blastocyst stage (276 were less than 35, 52 were greater than or equal to 35). All of these women underwent traditional methods of IVF- that is they were initially treated with Gonadotropin Releasing Hormone to stimulate follicular development. When two or more follicles were greater than 18mm Human Chorionic Gonadotropin was injected to assist follicular maturation. 24-26 hours later the ova were collected (Ovum Pick Up/OPU) and 4-6 hours after OPU IVF or Intracytoplasmic Sperm Injection (ICSI) were performed on the ova. The embryos were assessed by morphology and rate of development and at day three they are transferred onto a blastocyst medium and cultured for 2-3 days until it forms a blastocyst. The blastocysts are socred according to the Gardner standard and usually 1-2 good embryos are implanted. The remaining viable embryos are cryopreserved via vitrification and may be used if the current IVF cycle is unsuccessful. The Estrogen and Progesterone levels are monitored and regulated throughout the process according to the characteristics of the patient. Clinical pregnancy was defined by the presence of a gestational sac with or without a heart beat 30 days after implantation.

From this experiment it was found that there was a greater amount of successful pregnancies in women less than 35 years old resulting from implantation of fresh embryos at the cleavage stage (52.7% success) as opposed to the blastocyst stage (35.88%). There was no statistically significant differences clinically between the two types of implantation [ie- multiple pregnancies, abortion or ectopic pregnancy]. There were also a significantly higher number of pregnancies in the cleavage stage [41.24%] vs the blastocyst stage [26.92%]. However, this was not that case for those whom has frozen-thawed embryo transfers, as there was generally a much greater success rate for pregnancy in those who had blastocyst stage transfers than those who had cleavage stage transfers. Furthermore, there is a significantly greater pregnancy rate between in fresh embryo transfers compared to frozen thawed embryo transfers at the cleavage stage. Overall, there was a greater incidence of clinical pregnancy resulting from fresh cleavage stage embryo transfers compared to any other type of transfer [ie fresh blastocyst stage, frozen thawed cleavage stage and frozen thawed blastocyst stage]. These researchers concluded that this type of implantation should be used under normal conditions, and other methods should only be considered if the mother is of compromised health (eg has Ovarian Hyper Stimulation Syndrome), in which case as fresh blastocyst stage embryo is used.

===ARTICLE 2===
<pubmed>25017405 </pubmed>
This article aimed to assess the success rate of clinical pregnancy of women at differing age groups whom have undergone assisted reproductive methods such as In-Vitro Fertilzation and Intracytoplasmic Sperm Injection. Based on previous literature it was expected that the success rate would decline as the woman ages, as typically the most successful IVF cycles are seen in women whom are 25-30 years old. Also based on natural conception rates, spontaneous conception rates begin to decrease around 31-35 years old, and women tend to have difficulty conceiving around the ages of 35-39. General fecundabilty (probability of released ovum becoming fertilized and resulting in a successful pregnancy in one menstrual cycle) tend t decrease as the woman reaches menopause (around the early fifties) and at 5-10 years prior to this (40-44 years old), half of the women have reduced reproductive capacity.

This study observed 2,900 women undergoing IVF at the KK Women and Children’s hospital, of which yielded 3,412 fresh IVF cycles. The women were classifies into sub groups based only on age [< 30 years; 30–35 years; 36–37 years; 38 years; 39 years; 40–44 years; and ≥ 45 years]. The IVF cycles were monitored and the average number of occytes, average duration of stimulation and fertilization rates were observed. Furthermore, the number of cycles until successful embryo transfer, clinically successfully pregnancy rates, miscarriage rates and multiple pregnancy rates were also reported.
In this study, most of the patients undergoing IVF were between the ages of 30-35 and 36-37, and the least amount of patients belonged to the ≥ 45 years group. Of these, it was found that there was a 15% miscarriage rate in those younger than 30 years old, but this figure doubled to 30% at the age of 38 and among women aged 40-44, the miscarriage rate was as high as 55%. Only half of the women aged greater than 45 reached embryo transfer, and of those, none proceeded to successful clinical pregnancy. Furthermore, compared to other age groups, these women had the lowest amount of oocytes collected and the lowest fertilization rate with only 50% of oocytes proceeding to fertilization, compared to 95% in women less than 30 years old. However, it was found that there was no differences in mean duration of ovarian stimulation prior to ovum collection based on age. Finally, it was found that there was a general decreasing trend of successful clinical pregnancies as age increased in women undergoing IVF, as the rate of live births was highest in women who were less than 30 years old. The occurence of multiple births was highest in this age group also.

Overall it was found that the age of the woman undoubtedly has an effect on the reproductive capacity of a woman undergoing IVF. The researchers hypothesized that the general decreased success of an aging woman may be due to decreasing ovarian reserve, poorer oocyte quality, lower embryo implantation rates, altered hormonal environment resulting in ovulatory dysfunction and uterine problems. Male factors were also considered to be causative.

--[[User:Z8600021|Mark Hill]] These papers are suitable for the assessment exercise and you have included an appropriate summary. (5/5)

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==Lab Assessment 2==
[[File:Mutation of Gene Wt1 Causes Aberrant Gonadal Development.jpeg|300px]]

Mutation of Gene Wt1 Causes Aberrant Gonadal Development<ref><pubmed>23497137 </pubmed>| [http://www.biomedcentral.com/1741-7007/11/22/figure/F1]</ref>

<references/>

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:08, 20 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] This is a relevant image. I have fixed a few formatting issues in the associated file information, don't include the .jpeg in the figure legend, see the image page history for changes. (5/5)

==Lab Attendance: LAB 2==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:56, 20 August 2014 (EST)
Forgot to do my attendance at the lab of week 3 given by guest Speakers Hayden Homer and Rob Gilchrist about meiosis, oocyte quality and various technologies in assisted reproduction

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==Lab Attendance week 4==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:39, 20 August 2014 (EST)

==Lab three Online Assessment==
Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 20:10, 26 August 2014 (EST)

--[[User:Z8600021|Mark Hill]]These 3 references meet the assessment requirement, it appears that you have just included the references without a description? Your description of genital differentiation is not quite accurate and should be clarified by the future Genital Development Lecture. (4/5)

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==Lab 4 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 27 August 2014 (EST)

==Lab 4 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:23, 2 September 2014 (EST)

<pubmed>25137413</pubmed>

Hepatocellular carcinoma and other degenerative liver diseases often result in hepatic dysfunction and ultimately organ failure. To avoid this otherwise fatal diagnosis, bio-artificial livers and hepatocyte transplantation provides some leg- room whilst waiting on a full-organ transplant. However liver transplants, much like many other organs, are often hard to come by and are usually sensitive to the immune response of the host. As a result, researchers are looking towards stem cells as an answer to this problem. Mesenchymal stem cells derived from the Wharton’s Jelly of the umbilical Chord are often chosen because they have been found to have a slightly higher multipotency and immunogenicity. The umbilical stem cells were selected because they are more primitive compared to other Mesenchymal stem cells and do not express the major histocompatibility complex class II antigens- a key determinant in illiciting an immune response form the host. However, hepatocyte like cells derived from stem cells are not clinically used because they do not express enough functional proteins and do not exhibit a full level of metabolic activity.

This study aimed to identify and observe the transcription factors involved in hepatocyte differentiation from Human umbilical cord Mesenchymal Stem Cells (HuMSCs), they were particularly interested in Hepatocyte Nuclear Factor 4-alpha (HNF-4alpha) which is believed to behave like a “master gene” in driving hepatocyte differentiation and maturation. This study continued to expose the differentiating HuMSCs to excess amounts of HNF-4alpha and hypothesized a significant improvement in the differentiation status of the hepatocyte-like cells, providing a basis for future clinical application of HuMSCs in the treatment and management of liver diseases.

The research initially confirmed that the HuMSCs are of low immunogenicity- a critical issue with organ transplantation. Once this was confirmed, they observed that there was an up-regulation of functional hepatic enzymes once the differentiating hepatocyte-like stem cells were exposed to HNF-4alpha. An important finding they discovered that the time at which the stem cells were exposed to HNF-4alpha were integral in ensuring correct hepatocyte differentiation. Ultimately they concluded that the differentiation of HuMSCs could be improved by exposure to high levels of HNF-4alpha at specific times in the development of hepatocyte-like stem cells, an important discovery for the progression of the therapeutic application of stem cells.

The three shunts which are present in fetal development but are closed postnatally are:

• ductus arteriosis → channel between the pulmonary artery and aorta in the fetus which bypasses the lungs to distribute oxygenated blood from the placenta derived from the mothers circulation.

• ductus venosus → shunts a portion of the left umbilical vein blood flow which would flow directly to the inferior vena cava- allows b=oxygenated blood to bypass the liver.

• foramen ovale → allows passageway of blood from left atrium to right atrium in the fetus.

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==Lab 5 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 3 September 2014 (EST)

==Lab 5 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:10, 16 September 2014 (EST)

Congenital Lobar emphysema (CLE) is a condition of the respiratory system which results in hyperinflation of one or more pulmonary lobes and is usually diagnosed postnatally, usually in the neonatal period- however there have been cases where CLE is not diagnosed until 10 years after birth. The clinical symptoms of CLE are often at birth as dyspnea, cyanosis and recurrent respiratory tract infections, as well as generalized neonatal respiratory distress and hyperinflation and hyperaeration of the pulmonary lobes- often seen as visible enlargements or imaged through CT. CLE is a rare disorder affecting only 1 in 20,000 to 30, 000 newborns, and appears to have a slight male predominance [3:1 male to female ratio], although the cause of this gender predilection is not fully understood.

The developmental causes of CLE are often as final result of a number of bronchopulmonary disturbances during development. These result from abnormal interactions between embryonic endodermal and mesodermal components of the lung which may result in abnormalities in airway or alveoli number and size, however the exact pathogenesis of CLE is not able to be determined in approximately half of cases. Another frequently observed cause of CLE is an obstruction of the developing airway, which creates a “ball valve” resulting in an uneven distribution of air- favoring greater airflow to the affected lobe during inspiration than is able to be cleared in expiration- resulting in air trapping. There may also be vascular abnormalities which produce compression, bronchial stenosis, bronchogenic cysts and congenital cytomegaloviral infections observed.

<pubmed>PMC2141574</pubmed>

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==Lab attendance week 8==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 17 September 2014 (EST)

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==Lab Report- week 8==

==lab Attendance WEEK 9==

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==Lab attendance week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)
==lab report week 9==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)

----

==Lab assessment week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 00:56, 15 October 2014 (EST)
'''Group 1'''
This project is extremely well done. I found the overall layout of your work to be easy to read and succinct. It captured my attention throughout the entirety of the project and was engaging with the use of bullet points. I thought your use of diagrams was great in aiding the understanding of this topic, however I thought that more diagrams or pictures could be added in order to help the reader visualize exactly what’s going on. I thought that te developmental timeline was a great idea, however could benefit from some more images or diagrams to assist in understanding the developmental stages. I thought the historic findings sections was especially well done as it appears well researched and thoroughly informative. The abnormalities was also well done, however again could benefit from the addition of a few more diagrams.

I think that with the addition of more drawings needs to be some attention to detail when referencing and stating copyright. I’ve noticed that some pictures lack copyright and some don’t have a description, making it difficult to understand the context of the picture and to envisage how it relates to the content. Whilst this is mostly self explanatory- I think that because this is an informative piece it pays to spoon-feed us a bit. Also, your referencing could use a bit of a tidy, but that can easily be fixed before submission. I think that overall this has great potential to be a wonderful project and I look forward to seeing it at its completion!

'''Group 2'''
I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

'''Group 3'''
Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

'''Group 5'''
Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once.

I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

'''Group 6'''
Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

'''Group 7'''
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.
The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.
The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing.
Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

'''Group 8'''
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

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==Lab Attendance week 11==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:43, 15 October 2014 (EST)

==Lab attendance week 12==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:51, 22 October 2014 (EST)

==Lab Attendance week 13==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 29 October 2014 (EST)

2014 Group Project 4

2014-10-24T06:20:18Z

Z3416697:

{{ANAT2341Project2014header}}
=Genital=
==Introduction==

[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]

This page will explain the development of the genital system in the fetal stage of development, of both males and females, after briefly explaining the embryonic development. It explores the models of fetal development of the internal and external genitalia, including the timeline of development. This page also lists some animal models used in research and outlines some current research and findings regarding the development of the genital system, including historic findings. Finally, this page also discusses some of the congenital abnormalities of the genital system.

==System Development==

[[File:Paramesonephric duct.jpg|200px|thumb|Paramesonephric duct development]]
[[File:Infant ovary.jpg|200px|thumb|Histological image of primordial follicles in infant ovary]]

'''Timeline of Genital Development'''<ref>Hill, M.A. (2014) Lecture - Genital Development. Retrieved October 24, 2014, from https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Genital_Development</ref>
{| class="wikitable"
|-bgcolor="purple"|align="centre"
|'''Week''' || '''Development'''
|-bgcolor="lavender"
| 3-4 || Primordial germ cells migrate during gastrulation
|-
| 4 || Intermediate mesoderm, pronephros primordium
|-bgcolor="lavender"
| 5 || Mesonephros and mesonephric duct
|-
| 6 || Ureteric bud, metanephros, genital ridge
|-bgcolor="lavender"
| 7 || Cloacal divison, gonadal primordium - indifferent to first appearance of testis cords
Female - Paramesonephric duct preservation or regression begins
|-
| 8 || Paramesonephric duct, clear gonadal differentiation
|-bgcolor="lavender"
| 9 || Paramesonephric duct fusion in the female forming the uterus and lack of fusion laterally forming the fallopian tubes. Also forms vagina.
|-
| 15 || Primary follicles (ovary)
From the 26th week (between week 4 and 5), the gubernaculum starts to pull the testes down and results in descent of the testes into the scrotal sac.
Both male and female gonads undergo descent.
|-bgcolor="lavender"
| Puberty || Development of secondary sexual characteristics
Female - start of menstruation, first egg released.
Male - development of course voice, body hair and sperm formation.
|-
|}

'''Related video'''

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

===Development of Internal Genitalia===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
|bgcolor="aliceblue"| The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression. <ref name=PMID11315960><pubmed>11315960</pubmed></ref> <ref name=PMID24240231><pubmed>24240231</pubmed></ref>

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the '''epididymis''' <ref name=PMID24240231><pubmed>24240231</pubmed></ref>. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate. <ref name=PMID24240231><pubmed>24240231</pubmed></ref>
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

| bgcolor="lavenderblush"| The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.<ref name=PMID11315960><pubmed>11315960</pubmed></ref>

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males. <ref name=PMID11315960><pubmed>11315960</pubmed></ref>
|-
|- style="height:10px"
| style="width:50%"|
|}

===Development of the External Genitalia ===

[[File:External genitalia current model.jpg|400px|centre|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings. <ref name=PMID11315960><pubmed>11315960</pubmed></ref>
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''

|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.<ref name=PMID11315960><pubmed>11315960</pubmed></ref>
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* The tubercle itself goes on to form the mons pubis.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID11315960><pubmed>11315960</pubmed></ref>

[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]
|-
|- style="height:10px"
| style="width:50%"|
|}

===Descent of the Gonads===

[[File:Testis-descent end.jpg|200px|thumb|right|Descent of testes]]

'''Male:''' The testis undergo transabdominal and transinguinal descent. The testis lies in the subserous fascia. The processus vaginalis evaginates into the scrotum and the gubernaculum draws it into the scrotal sac. As it descends, it traverses past the superficial (external oblique fascia) and deep (transversalis fascia) inguinal rings of the inguinal canal. This begins in between the 4th and 5th week (usually around day 26) and spans over many days. It can occur unilaterally or bilaterally, more common in premature babies and can conclude postnatally.<ref>Hill, M.A. (2014) Lecture - Genital Development. Retrieved October 24, 2014, from https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Genital_Development</ref>

'''Female''': ovaries undergo caudal and lateral shifts to be suspended in the broad ligament of the uterus. The gubernaculum does not shorten, attaches to paramesonephric ducts and causes medial translocation into the pelvis. The remnant in adult life of the gubernaculum is the ovarian and round ligament of the uterus, which suspend the ovaries and uterus respectively.<ref>Hill, M.A. (2014) Lecture - Genital Development. Retrieved October 24, 2014, from https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Genital_Development</ref>

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==Current Research, Models and Findings==

===Current Models===

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

All animal experiments must be performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. [[http://grants.nih.gov/grants/olaw/Guide-for-the-care-and-use-of-laboratory-animals.pdf | Guide for the Care and Use of Laboratory Animals]]

===Current Research and Findings===
====Male====
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{|
|-bgcolor="aliceblue"
|
[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

[http://npesu.unsw.edu.au/sites/default/files/npesu/surveillances/Congenital%20anomalies%20in%20Australia%202002-2003.pdf | Statistics regarding congenital abnormalities, including hypospadias and epispadias for 2002 and 2003 in Australia]

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{|
|-bgcolor="aliceblue"
|
[[File:POPs and risk of hypospadias.jpg|400px|thumb|left|Table of levels of POPs in maternal serum samples and risk of hypospadias in infants]]

'''A Nested Case-Control Study of Intrauterine Exposure to Persistent Organochlorine Pollutants and the Risk of Hypospadias (2012)'''<ref name=PMID23028613><pubmed>23028613</pubmed></ref>

Hypospadias are a common congenital abnormality resulting from the failure of fusion of the urethral folds within the fetal period of development (8th-14th week of gestation). Whilst it is known that sexual differentiation of the male external genitalia depends on testosterone and its conversion into dihydrotestosterone, the risk factors of hypospadias are not thoroughly researched. This article aims to examine environmental exposure to endocrine disrupting chemicals (EDCs) and understand their potential to act as antagonists on androgen receptors, thereby disrupting the hormonal balance of the endocrine system ultimately leading to hypospadias.<ref name=PMID11469497><pubmed>11469497</pubmed></ref>
More specifically, a major group of EDCs known as persistent organochlorine pollutants (POPs), for example, polychlorinated biphenyls, dioxins, pesticides (dichlorodiphenyl trichloroethane, DDT) and hexachlorobenzene (HCB). Such chemicals are lipophilic, resistant to biodegradation and are present throughout the hydrosphere and atmosphere. Although these chemicals were banned in the 1970’s and 1980’s, due to the potency of these chemicals, they are still found within humans<ref name=PMID22425898><pubmed>22425898</pubmed></ref> and are able to traverse the placenta, becoming exposed to the developing fetus<ref name=PMID6431068><pubmed>6431068</pubmed></ref>.
Therefore, the aim of the present study was to investigate the linkage between exposures of the fetus to POPs and risk of developing hypospadias.

This was a case-controlled study of the risk of hypospadias of single-born boys with regards to levels of POPs within the mothers’ blood during pregnancy. The study used 390 boys with hypospadias and controls were used. Boys with any cryptorchidisms, major malformations or even minor hypospadias were excluded from the study.

This study concluded that EDCs such as PCBs, p,p’-DDE and HCB possess the potential to alter hormonal levels and affect the fetus, resulting hypospadias. It shows that in uterine exposure to HCB and possibly p,p’-DDE are risk factors and may affect androgen-signaling.
|}

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{|
|-bgcolor="aliceblue"
|
'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

[[File:Male testosterone and AMH level graph.jpg|thumb|300px|right|Graph showing male testosterone and AMH levels]]

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.
|}

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{|
|-bgcolor="aliceblue"
|
'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.
|}

====Female====
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{|
|-bgcolor="lavenderblush"
|
'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.
|}

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{|
|-bgcolor="lavenderblush"
|
'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name= Abbott>Abbott David, H. '''Fibrillin-3 in the fetal ovary: can it contribute to polycystic ovary syndrome?'''. Expert Review of Endocrinology & Metabolism: 2012, 7(1); 31-34</ref>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

[[File:Human Y chromosome SRY region.jpg|400px|right|thumb| Human Y chromosome showing SRY gene]]

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.
|}

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research findings and interesting reads:'''
|-
| * A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Findings==

Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for Historical Findings

==Abnormalities==

Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for foetal genital abnormalities

==References==
<references/>

2014 Group Project 4

2014-10-23T14:38:41Z

Z3416697: /* References */

{{ANAT2341Project2014header}}
=Genital=
==Introduction==

[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]

This page will explain the development of the genital system in the fetal stage of development, of both males and females, after briefly explaining the embryonic development. It explores the models of fetal development of the internal and external genitalia, including the timeline of development. This page also lists some animal models used in research and outlines some current research and findings regarding the development of the genital system, including historic findings. Finally, this page also discusses some of the congenital abnormalities of the genital system.

==System Development==

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – Genital Development''
|- bgcolor="lavender"
|
# Genital System development begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally on the coelomic cavity
# The proliferation of this coelomic epithelium leads to an outgrowth due to the ingression of the coelomic epithelium, proliferation and recruitment of adjacent mesonephric cells
# This bipotential genital ridge is indifferentiated in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively
|}

===Internal Genital Development===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
|bgcolor="aliceblue"| The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression. <ref name=PMID11315960><pubmed>11315960</pubmed></ref> <ref name=PMID24240231><pubmed>24240231</pubmed></ref>

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the '''epididymis''' <ref name=PMID24240231><pubmed>24240231</pubmed></ref>. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate. <ref name=PMID24240231><pubmed>24240231</pubmed></ref>
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

| bgcolor="lavenderblush"| The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.<ref name=PMID11315960><pubmed>11315960</pubmed></ref>

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males. <ref name=PMID11315960><pubmed>11315960</pubmed></ref>
|-
|- style="height:10px"
| style="width:50%"|
|}

[[File:External genitalia current model.jpg|300px|right|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]

===Development of the External Genitalia ===

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings. <ref name=PMID11315960><pubmed>11315960</pubmed></ref>
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''

|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.<ref name=PMID11315960><pubmed>11315960</pubmed></ref>
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* The tubercle itself goes on to form the mons pubis.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID11315960><pubmed>11315960</pubmed></ref>

[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]
|-
|- style="height:10px"
| style="width:50%"|
|}

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===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

===Current Research and Findings===
====Male====
----
{|
|-bgcolor="aliceblue"
|
[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

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{|
|-bgcolor="aliceblue"
|
'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.
|}

----

{|
|-bgcolor="aliceblue"
|
'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.
|}

====Female====
----

{|
|-bgcolor="lavenderblush"
|
'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name= Abbott>Abbott David, H. '''Fibrillin-3 in the fetal ovary: can it contribute to polycystic ovary syndrome?'''. Expert Review of Endocrinology & Metabolism: 2012, 7(1); 31-34</ref>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.
|}

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research findings and interesting reads:'''
|-
| * A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>
24. <pubmed>PMC3841730</pubmed>
25. <pubmed>11315960</pubmed>
26. <pubmed>25247640</pubmed>
27. <pubmed>24240231</pubmed>
28. <pubmed>24928207</pubmed>
29. <pubmed>24741072</pubmed>

2014 Group Project 4

2014-10-23T14:35:20Z

Z3416697: /* Genital */

{{ANAT2341Project2014header}}
=Genital=
==Introduction==

[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]

This page will explain the development of the genital system in the fetal stage of development, of both males and females, after briefly explaining the embryonic development. It explores the models of fetal development of the internal and external genitalia, including the timeline of development. This page also lists some animal models used in research and outlines some current research and findings regarding the development of the genital system, including historic findings. Finally, this page also discusses some of the congenital abnormalities of the genital system.

==System Development==

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – Genital Development''
|- bgcolor="lavender"
|
# Genital System development begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally on the coelomic cavity
# The proliferation of this coelomic epithelium leads to an outgrowth due to the ingression of the coelomic epithelium, proliferation and recruitment of adjacent mesonephric cells
# This bipotential genital ridge is indifferentiated in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively
|}

===Internal Genital Development===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
|bgcolor="aliceblue"| The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression. <ref name=PMID11315960><pubmed>11315960</pubmed></ref> <ref name=PMID24240231><pubmed>24240231</pubmed></ref>

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the '''epididymis''' <ref name=PMID24240231><pubmed>24240231</pubmed></ref>. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate. <ref name=PMID24240231><pubmed>24240231</pubmed></ref>
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

| bgcolor="lavenderblush"| The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.<ref name=PMID11315960><pubmed>11315960</pubmed></ref>

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males. <ref name=PMID11315960><pubmed>11315960</pubmed></ref>
|-
|- style="height:10px"
| style="width:50%"|
|}

[[File:External genitalia current model.jpg|300px|right|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]

===Development of the External Genitalia ===

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings. <ref name=PMID11315960><pubmed>11315960</pubmed></ref>
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

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'''The current model for fetal development of the external genitalia in humans and mice:'''
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''

|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.<ref name=PMID11315960><pubmed>11315960</pubmed></ref>
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* The tubercle itself goes on to form the mons pubis.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID11315960><pubmed>11315960</pubmed></ref>

[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]
|-
|- style="height:10px"
| style="width:50%"|
|}

----

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

===Current Research and Findings===
====Male====
----
{|
|-bgcolor="aliceblue"
|
[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

{|
|-bgcolor="aliceblue"
|
'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.
|}

----

{|
|-bgcolor="aliceblue"
|
'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.
|}

====Female====
----

{|
|-bgcolor="lavenderblush"
|
'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name= Abbott>Abbott David, H. '''Fibrillin-3 in the fetal ovary: can it contribute to polycystic ovary syndrome?'''. Expert Review of Endocrinology & Metabolism: 2012, 7(1); 31-34</ref>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.
|}

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research findings and interesting reads:'''
|-
| * A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>
<pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>
<pubmed>25247640</pubmed>
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

2014 Group Project 4

2014-10-23T14:27:26Z

Z3416697: /* System Development */

{{ANAT2341Project2014header}}
=Genital=
==Introduction==

[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]

This page will explain the development of the genital system in the fetal stage of development, of both males and females, after briefly explaining the embryonic development. It explores the models of fetal development of the internal and external genitalia, including the timeline of development. This page also lists some animal models used in research and outlines some current research and findings regarding the development of the genital system, including historic findings. Finally, this page also discusses some of the congenital abnormalities of the genital system.

==System Development==

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – Genital Development''
|- bgcolor="lavender"
|
# Genital System development begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally on the coelomic cavity
# The proliferation of this coelomic epithelium leads to an outgrowth due to the ingression of the coelomic epithelium, proliferation and recruitment of adjacent mesonephric cells
# This bipotential genital ridge is indifferentiated in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively
|}

===Internal Genital Development===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
|bgcolor="aliceblue"| The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression. <ref name=PMID11315960><pubmed>11315960</pubmed></ref> <ref name=PMID24240231><pubmed>24240231</pubmed></ref>

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the '''epididymis''' <ref name=PMID24240231><pubmed>24240231</pubmed></ref>. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate. <ref name=PMID24240231><pubmed>24240231</pubmed></ref>
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

| bgcolor="lavenderblush"| The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.<ref name=PMID11315960><pubmed>11315960</pubmed></ref>

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males. <ref name=PMID11315960><pubmed>11315960</pubmed></ref>
|-
|- style="height:10px"
| style="width:50%"|
|}

[[File:External genitalia current model.jpg|300px|right|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]

===Development of the External Genitalia ===

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings. <ref name=PMID11315960><pubmed>11315960</pubmed></ref>
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''

|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.<ref name=PMID11315960><pubmed>11315960</pubmed></ref>
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* The tubercle itself goes on to form the mons pubis.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID11315960><pubmed>11315960</pubmed></ref>

[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]
|-
|- style="height:10px"
| style="width:50%"|
|}

----

'''References'''

<pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>
<pubmed>25247640</pubmed>
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

===Current Research and Findings===
====Male====
----
{|
|-bgcolor="aliceblue"
|
[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

{|
|-bgcolor="aliceblue"
|
'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.
|}

----

{|
|-bgcolor="aliceblue"
|
'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.
|}

====Female====
----

{|
|-bgcolor="lavenderblush"
|
'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name= Abbott>Abbott David, H. '''Fibrillin-3 in the fetal ovary: can it contribute to polycystic ovary syndrome?'''. Expert Review of Endocrinology & Metabolism: 2012, 7(1); 31-34</ref>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.
|}

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research findings and interesting reads:'''
|-
| * A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-23T14:19:12Z

Z3416697: /* Internal Genital Development */

{{ANAT2341Project2014header}}
=Genital=
==Introduction==

[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]

This page will explain the development of the genital system in the fetal stage of development, of both males and females, after briefly explaining the embryonic development. It explores the models of fetal development of the internal and external genitalia, including the timeline of development. This page also lists some animal models used in research and outlines some current research and findings regarding the development of the genital system, including historic findings. Finally, this page also discusses some of the congenital abnormalities of the genital system.

==System Development==

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – Genital Development''
|- bgcolor="lavender"
|
# Genital System development begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsallu on the coelomic cavity
# The proliferation of this coelomic epithelium leads to an outgrowth due to the ingression of the coelomic epithelium, proliferation and recruitment of adjacent mesonephric cells
# This bipotential genital ridge is indifferentiated in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively
|}

===Internal Genital Development===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
|bgcolor="aliceblue"| The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

| bgcolor="lavenderblush"| The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males.
|-
|- style="height:10px"
| style="width:50%"|
|}

[[File:External genitalia current model.jpg|300px|right|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]

===Development of the External Genitalia ===

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''

|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* The tubercle itself goes on to form the mons pubis.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]
|-
|- style="height:10px"
| style="width:50%"|
|}

----

Until the seventh week of development, the external genitalia of both XX and XY embryos is indistinguishable,. Sexual characteristics only become apparent after the ninth week, however are only clearly different between male and female after the twelfth week of development. In the fourth week of the embryonic phase of development, the cranial end of the cloacal membrane begins to swell and proliferate and produce a protrusion called the ‘”genital tubercle”’. This protrusion acts as a precursor for the major sexual organs, the glans penis in males and the glands clitoris in females.

Also in the forth week, swellings begin to form around the cloacal membrane called the labioscrotal swellings and urogenital folds. The genital tubercle elongates in both sexes and forms a primordial phallus. The urogenital membrane which lies on the floor of the cleft formed by the urethral folds

“’Male”’
Testosterone produced by the interstitial Leydig cells of the fetal testes stimulates the masculinization of this indifferent genitalia. It stimulates the phallus to enlarges and elongates to form the “’glans penis”’, and the urethral folds begin to form the lateral walls of the urethral groove on the ventral aspect of the penis. A proliferation of endodermal cells lines the urethral groove and is referred to as the urethral plate, and it extends from the phallic portion of the urogenital sinus.

The urethral fold fuse with each other to form the ‘”spongy urethra”’ on the ventral surface of the penis. As the surface endoderm fuses in the median plane of the penis it encloses the spongy urethra- this fusion is called the “’penile raphe”’.
At the tip of the penis, the an endodermal ingrowth forms a cellular endodermal chord which grows inside the penis towards the base. This cord canalizes and the lumen joins the previously formed spongy urethra, thus completing the terminal part of the urethra, mobbing the external urethral orifice to the tip of the penis.

During the twelfth week of development, an ectodermal circular ingrowth develops around the periphery of the penis and sits like a cap. The ingrowth breaks down and forms the ‘”prepuce”’ (foreskin) which remains as a fold of skin covering the tip of a penis. The mesenchyme of the phallus gives rise to the corpus cavernosum and the corpus spongiosum. The labioscrotal swellings grow toward eachother and fuse in the center to form the “’scrotum”’, this line of fusion is eferred to as the “’scrotal raphe”’.

“’Female”’
Much like the male genitalia, the genital tubercle swells and elongates to form the “’glans clitoris”’. At eighteen weeks, the clitoris is still a prominent swelling. In females, the urethral folds only fuse at the posterior aspect and form the ‘”labia minora’’. The labioscrotal folds fuse only at two points, posteriorly to form the posterior labial commissure, and anteriorly to form the “’mons pubis”’, the remain unfused portions remain as the “’labia majora”’.

'''References'''

<pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>
<pubmed>25247640</pubmed>
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

===Current Research and Findings===
====Male====
----
{|
|-bgcolor="aliceblue"
|
[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

{|
|-bgcolor="aliceblue"
|
'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.
|}

----

{|
|-bgcolor="aliceblue"
|
'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.
|}

====Female====
----

{|
|-bgcolor="lavenderblush"
|
'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name= Abbott>Abbott David, H. '''Fibrillin-3 in the fetal ovary: can it contribute to polycystic ovary syndrome?'''. Expert Review of Endocrinology & Metabolism: 2012, 7(1); 31-34</ref>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.
|}

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research findings and interesting reads:'''
|-
| * A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-23T14:17:08Z

Z3416697: /* Introduction */

{{ANAT2341Project2014header}}
=Genital=
==Introduction==

[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]

This page will explain the development of the genital system in the fetal stage of development, of both males and females, after briefly explaining the embryonic development. It explores the models of fetal development of the internal and external genitalia, including the timeline of development. This page also lists some animal models used in research and outlines some current research and findings regarding the development of the genital system, including historic findings. Finally, this page also discusses some of the congenital abnormalities of the genital system.

==System Development==

===Internal Genital Development===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
|bgcolor="aliceblue"| The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

| bgcolor="lavenderblush"| The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males.
|-
|- style="height:10px"
| style="width:50%"|
|}

[[File:External genitalia current model.jpg|300px|right|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]

===Development of the External Genitalia ===

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''

|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* The tubercle itself goes on to form the mons pubis.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]
|-
|- style="height:10px"
| style="width:50%"|
|}

----

Until the seventh week of development, the external genitalia of both XX and XY embryos is indistinguishable,. Sexual characteristics only become apparent after the ninth week, however are only clearly different between male and female after the twelfth week of development. In the fourth week of the embryonic phase of development, the cranial end of the cloacal membrane begins to swell and proliferate and produce a protrusion called the ‘”genital tubercle”’. This protrusion acts as a precursor for the major sexual organs, the glans penis in males and the glands clitoris in females.

Also in the forth week, swellings begin to form around the cloacal membrane called the labioscrotal swellings and urogenital folds. The genital tubercle elongates in both sexes and forms a primordial phallus. The urogenital membrane which lies on the floor of the cleft formed by the urethral folds

“’Male”’
Testosterone produced by the interstitial Leydig cells of the fetal testes stimulates the masculinization of this indifferent genitalia. It stimulates the phallus to enlarges and elongates to form the “’glans penis”’, and the urethral folds begin to form the lateral walls of the urethral groove on the ventral aspect of the penis. A proliferation of endodermal cells lines the urethral groove and is referred to as the urethral plate, and it extends from the phallic portion of the urogenital sinus.

The urethral fold fuse with each other to form the ‘”spongy urethra”’ on the ventral surface of the penis. As the surface endoderm fuses in the median plane of the penis it encloses the spongy urethra- this fusion is called the “’penile raphe”’.
At the tip of the penis, the an endodermal ingrowth forms a cellular endodermal chord which grows inside the penis towards the base. This cord canalizes and the lumen joins the previously formed spongy urethra, thus completing the terminal part of the urethra, mobbing the external urethral orifice to the tip of the penis.

During the twelfth week of development, an ectodermal circular ingrowth develops around the periphery of the penis and sits like a cap. The ingrowth breaks down and forms the ‘”prepuce”’ (foreskin) which remains as a fold of skin covering the tip of a penis. The mesenchyme of the phallus gives rise to the corpus cavernosum and the corpus spongiosum. The labioscrotal swellings grow toward eachother and fuse in the center to form the “’scrotum”’, this line of fusion is eferred to as the “’scrotal raphe”’.

“’Female”’
Much like the male genitalia, the genital tubercle swells and elongates to form the “’glans clitoris”’. At eighteen weeks, the clitoris is still a prominent swelling. In females, the urethral folds only fuse at the posterior aspect and form the ‘”labia minora’’. The labioscrotal folds fuse only at two points, posteriorly to form the posterior labial commissure, and anteriorly to form the “’mons pubis”’, the remain unfused portions remain as the “’labia majora”’.

'''References'''

<pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>
<pubmed>25247640</pubmed>
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

===Current Research and Findings===
====Male====
----
{|
|-bgcolor="aliceblue"
|
[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

{|
|-bgcolor="aliceblue"
|
'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.
|}

----

{|
|-bgcolor="aliceblue"
|
'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.
|}

====Female====
----

{|
|-bgcolor="lavenderblush"
|
'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name= Abbott>Abbott David, H. '''Fibrillin-3 in the fetal ovary: can it contribute to polycystic ovary syndrome?'''. Expert Review of Endocrinology & Metabolism: 2012, 7(1); 31-34</ref>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.
|}

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research findings and interesting reads:'''
|-
| * A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-23T14:13:20Z

Z3416697: /* Genital */

{{ANAT2341Project2014header}}
=Genital=
==Introduction==

[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]

This page will explain the development of the genital system in the fetal stage of development, of both males and females, after briefly explaining the embryonic development. It explores the models of fetal development of the internal and external genitalia, including the timeline of development. This page also lists some animal models used in research and outlines some current research and findings regarding the development of the genital system, including historic findings. Finally, this page also discusses some of the congenital abnormalities of the genital system..

==System Development==

===Internal Genital Development===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
|bgcolor="aliceblue"| The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

| bgcolor="lavenderblush"| The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males.
|-
|- style="height:10px"
| style="width:50%"|
|}

[[File:External genitalia current model.jpg|300px|right|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]

===Development of the External Genitalia ===

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''

|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* The tubercle itself goes on to form the mons pubis.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]
|-
|- style="height:10px"
| style="width:50%"|
|}

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Until the seventh week of development, the external genitalia of both XX and XY embryos is indistinguishable,. Sexual characteristics only become apparent after the ninth week, however are only clearly different between male and female after the twelfth week of development. In the fourth week of the embryonic phase of development, the cranial end of the cloacal membrane begins to swell and proliferate and produce a protrusion called the ‘”genital tubercle”’. This protrusion acts as a precursor for the major sexual organs, the glans penis in males and the glands clitoris in females.

Also in the forth week, swellings begin to form around the cloacal membrane called the labioscrotal swellings and urogenital folds. The genital tubercle elongates in both sexes and forms a primordial phallus. The urogenital membrane which lies on the floor of the cleft formed by the urethral folds

“’Male”’
Testosterone produced by the interstitial Leydig cells of the fetal testes stimulates the masculinization of this indifferent genitalia. It stimulates the phallus to enlarges and elongates to form the “’glans penis”’, and the urethral folds begin to form the lateral walls of the urethral groove on the ventral aspect of the penis. A proliferation of endodermal cells lines the urethral groove and is referred to as the urethral plate, and it extends from the phallic portion of the urogenital sinus.

The urethral fold fuse with each other to form the ‘”spongy urethra”’ on the ventral surface of the penis. As the surface endoderm fuses in the median plane of the penis it encloses the spongy urethra- this fusion is called the “’penile raphe”’.
At the tip of the penis, the an endodermal ingrowth forms a cellular endodermal chord which grows inside the penis towards the base. This cord canalizes and the lumen joins the previously formed spongy urethra, thus completing the terminal part of the urethra, mobbing the external urethral orifice to the tip of the penis.

During the twelfth week of development, an ectodermal circular ingrowth develops around the periphery of the penis and sits like a cap. The ingrowth breaks down and forms the ‘”prepuce”’ (foreskin) which remains as a fold of skin covering the tip of a penis. The mesenchyme of the phallus gives rise to the corpus cavernosum and the corpus spongiosum. The labioscrotal swellings grow toward eachother and fuse in the center to form the “’scrotum”’, this line of fusion is eferred to as the “’scrotal raphe”’.

“’Female”’
Much like the male genitalia, the genital tubercle swells and elongates to form the “’glans clitoris”’. At eighteen weeks, the clitoris is still a prominent swelling. In females, the urethral folds only fuse at the posterior aspect and form the ‘”labia minora’’. The labioscrotal folds fuse only at two points, posteriorly to form the posterior labial commissure, and anteriorly to form the “’mons pubis”’, the remain unfused portions remain as the “’labia majora”’.

'''References'''

<pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>
<pubmed>25247640</pubmed>
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

===Current Research and Findings===
====Male====
----
{|
|-bgcolor="aliceblue"
|
[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

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{|
|-bgcolor="aliceblue"
|
'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.
|}

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{|
|-bgcolor="aliceblue"
|
'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.
|}

====Female====
----

{|
|-bgcolor="lavenderblush"
|
'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.
|}

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{|
|-bgcolor="lavenderblush"
|
'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.
|}

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{|
|-bgcolor="lavenderblush"
|
'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name= Abbott>Abbott David, H. '''Fibrillin-3 in the fetal ovary: can it contribute to polycystic ovary syndrome?'''. Expert Review of Endocrinology & Metabolism: 2012, 7(1); 31-34</ref>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.
|}

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{|
|-bgcolor="lavenderblush"
|
'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.
|}

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{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research findings and interesting reads:'''
|-
| * A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

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==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

Talk:2014 Group Project 4

2014-10-23T14:08:32Z

Z3416697: /* Group Topic */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==

Your group project is of excellent quality, there are just a few minor things to take in to consideration if you wish.

Firstly, well done in creating a timeline in a table format that seperates the key events that occur between male and female gonad development. This is exactly the type of information I wouldve expected to see if I was interested in looking up information about the differences between male and female internally and externally and when these events take place. There is, however, much information about the male in this table and not as much information as there is in the female. You might also like to consider selecting one type of font for your table, just so that it looks a little neater.

Your section of current research and findings looks fantastic, with a lot of text, but sadly not enough images! Good work though with the and drawn image! There are a few hand drawn images on this group project page so well done for that! There are a few parts in the project where an image still needs to be uploaded/formatted but it looks like you are aware of these things with mention of [draw image here] as an example. In this same section, there is a great number of dot points, perhaps try to part of it in paragraphs so that not all the information is simply presented in dot point form. You can tell you have done a lot of research here, so well done.

In the historic finding section, there is a lot of text and only one image (a hand draw one, which is really good!). However, the amount of text is not matched with a visual component such as more images, or a diagram or table. Perhaps increase the amount of visual things in this section so there is appropriate balance-awesome work really!

Great choice of a youtube video! It showed the different stages of gonad development, both at the indifferentiation stage and when the gonads differentiate, into male and female. However, the video is quite long, it is approximately 10 minutes long, would you perhaps consider a shorter video? or trimming the video down? With that being said, I do think it provides a great visual for the key developmental aspects, so great choice there!

The abnormalities section is well researched. The abnormalities are listed from the most common to those that are rare, that a great way of giving the reader a general idea of its frequency in society. There are any abnormalities described in this section, and information is presented equally for both sexes as well as abnormalities that affect both sexes. There is also an excellent hand drawn image from the textbook that is correctly cited and contains the appropriate copyright information as well permission for this image to be reused after 6 months.

One last thing, before submission place all your references in one reference list.

Well done project group 4! I enjoyed reading about your project. All the best!

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There is definitely plenty of useful information and your group has clearly put in a lot of effort to do extensive research on the topic. However there are some inconsistencies with formatting and references, which you can easily iron out once you have time for a final edit.

There’s a lot of content on the page and understandably its difficult to organize it in a way that’s meaningful and easy to read. I think there are a few too many subheadings and it becomes a little confusing to follow, for example under the current research, models and findings heading, the female subheading was hard to follow so I think that just needs a brush up. I think it would be a good idea to avoid presenting all the information under this heading just as bullet points. Try to have at least 2-3 current research articles and under them elaborate on what the findings were and what they may imply. I think it would be much more interesting if it was presented that way rather than spread over so many bullet points.

I particularly liked the use of original hand-drawn diagrams with colour helps to make the page more visually appealing and interesting to read. I see there is still work to be done under the current findings section. It would be a good idea to summarise the findings and state their implications on current knowledge under each article. The historical findings section is definitely extremely elaborate but I feel it may be a little too much. I think it’s important to keep in mind the purpose of the assignment and focus more on the actual fetal development and keep information succinct and relevant rather than overloading with information. The Abnormalities section was done extremely well and had a lot of useful information on many different diseases.

Overall a great effort by the group, definitely can see how much effort you have all put in.

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This page overall looks really fantastic and highly informative! A brief introduction is lacking at the start of the page- would be nice to briefly introduce the topic of the page and the intended goals for the page to achieve to present to the reader. This section would also nicely unify the contents of the project as a whole. The system development part has very extensive information with a great use of formatting styles- with the use of bullet points and the table format. Perhaps the placement of the image and video could be re-integrated into this section as it seems fairly isolated and doesn’t unify this section greatly. Also a brief description could be added to the image and video to describe what is being presented. The video however is a great idea and a good choice of one too! Very informative and simplifies the information being presented. Current research section looks great so far; few changes to formatting would be beneficial (i.e. with font styles and the general structure of bullet points can be made more visually presentable). There is evidence of extensive research however and the use of subheadings also nicely structures this section. There is an error with one of the uploaded images, which should be corrected however. The information presented within the historic findings section seems highly extensive, although perhaps the formatting could be altered to make it look less bulky and easier to read and understand for the reader. The abnormalities section is greatly done, very informative and looks fantastic, well done! All references should be integrated into the final references section that is already been established.

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Great progression on the table in text citation for it is missing. Also in the table for week 5 you have bullet points and for weeks 1-7 you have a different type of bullet point. Try keeping it consistent.
The diagram used to illustrate the genital development of different genders is very good and effective.
Current research and models section needs more pictures to help aid with the information. Under current models section, the hand drawn image is very good and effective in portraying the overview. Also in the current research and model section, try using more than one reference.
Current findings section is currently empty but that’s ok as you still might have 1-2 weeks to finish the project.
Historic findings needs more images as it seems like a big bulk of text. However it is very well researched.
Abnormalities needs more pictures as it seems like a bulk of text. I suggest obtaining a picture for each abnormality you talk about if possible. This aids the readers’ understanding of that specific abnormality. Also ‘pictures say a thousand words’ so it would be great if you can include pictures.
All hand drawn images are great and clear to read and understand.
Your references from other sections need to be in the end of the page in a bulk.

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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. 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.

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The Introduction, Current Models and Current Research section all in dot-point form, which obviously allowed you to more easily, put information on the page. These need to be converted into paragraph form to give the content greater readability and flow.

Presuming the system development is supposed to be the introduction, there should be inclusion of current research, historical research and abnormalities. Without these the reader will not know all the sections of the page after reading the introductory section, which is the intros purpose. The use of bold and capital letters is unneeded. The existence of a table is good though has a bunch of formatting and text problems (capitals, bold, captions, lack of lines). “(around week 4-6) that sexual differentiation occurs in the fetus ” this statement is incorrect since it is an embryo during the week4-6, it becomes a later around week 10. “450px” has not been inserted properly, the sexual differentiation image requires caption and references.

Current Research and Models has in-depth content for undifferentiated and male, though limited information on current female genital research. The headings are repetitive also many without any content, similar content needs to be merged under single headings. In Historic findings the content and wording is good but same trend continues significantly more text on Male development compared to female.

Abnormalities section is great with even attention given to female, male and both. Information is appropriately in-depth and referenced, addressing causes, process and treatment. Addition of 1-2 images in the “both” section is advised, to allow readers to identify clinical features of the diseases. Like the use of drawings especially “Abnormalities of the Uterus and Vagina” and “Anat of Testes”, you should change the caption of the testes drawing from “alt text”.

For improvement; covert of dot-points into paragraphs, expand on female sections of “current research” and “historical research”, fix a few image problems and remove unnecessary bold/capitals/captions.

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A great start on tabulating the information about the development of this system. There are references but I don’t see any in-text citations. The image used in this section is really good and relevant. It clearly shows the major processes in the development of the genital system. However, it is a bit pixelated so maybe try resizing the image to a smaller size. Maybe try uploading the image again with a different filename, change it to something more appropriate rather than “Image.jpg”. And also, if possible, try to include it in the table. Good job on embedding a video! I think this is the only group so far that has included a video. It’s a good video about the development, I just wish it had a voice-over explaining what is happening but that’s not really the group’s fault. Nonetheless, great job on the development section.

With the current research section, great use of dot points but a bit excessive. Maybe try to make paragraphs where it is appropriate. It is well-researched, very detailed and very informative. It’s good to see student drawings. Great job on that. I see that an image was not properly uploaded into the page, so just fix that. Good job on referencing. All research articles seem to be relevant to this section but try to incorporate some of the in-text citations of the remaining articles, not just the first three. Overall, really great job on the content of this section. It is evident that the person responsible for this section put a lot of effort in research.

As for historic findings, great job! I know this is probably the hardest of all the four sections in terms of finding information and this section is well-researched, very detailed, and very informative much like the current research section. Maybe try to use some dot points to lessen the bulk of this section. Great drawing included in this section. Try to add more, especially for the males since that is the bulk of this section.

Lastly, for abnormalities, great job on finding lots of abnormalities! Lots of references and each area of this section seems to be well-cited. The content of this section is very concise. All the important information about the disease is included, from the cause to the treatment. Good work! Try to find more images for the other abnormalities. It may be tedious but it will help in visualising the clinical manifestations of each disease. Overall, this group has done their research and did it well. Great job on the table for development and images. Their page is very clean and very organised, particularly the references. Don’t forget to write an introduction for your project’s page.

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Just looking at the contents, if feels a little intimidating both in that it is so long as well as the use of caps. You should try and limit both; the use of all caps can be quite annoying in text and the extensive contents list can make people dread reading through your page if it looks like it’s quite long.

An introduction is recommended as it is usually a good starting point to provide the reader as sense of everything the page will cover. The system development is a little messy, but I will heed your note and pay attention to only the table. The table itself is a great idea to lay out all the events happening in the corresponding weeks, making it look neat and concise. However, the use of all caps, bold text, and two different fonts still makes this section look messy. Having both male and female events on the same table makes it look as if there is a chunk of info missing for the female side as well. I would suggest having them in separate tables next to each other, which would eliminate the empty rows in both areas. Both the image and the video (congrats on finding a video! Really good addition to the page) should be captioned.

The current research, models and findings seems well researched as there are a lot of points made. However, it is all presented in bullet points which can be visually unappealing. Some sections look incomplete as well, so an effort needs to be made to finish these areas as well as present them in an appealing manner e.g. in paragraph form with a picture next to it to both describe the text visually and offset the amount of text. The drawing of the testes should be captioned appropriately instead of the ‘alt text’ provided. It should also be enlarged, as its current size isn’t large enough to view any of the labels properly.

Historic findings looks well researched on first glance, but then I saw that only 4 sources were used to reference the section. It looks really bad when only one source is used to reference a large slab of text, which you have done twice. I suggest finding articles that state similar information and using them as references as well, to back up your current information found. Other than that, I suggest possibly formatting your section in a more appealing way; either summarize some areas in dot points, and add a picture.

The abnormalities section is nice and concise, without going into too much detail which is good. Just make sure you explain what it is, how it is formed/how you get it, some statistics and possibly an image to show what it looks like, and that’s all I believe you really need for this section.

Overall, your page is well researched with lots of info. Just make sure it looks visually appealing, is consistent in terms of font and presentation, images are used and captioned correctly, and all references are placed at the bottom of the page.

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Firstly, great job on all the contents you guys managed to present, it’s quite detailed. There seems to be no introduction though, and the page jumps straight into explaining genital development. I think if an introduction were added, it would give the whole page better structure and formatting so the reader knows what to expect when they decide if they want to read on. The dot points used for the developmental section allows for easy readability of the contents, however, the use of caps lock and arrows takes away from the overall presentation of the page. I would suggest any text you want to emphasize to make bold or underline the word. I also noticed that there was a note stating the attempt to put all the developmental information into a table, but had issues. I suggest you look at the editing basic page you can search for in the top right hand corner as it outlines a step-by-step guide into making tables etc.

In regards to referencing, there are no in-text citations for the first two subheadings. The sections were they do have citations also have a list of references at the bottom of each section. I would recommend just adding a final list of references at the bottom of the page, as it looks much neater.

I’m impressed with the level of hand-drawn diagrams uploaded. I would also recommend adding captions to the image. For example:
[[File: Flow Diagram of Fetal Development of External Genitalia.pptx|1000px|thumb|right|alt text]]. The “alt text” should be edited to describe the caption of the drawing. This particular image seems to have a broken link though; the “alt text” also appeared in the labeled diagram of the testes. Otherwise, good job on the other images.

The current findings section seems to be untouched, with the exception of some pubmed journal article links, I’m assuming you are still in the process of adding content. The historic findings, however, is extensive and well researched. Good job.

The abnormalities section is done well. There is more than enough abnormalities listed, and they are researched well, I would just suggest adding a few more images for better visualization. Overall, great page, just needs better formatting for the mentioned sections.
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Nice amount of content on this page. some work needs to go in reformatting the development and Current model sections as the dot points don't bring some of the information across effectively. Perhaps a table could remedy some parts

The Table included is well done but could use some references integrated.

Referencing is very poor in the development and current research sections. more work needs to be done here in not only obtaining more citations for the content as there is next to none for the amount of content, some reformatting needs to be done so the citations are all listed in the same spot

A few points where information is missing as per your edits. just make sure to remedy this and proof read before submission to add relevent content or remove the text.

Great work so far. More images can't hurt
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This project would benefit from having an introduction to prepare the reader for what is to come and summarise everything briefly. The system development part is interesting and clearly there has been a lot of research put into finding the information. I suggest adding pictures or student-drawn diagrams, particularly of the chromosome and the SRY gene location to make it more comprehendible. If you’re not a geneticist, it can be difficult to picture that much detail at an embryonic level.

It is clear you have considered inserting images so it would be important to follow through with that before the final stages of marking. I’m not really sure why you’ve inserted a table here as well since a lot of the information was already covered previously. Maybe use less information in the table. The references at the end of this section should appear at the very end of the wiki page. A lot of other groups have already done that so if you need to copy the formatting, it’s definitely possible. The use of a video on your page is commendable and sets this project above others in that sense. It’s a great idea to have a youtube clip. However, it is 9 minutes long which is a bit long for a student page that is designed to inform students on the genital system on a wholistic scale rather than tackling complicated ideas. Maybe try editing the youtube video so you only use a 30 second or 1minute clip.

The male and female genital development section is clearly presented and the use of bullet points make it easy to follow. However reading the information, it appears that a lot of it I recognised from the lectures. This doesn’t suggest the student explored external embryology sources. On another note, perhaps the lecture on the genital system was very indepth and this student did do research but found all the relevant information had already been covered. None the less, I think it would be advantageous to add a subheading in the section that looks at recent findings. This would broaden the understanding an embryology student can achieve by reading this wiki-page. Also there has been an error uploading an image so that should be fixed.

Although the information is presented well, the bulk of references should be included at the very end of the page. This project is very good but there is still some further research needed, particularly under the current findings subheading. The information presented under the historical findings subheading is quite dense and would benefit from being broken up into a table or simple bullet points. The abnormalities part is excellent and there has clearly been broad research into different embryological resources.

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

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

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

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

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

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Don’t forget to add an introduction which clearly lists the outcomes that the page hopes to achieve!

The table in the development section is excellent and very clear and informative. I believe you could summarise the text above and add it to table to improve the presentation. There is a very good choice of categories and headings/subheadings. The information presented is excellent. Remember to just correctly cite the information and improve the overall format of this section.

There is an excellent choice of headings and subheadings in the current research section. It is very informative and demonstrates significant scientific research. I do believe that this section could be summarised or the presentation improved? It is a bit wordy- try to summarise more or present the information in paragraphs/a table? (only a suggestion though). The addition of hand-drawn diagrams was excellent and very admirable

The historic findings section was excellent. There was a very good choice of headings/subheadings. The information provided was very informative and demonstrated significant scientific research. However, it is a bit wordy and would be benefited with summarising the content further. Though the content has been referenced correctly, I believe it could be further enhanced with more references to verify the possible points. The addition of pictures would also benefit. Excellent work nevertheless. Very informative section

The abnormalities section was excellent. A very good choice of headings/subheadings and a good variation of abnormalities included. It was referenced and cited correctly. Demonstrated strong scientific research. Maybe improve this section with the addition of more images? Nevertheless, an excellent, clear and informative section.

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The project would be easier to follow by having an introduction that give readers an idea about what is going to be covered in the website.

Under the section about system development, it contains lots of information and it is well researched. Using bullet points is good as it is easier to read, however some of them could be join together into a small paragraph which would increase the readability. It is good to see a related video about the development of reproductive system and it explains well about this topic.

It is a great way to explain abnormalities in terms of female, male, and both. Maybe try to put a table at the top to summarise the abnormalities so that it would be easier to follow. More images are needed in this section, just like the one illustrating abnormalities of uterus and vagina.

It is well-researched under historic findings, try to put more related images to make this section more interactive. Also, it would also be good to illustrate the content in this part by a timeline, followed by the explanation of each event.

In terms of referencing, in-text references are missing in the system development, current research and historic findings.

For the image file “Image.jpg”, which is about sexual differentiation, it is a good image that explains the differentiation clearly, however, it would be better to put a description or title below it to make it more relevant to the project. It is good to see some hand-drawn diagram and they match the topic and explain information well. I found it a bit hard to read the labels on the image “labelled drawing of testes.jpeg”, maybe upload the image by scanning rather than taking a photo of it would be better.

It is overall a well-researched project. The next thing to do is to include an introduction, some more in-text references and some related images.

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The table of development is good and visual however to make it look clearer the formatting could be slightly changed so that all of the text is in the same style and format. Nice use of video as well as diagrams. Historic findings could benefit from some diagrams, bullet points or subheadings in order to break up the large amount of text in order to make it easier to read. Good list of all the abnormalities with the relevant information. You could put all of the references at the end to make the main text flow better.
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Genital

There is a lot of information with hardly any pictures or diagrams to support the information. It is currently very not appealing visually.
System developments, Current research, and models and findings are all written in dot point form which should be converted in paragraph format before final submission to match the wiki format. I think that you should add an introductory section to tell the readers what the genital system is about, and what its function is in the adult. Also you should definitely put the references together before the final submission date.

The historic finding section is very detailed and well explained; it’s very well done. The abnormalities section was very well done and easy to understand with no punctuation errors etc; the drawing of the uterus/vaginal abnormalities were very easy to understand and self explanatory. I found it really nice that the abnormalities section was further divided up into female / male and those which both genders can have.

As for points to improvement, flow of information and it’s formatting can be improved by moving subheadings to more appropriate places, and also by labelling the pictures and diagrams.The contents at the start of the page is very well sectioned. I love the video; your group wiki page is the only one with a video, and it’s really informative and helpful, especially for visual learners like myself.
Overall: VERY well researched and detailed!!

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In this review I will attempt to highlight the merits of your project and provide some constructive criticisms in light of the marking criteria.

Great work on system development, a lot of research has been done and the page seems well organised. I suggest using the information you have collected to write up succinct paragraphs, with forget in-text referencing. Furthermore, I find that that the table is a really effective means of summarising everything, you’ve made good progress so far. I also feel that the diagrams and video really support the text and have been appropriately selected.
The current research section is a looking good, it’s great that you are exploring the molecular signals driving genital development, with references to FGFs, SHH and BMPs. I think this area needs to be addressed in further depthg. I also suggest including relevant studies, methods and findings. Finally don’t forget to include references!

I see that a significant amount of research has been conducted on the historical understanding of genital system development. Your project provides a particularly interesting insight into the debate on mechanisms of testicular decent. To make this section more interactive and engaging I would suggest the inclusion of historic illustrations and diagrams. There are many images available on both the UNSW embryology database and the UNSW library database. I also suggest that further research of the female genital system. Finally use in text referencing to support your data.

The section final section of your project investigates a number of male and female genital abnormalities. The diagram on abnormalities of the vagina and uterus is particularly interesting and certainly assists my understanding of these abnormalities. I simply suggest that you provide a little more depth on each abnormality. Ensure that you address the following areas are addressed: Cause; Description; Treatments.
The page is well structured and incredibly cohesive. The references are well organised. Finally I’m really impressed by the drawing and diagrams. Great work so far! Just make sure you include that introduction in the end and add all the diagrams and images you plan to.

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An introduction is recommended as it is usually a good starting point. I suggest starting by giving background information on the anatomy of male and female genital systems. You can then talk about the embryonic period and give a brief summary of how this period is different to fetal period. You can then briefly mention the significant events that occur during fetal period and the sections you are including in your project (including abnormalities and research findings).

The table in the system development is a good summary however it looks a bit messy at this stage. I suggest having two different tables for male and female, avoid using all capital letters and bold texts in the table. I also suggest starting the development section with a brief paragraph on early stages of development. The image included under ‘system development” is a very good summary but it needs to be captioned and referenced. I also recommend re-uploading the image in a smaller size to improve the quality. The use of the video is also very creative. Well done for finding this helpful video!! It would be perfect if you could reference the video and maybe include a few sentences on what it is showing. Overall, the development section is very good with the use of different methods to help in learning. To make this section perfect, you can add some details in paragraphs to explain more on different stages of development.

There is a lot of information under “current models” which shows extensive research, however I find this section hard to follow. Using paragraphs instead of dot points will result in a more coherent flow. Also the studies need to be referenced appropriately; it would be a good idea to include the name and year of the article in the text. The division into “current research” and “current models” is a smart thing to do however in both sections the amount of information provided for male is much more than female therefore more research needs to be done for female. I like how a self-drawn image is used; it would be a good idea to include a description for the image (rather than “alt text”). Also make sure that all the references are listed at the end under one reference subheading instead of having different references for each section. Also, great job for historic findings! This is the most difficult section but you have managed to include detailed information. Similar to current research section however, most of the information found is for the development of male system. Try to add to historic findings on female system if possible.

Abnormalities section includes a significant number of abnormalities with causes and treatment of each abnormality addressed precisely. I also like how you divided this section into female, male and both. Information is well referenced and helpful images are included. Make sure that your images are referenced. If self-drawn images are used, then you can briefly mention that in your text. I would also recommend adding more images for other diseases to illustrate the clinical manifestations of each disease. Overall this group has done an extensive research and the methods used (such as drawings and videos) are very creative and helpful. Well done!

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The definite strengths of this page are the ‘Historic Findings’, ‘Current Models and Findings’ and ‘Abnormalities’ sections. They have plenty of detail and are well referenced but could benefit further with the addition of more images (some historic images would really make the ‘Historic Findings’ section even better). The ‘Historic Findings’ section would also be easier to follow if it were broken up (perhaps by using dot points or tables). Some of the uploaded images need captions to help explain them to the audience.

The attempt to tabulate the information in the ‘Development’ section of this page is a good way of presenting the text and makes it easier to understand. It needs to be completed and supported by more images. The inclusion of the video is also a great addition to this page but it does suffer from a lack of explanation. A brief explanation of the video or some time links in your table would make it easier for the audience to understand.

Overall your page has some great detail and it is apparent that a lot of research has been carried out to give plenty of citations to your text. An introduction to your page would be a great asset as it would introduce your page to the audience and give a general overview of what this page is presenting.

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Progression of ideas in this group project page is great as concepts are easily understood and conveyed to the reader. Furthermore, genital development for both female and males in the embryonic period are excellent summaries. An introduction would further help introduce the reader to what the page will be discussing and other important information. For improvement, technical problems such as text error and image problem fix-up would make the page more credible.

====Strengths====

• The use of the video clearly explains the development of the reproductive system as well written-up images indicate dedication and convey information easily.

• Use of bullet points for current research is easier on the eyes to read and improves structure.

• Headings and short and clear.

• Good amount of references used for the project page.

• Current research finding are good but can still be improved.

• Abnormalities section clearly describes the various defects that can occur in both sexes.

• Table summarises timeline quite well but can be improved.

====Weaknesses====

• Consistency in terms references being placed after paragraphs such as system development. These should be placed in the end.

• More in text citations are needed to show up to date links to current research articles.

• Paragraph and heading errors need to be fixed.

• Some images need to have an image and name and description as this may confuse the reader.

• Historic findings has been stated within the project page should be added as well as current research needs to indicate current research articles and the areas to which they are heading to.

• Grammatical error found and should be fixed.

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Overall this is a good project, and it is evident that you all have put a great deal off effort into researching this developmental stage. I enjoy the use of diagrams, especially the diagrams which you have drawn yourself- as it shows that you have a clear understanding of the topic at hand and eases our understanding of a complex topic. Although, I must comment that the first diagram you have used- whilst extremely helpful, is a bit pixelated and I think that if this is changed it will greatly aid the look of your project.

I found your project to be a bit too wordy. I understand that genital development is a complex topic since you have to cover two different methods of development, however I think that the use of tables and dot points will greatly aid the clarity of your work. I think that “System Development” is off to a good start, and once the formatting issues are resolved, the table will be a good way to express the development.

I enjoyed the diagrams in current research models, however I think the presentation of your work overall can be improved. For example try scanning in the picture instead of taking a photo showing the background. Further, the paragraphs are a bit too long to retain interest and I think this section can benefit from shorter dot points or a time line.

Again, the historic findings seems very well researched, however for this purpose it is a little *too* exhaustive. I think it would be a better idea to cut back on so much detail and make it easier to read. Or consider formatting your work in a different manner so as to appeal to the reader.

The abnormalities was well done, and I think its on the right track with the use of subheadings to break up the work. I understand there is a lot to talk about in this section, but the paragraphs are not succinct enough to retain my attention throughout the entire piece.

Overall, the grammar and punctuation is quite well done, I think that the project as a whole needs some cutting down and tightening to make it more easy to read, but off to a good start.

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There is no introduction, not having an introduction would mean there is no overview of what this page would be about and what it will discuss in detail. If an introduction could be uploaded maybe consider an image that would be able to sum the introduction up.
I appreciate the detail that went into the genital system development with dot points however there is a comment above stating that you are having formatting issues in trying to put the following information into a table. I hope this works out because it would be very effective.

On the down side there is no reference in the first two sections of the page. If you could include in text references, this would be more professional and also allows the audience to refer to the paper if interested.
I like the youtube video you added on your page this is definitely a benefit for your page as it will reinforce the information you have been trying to get across, and it would be a break from reading information and some what relaxing -just watching the video while being informed of the genital system.

For the “Current research” section there isn’t much information here, maybe you haven’t had the chance to upload anything in this section. This is definitely a section that needs improvement. Also include some citations and pictures.

Overall this page needs to focus on getting all of the information uploaded and pictures with correct references.

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Your group have excellent topics that cover the genital topic extensively. I feel it was a good approach to discuss the background to genital development in the ‘System Development’ section. It sets a good basis for the rest of the page which is focusing on fetal development. There could be some mentioning that the page is primarily focusing on fetal development for viewers who might read it in the future. There is information missing on about femal genital development in the first table, ‘System development’ section. Likewise there are some information missing on male genital development for example in the current findings. I’m sure you guys will add that information as the assignment progresses.

There is a good use of diagrams. The first diagram in the ‘System Development’ maybe needs a description. Under current models there is a diagram which seems not to be working. This can be easily fixed by referencing to the manual on editing as you guys would have already known. Otherwise there are a lot of really good hand drawn diagrams throughout the page which are helpful and show a good knowledge of the concepts. There are some references in the ‘System Development’ section which could be added to the main reference list. Likewise in other sections there are small references lists which could be added to the main reference list for easy reading through of topics. There must be a lot citations for current research, maybe the in text number links can be added if future readers want to know the original source.

The page shows an extensive amount research and it is clear that the group has done a lot of work. There is an element of teaching at a peer with the good diagrams as previously discussed. Research beyond the level of teaching is also evident and this can be further explored with the remaining time left for the assignment.
Overall good job guys! Keep going

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Group 4

There are key points relating to the topic shown in table format and bullet points. The table is well used for the timeline of events occurring in both female and male and provides simplicity however it looks incomplete and disorganise. Majority of the table shows embryonic stage and female development looks incomplete. Under the timeline there is a paragraph introducing the genital system development, it does not fit there and does not flow with the information given in the timeline above. There is also diagram placed below it with which is not labelled however it is relevant and good as it provides an overview of how the two different genitals develop.

Current research and model heading has some relevant information such as what signalling and growth factor could affect the system in development as well as showing mouse models being used however there is some irrelevant information that doesn’t clearly show what model is being used such as that under the “Female” heading. It looks like they have just stated the event occurring in the development. There isn’t much research shown in this section.

Historic findings is well researched for male genital system. It’s clear and shows events occurring in chronological order. Appropriate information is used and it’s highly detailed for testicular descent and prostate formation however some information is not citied. A picture or video could be included in this section to make it more understandable and engaging. The female historic finding does not have a time frame into when in history theories of its formation occurred. There is also no subheading like that of male system to make it clear and distinct. Diagram of mullerian duct is good and relevant just needs clearer information about vagina formation and ovary, possibly could include a diagram of either vagina, uterus or ovary formation.

Abnormality section is well written, it is organised appropriately by first discussing male abnormality and then female abnormality and then both. It clearly defines the abnormality and there is a range of picture that relate with the information given used (hand drawn and labelled diagram).

Overall the headings in this project page are related to the objects of the assignment, some good use of drawings and diagram however they need to be better organised (such as the very first diagram) and some are not properly labelled which needs to be fixed. Group has also shown a relevant video of development of reproductive system however it looks out of place on the page needs to be placed somewhere better. The research model section has some key points relating to their topic however some section talks too much of embryonic period which not relevant to the project. More pictures could be added into this section and information could be better organised instead of having list of points where some don’t relate with the point above it. Citation and reference is correctly done however having a list throughout the page and also at the end makes it look disorganised. Having in one section would make it neater and easier for readers to navigate.

---

==Group Topic==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 01:08, 24 October 2014 (EST)
The following are excerpts from this groups Facebook conversations regarding the project- names have been removed.
1. Hey everyone,
Did you all want to maybe have just one reference list for our group page ?

sounds great October 8 at 5:11pm · Like      

Okay I'll wait for everyone to reply and then I'll try to do it  October 8 at 5:24pm · Like · 1      

Hey that's sounds good, do whatever you think needs to be and we can alter it for the final if need be
I have work now so I'm sorry if I can't answer any questions this evening October 8 at 5:33pm · Like      

Alright great, no problem  October 8 at 6:47pm · Like      

   oh also I've added a video so feel free to move it wherever you guys like, I don't think it really matters that much at this point anyway  October 8 at 6:49pm · Like

2. Hey, when you have drawn something from an article, do you have to include the copyright information? Say my article is from pubmed, what copyright info do I have to add?
Also if I add a pic from an article in the 1800s, which mark said I can since copyright has expired. Do I just say eg.
Copyright has expired. Model was illustrated in 1896.
That's what I did for mine, if you guys can confirm this or tell me what to do. Thanks

i would just write everything it says on the reference tutorial page mark made becuase that is what he is looking for 4 hrs · Like      

Yeah I agree with just include everything to be safe 4 hrs ·

3. Hi does any of you know how to make an image stay in the same section, cause my images move below the content I've written

maybe aline it to the left or right? October 22 at 6:49pm · Like      

   I tried its just keeps going to way below but I can't make it smaller cause then the quality will be bad hmmm..... October 22 at 6:51pm · Like      
did you try putting it before the text? October 22 at 6:53pm · Like      

yeah October 22 at 7:01pm · Like      
I am going to try spacing October 22 at 7:01pm · Like      

your a wiz with colours, is there a way I can make my headings for the male and female sections to be blue and pink ? October 22 at 7:16pm · Like      

‪https://embryology.med.unsw.edu.au/.../Help:Font_Colour... Help:Font Colour Tutorial - Embryology These are the standard color names supported by most modern browsers. If the color matches the name, your browser supports the color name. EMBRYOLOGY.MED.UNSW.EDU.AU             October 22 at 7:23pm · Like · Remove Preview      

Yay thank you  October 22 at 7:24pm · Like      

no problem

4. Just to reiterate what Mark told Dinithi, Barbora and I. He has set up a new page called group 9, I'm going to copy and paste the commands from our group there (section by section) to find where the issue is. He believes that it is one of our uploading or commands that has corrupted the system. So please do not upload anything now until I have tried that. I should be able to do this by late afternoon, at the latest. I will let you all know when you can start editing again.

Like
Like ·
Seen by everyone

Okay great thank you  October 21 at 2:42pm · Like      
Thanks Abdo October 21 at 2:50pm · Like      
Ok, so I have done what Mark said and each section uploads fine, so there is not an issue with any commands. I then tried to upload each section together and that is when there was a database error, so I am assuming maybe the size is too big and the system can't handle it. When I upload everything excluding one section, then it works again. October 21 at 3:08pm · Like      

Also, uploading each section, the current research and the abnormalities take a while to upload, whereas the system and the historical do not. But that is because they don't have as many images as the others. October 21 at 3:09pm · Like      

Can we tell him I hasn't worked so we can get an extension hahah my eyeball is on fire reading hurts October 21 at 3:10pm · Like      

Okay i see, so maybe just tell him what you've done and see what he says. I can't login to the wiki page for some reason :S October 21 at 3:12pm · Like      
I just want this assessment out of the way, we need to start our presentation this week too October 21 at 3:15pm · Like      
I am emailing him now, you all should get a copy of that email also. October 21 at 3:18pm · Like      
Okay thank you, I hope it all just gets fixed asap, we can still gather our info and then just wait till we can upload it all.

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 14:08, 18 August 2014 (EST)
Hi everyone :),
We all need to decide on a system for our group asap, does anyone have any suggestions ? I was thinking we could do the Genital or Musculoskeletal ?

--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 17:45, 19 August 2014 (EST)
Hello, I was thinking of covering the genital system development as well.

--[[User:Z3417753|Z3417753]] ([[User talk:Z3417753|talk]]) 20:39, 19 August 2014 (EST)
Genital it is :)

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 20 August 2014 (EST)
Great can't wait! there seems to be a lot of info about genital embryogenesis

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 21:07, 26 August 2014 (EST) Hey everyone, just wanted to make a note of what each of us was going to research. So as we all discussed last week, I am happy to do part 5. Abnormalities :)

--[[User:Z3417753|Z3417753]] ([[User talk:Z3417753|talk]]) 23:18, 26 August 2014 (EST) Hey ! Yes im doing current research models and findings :)

--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 01:05, 27 August 2014 (EST) Thank you all for referencing your articles. I am having some difficulty with referencing 1 of my 3 articles mainly because they are not from Pubmed. I will consult with Mark tomorrow and have my part completely uploaded during the lab. Thanks for your understanding.

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 14:57, 1 September 2014 (EST) Hey All, just wanted to let you know that there are some really good pictures showing the differentiation between the male and female genital development in the textbooks. So maybe this week we could decide which ones we like and then I can try to draw them. :)

--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 17:27, 2 September 2014 (EST) That sounds really good. If we are not given some time tomorrow during the lab to meet with our group and if you all don't mind we can stay back for 10 minutes or so to have a look at the images you found and if anyone has found any interesting material. See you all tomorrow in the lab.

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 18:06, 9 September 2014 (EST) Hi, I know we can only use one image from wikipedia so maybe we could use this one ? Or has anyone found any others ? Heres the link -- > http://en.wikipedia.org/wiki/Sexual_differentiation#mediaviewer/File:2915_Sexual_Differentation-02.jpg

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 18:14, 16 September 2014 (EST) Hi everyone, I am going to post 2 images on here tonight, please let me know which you prefer :)

1. [[File:Image.jpg|350px]]

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 21:04, 16 September 2014 (EST) Or this one ->

2. [[File:Sexual Differentiation.jpg|350px]]

--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 14:42, 21 September 2014 (EST) Since my part is historical findings, I have found a few old articles around 50-100+ years old. Below I'm going to past a paragraph about the female genital system development I have composed from information of two articles, one is from the 1950s and the other is 1890s. My only concern is what I have written doubles up with the system development part of this assignment so I have not uploaded onto the page but if you guys think it's fine for historical finding then I will, if not we can add that into system development and the timeline. I am still searching for historical teachings and images that can be used in this assignment.

The mullerian (paramesonephric) ducts, found laterally to the wolffian ducts, are the original structures of the female reproductive system. Female sexual organs (the fallopian tubes, uterus and vagina) originate from the mullerian ducts, which differentiates within the foetal developmental phase. Initially the foetus contains two mullerian ducts, however by the ninth week fusion of the lower portion of the ducts is complete, creating the fundamental structure of the uterus and the vagina, however the these two organs are not continuous with vagina being solid. The non-fused upper part of the ducts emerge into the fallopian tubes. It is not until the fourth and fifth month of development that the uterus becomes continuous with the vagina, with both organs developing a hollow lumen. The muscular layers of the uterus is also present by this stage. The cervix begins to form within the fifth month, between the continuous vagina and uterus. Also within the same month, the formation of the hymen occurs. The hymen is described as a pouting vertical slit and represents the remains of the mullerian eminence

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 21:05, 22 September 2014 (EST) I think it can be added under your heading of historical findings :)

--[[User:Z3417753|Z3417753]] ([[User talk:Z3417753|talk]]) 12:26, 1 October 2014 (EST) hey guys hope you are all enjoying your break :) Hope your assignments are all going well :)

Also, I found this article that might be useful if you havent already found it - it goes under historic findings - it is from 1942!!

Schonfeld WABeebe GW Normal growth and variation in the male genitalia from birth to maturity. J Urol 1942;8759- 777

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 21:59, 2 October 2014 (EST) Hey, hope your enjoying your break too. Thats great :). If you any of you guys come across an image that we could use for the first page, post in on here so we can decide if we want to use it. :)

--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 16:16, 5 October 2014 (EST) Thank you, I'm doing the historical findings and I will have a look into that article. Thanks again. I have just redrawn an image from one of my articles about the Mullerian ducts and forming the female genital system. I will try and upload it following the steps Mark gave to us in the first lab so once it is up please let me know if you guys like it or not. Thanks

--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 16:57, 5 October 2014 (EST) Also another thing, please let me know if I am being too specific in my part (Historical findings). I still have more to add on other areas of genital development, so if what I am doing is fine then I will continue this way, if not please let me know so I can change what I have. Thanks again.

--[[User:Z3417458|Z3417458]] ([[User talk:Z3417458|talk]]) 16:15, 6 October 2014 (EST) Hey Everyone, I've found a video we could use on our page, the background music is a bit annoying but the drawings are really good, detailed and clear heres a link. Let me know if any of you have found some too. :)
https://www.youtube.com/watch?v=MureNA-RSZM

----

*Great progress on the table. Maybe once you've managed to format everything you need into it, don't forget to reference bits you need to
*I liked the diagram you used to show the different pathways of genital development for the different genders. It's just a bit blurry so maybe think of re-uploading a clearer image or of making the image on your page a little smaller
*Good use of dot points under the "current research" section but maybe think of connecting the separate points a bit more as it seems a bit disjointed and difficult to follow. Maybe think of having your write-up as normal and using points in particular parts that show a sequence of events, or separate components of something
*Look to getting more references for the current research and models section because you're just using 1 at the moment
*Proofread. I know maybe you guys are still at the collation of information stage, but I find it's easier to get it right as you go along rather than coming back to it later
*Re-phrase some bits like: female and male fetuses’ external genitalia --> The external genitalia of the female and male fetus
*Great drawn images! They're all so clear, well thought out and identify all relevant components of what you're trying to show all throughout your page
*I liked the detail of your "historical findings" section

2014 Group Project 4

2014-10-23T14:00:18Z

Z3416697: /* System Development */

{{ANAT2341Project2014header}}
=Genital=
==Introduction==

[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]

This page will explain the development of the genital system in the fetal stage of development, of both males and females, after briefly explaining the embryonic development. It explores the models of fetal development of the internal and external genitalia, including the timeline of development. This page also lists some animal models used in research and outlines some current research and findings regarding the development of the genital system, including historic findings. Finally, this page also discusses some of the congenital abnormalities of the genital system..

==System Development==

===Internal Genital Development===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
|bgcolor="aliceblue"| The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

| bgcolor="lavenderblush"| The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males.
|-
|- style="height:10px"
| style="width:50%"|
|}

[[File:External genitalia current model.jpg|300px|right|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]

===Development of the External Genitalia ===

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''

|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* The tubercle itself goes on to form the mons pubis.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]
|-
|- style="height:10px"
| style="width:50%"|
|}

----

Until the seventh week of development, the external genitalia of both XX and XY embryos is indistinguishable,. Sexual characteristics only become apparent after the ninth week, however are only clearly different between male and female after the twelfth week of development. In the fourth week of the embryonic phase of development, the cranial end of the cloacal membrane begins to swell and proliferate and produce a protrusion called the ‘”genital tubercle”’. This protrusion acts as a precursor for the major sexual organs, the glans penis in males and the glands clitoris in females.

Also in the forth week, swellings begin to form around the cloacal membrane called the labioscrotal swellings and urogenital folds. The genital tubercle elongates in both sexes and forms a primordial phallus. The urogenital membrane which lies on the floor of the cleft formed by the urethral folds

“’Male”’
Testosterone produced by the interstitial Leydig cells of the fetal testes stimulates the masculinization of this indifferent genitalia. It stimulates the phallus to enlarges and elongates to form the “’glans penis”’, and the urethral folds begin to form the lateral walls of the urethral groove on the ventral aspect of the penis. A proliferation of endodermal cells lines the urethral groove and is referred to as the urethral plate, and it extends from the phallic portion of the urogenital sinus.

The urethral fold fuse with each other to form the ‘”spongy urethra”’ on the ventral surface of the penis. As the surface endoderm fuses in the median plane of the penis it encloses the spongy urethra- this fusion is called the “’penile raphe”’.
At the tip of the penis, the an endodermal ingrowth forms a cellular endodermal chord which grows inside the penis towards the base. This cord canalizes and the lumen joins the previously formed spongy urethra, thus completing the terminal part of the urethra, mobbing the external urethral orifice to the tip of the penis.

During the twelfth week of development, an ectodermal circular ingrowth develops around the periphery of the penis and sits like a cap. The ingrowth breaks down and forms the ‘”prepuce”’ (foreskin) which remains as a fold of skin covering the tip of a penis. The mesenchyme of the phallus gives rise to the corpus cavernosum and the corpus spongiosum. The labioscrotal swellings grow toward eachother and fuse in the center to form the “’scrotum”’, this line of fusion is eferred to as the “’scrotal raphe”’.

“’Female”’
Much like the male genitalia, the genital tubercle swells and elongates to form the “’glans clitoris”’. At eighteen weeks, the clitoris is still a prominent swelling. In females, the urethral folds only fuse at the posterior aspect and form the ‘”labia minora’’. The labioscrotal folds fuse only at two points, posteriorly to form the posterior labial commissure, and anteriorly to form the “’mons pubis”’, the remain unfused portions remain as the “’labia majora”’.

'''References'''

<pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>
<pubmed>25247640</pubmed>
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

===Current Research and Findings===
====Male====
----
{|
|-bgcolor="aliceblue"
|
[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

{|
|-bgcolor="aliceblue"
|
'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.
|}

----

{|
|-bgcolor="aliceblue"
|
'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.
|}

====Female====
----

{|
|-bgcolor="lavenderblush"
|
'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name= Abbott>Abbott David, H. '''Fibrillin-3 in the fetal ovary: can it contribute to polycystic ovary syndrome?'''. Expert Review of Endocrinology & Metabolism: 2012, 7(1); 31-34</ref>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.
|}

----

{|
|-bgcolor="lavenderblush"
|
'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.
|}

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research findings and interesting reads:'''
|-
| * A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-22T01:41:05Z

Z3416697: /* System Development */

{{ANAT2341Project2014header}}
=Genital=
==System Development==

Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis

===Internal Genital Development===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
|bgcolor="aliceblue"| The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

| bgcolor="lavenderblush"| The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males.
|-
|- style="height:10px"
| style="width:50%"|
|}

===Development of the External Genitalia ===

Until the seventh week of development, the external genitalia of both XX and XY embryos is indistinguishable,. Sexual characteristics only become apparent after the ninth week, however are only clearly different between male and female after the twelfth week of development. In the fourth week of the embryonic phase of development, the cranial end of the cloacal membrane begins to swell and proliferate and produce a protrusion called the ‘”genital tubercle”’. This protrusion acts as a precursor for the major sexual organs, the glans penis in males and the glands clitoris in females.

Also in the forth week, swellings begin to form around the cloacal membrane called the labioscrotal swellings and urogenital folds. The genital tubercle elongates in both sexes and forms a primordial phallus. The urogenital membrane which lies on the floor of the cleft formed by the urethral folds

“’Male”’
Testosterone produced by the interstitial Leydig cells of the fetal testes stimulates the masculinization of this indifferent genitalia. It stimulates the phallus to enlarges and elongates to form the “’glans penis”’, and the urethral folds begin to form the lateral walls of the urethral groove on the ventral aspect of the penis. A proliferation of endodermal cells lines the urethral groove and is referred to as the urethral plate, and it extends from the phallic portion of the urogenital sinus.

The urethral fold fuse with each other to form the ‘”spongy urethra”’ on the ventral surface of the penis. As the surface endoderm fuses in the median plane of the penis it encloses the spongy urethra- this fusion is called the “’penile raphe”’.
At the tip of the penis, the an endodermal ingrowth forms a cellular endodermal chord which grows inside the penis towards the base. This cord canalizes and the lumen joins the previously formed spongy urethra, thus completing the terminal part of the urethra, mobbing the external urethral orifice to the tip of the penis.

During the twelfth week of development, an ectodermal circular ingrowth develops around the periphery of the penis and sits like a cap. The ingrowth breaks down and forms the ‘”prepuce”’ (foreskin) which remains as a fold of skin covering the tip of a penis. The mesenchyme of the phallus gives rise to the corpus cavernosum and the corpus spongiosum. The labioscrotal swellings grow toward eachother and fuse in the center to form the “’scrotum”’, this line of fusion is eferred to as the “’scrotal raphe”’.

“’Female”’
Much like the male genitalia, the genital tubercle swells and elongates to form the “’glans clitoris”’. At eighteen weeks, the clitoris is still a prominent swelling. In females, the urethral folds only fuse at the posterior aspect and form the ‘”labia minora’’. The labioscrotal folds fuse only at two points, posteriorly to form the posterior labial commissure, and anteriorly to form the “’mons pubis”’, the remain unfused portions remain as the “’labia majora”’.

[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]

'''References'''

[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

===Current Research and Findings===
====Male====
----

[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

----

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

----

'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.

====Female====
----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

----

'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research findings and interesting reads:'''
|-
| * A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-22T01:36:33Z

Z3416697: /* System Development */

{{ANAT2341Project2014header}}
=Genital=
==System Development==

[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]

Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis

===Internal Genital Development===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
|bgcolor="aliceblue"| The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

| bgcolor="lavenderblush"| The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males.
|-
|- style="height:10px"
| style="width:50%"|
|}

===Development of the External Genitalia ===

Until the seventh week of development, the external genitalia of both XX and XY embryos is indistinguishable,. Sexual characteristics only become apparent after the ninth week, however are only clearly different between male and female after the twelfth week of development. In the fourth week of the embryonic phase of development, the cranial end of the cloacal membrane begins to swell and proliferate and produce a protrusion called the ‘”genital tubercle”’. This protrusion acts as a precursor for the major sexual organs, the glans penis in males and the glands clitoris in females.

Also in the forth week, swellings begin to form around the cloacal membrane called the labioscrotal swellings and urogenital folds. The genital tubercle elongates in both sexes and forms a primordial phallus. The urogenital membrane which lies on the floor of the cleft formed by the urethral folds

“’Male”’
Testosterone produced by the interstitial Leydig cells of the fetal testes stimulates the masculinization of this indifferent genitalia. It stimulates the phallus to enlarges and elongates to form the “’glans penis”’, and the urethral folds begin to form the lateral walls of the urethral groove on the ventral aspect of the penis. A proliferation of endodermal cells lines the urethral groove and is referred to as the urethral plate, and it extends from the phallic portion of the urogenital sinus.

The urethral fold fuse with each other to form the ‘”spongy urethra”’ on the ventral surface of the penis. As the surface endoderm fuses in the median plane of the penis it encloses the spongy urethra- this fusion is called the “’penile raphe”’.
At the tip of the penis, the an endodermal ingrowth forms a cellular endodermal chord which grows inside the penis towards the base. This cord canalizes and the lumen joins the previously formed spongy urethra, thus completing the terminal part of the urethra, mobbing the external urethral orifice to the tip of the penis.

During the twelfth week of development, an ectodermal circular ingrowth develops around the periphery of the penis and sits like a cap. The ingrowth breaks down and forms the ‘”prepuce”’ (foreskin) which remains as a fold of skin covering the tip of a penis. The mesenchyme of the phallus gives rise to the corpus cavernosum and the corpus spongiosum. The labioscrotal swellings grow toward eachother and fuse in the center to form the “’scrotum”’, this line of fusion is eferred to as the “’scrotal raphe”’.

“’Female”’
Much like the male genitalia, the genital tubercle swells and elongates to form the “’glans clitoris”’. At eighteen weeks, the clitoris is still a prominent swelling. In females, the urethral folds only fuse at the posterior aspect and form the ‘”labia minora’’. The labioscrotal folds fuse only at two points, posteriorly to form the posterior labial commissure, and anteriorly to form the “’mons pubis”’, the remain unfused portions remain as the “’labia majora”’.

'''References'''

[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

===Current Research and Findings===
====Male====
----

[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

----

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

----

'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.

====Female====
----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

----

'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research findings and interesting reads:'''
|-
| * A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-22T01:33:12Z

Z3416697: /* System Development */

{{ANAT2341Project2014header}}
=Genital=
==System Development==

[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]

Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis

===Internal Genital Development===
---?
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
|bgcolor="aliceblue"| The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

| bgcolor="lavenderblush"| The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males.
|-
|- style="height:10px"
| style="width:50%"|
|}

===Development of the External Genitalia ===

Until the seventh week of development, the external genitalia of both XX and XY embryos is indistinguishable,. Sexual characteristics only become apparent after the ninth week, however are only clearly different between male and female after the twelfth week of development. In the fourth week of the embryonic phase of development, the cranial end of the cloacal membrane begins to swell and proliferate and produce a protrusion called the ‘”genital tubercle”’. This protrusion acts as a precursor for the major sexual organs, the glans penis in males and the glands clitoris in females.

Also in the forth week, swellings begin to form around the cloacal membrane called the labioscrotal swellings and urogenital folds. The genital tubercle elongates in both sexes and forms a primordial phallus. The urogenital membrane which lies on the floor of the cleft formed by the urethral folds

“’Male”’
Testosterone produced by the interstitial Leydig cells of the fetal testes stimulates the masculinization of this indifferent genitalia. It stimulates the phallus to enlarges and elongates to form the “’glans penis”’, and the urethral folds begin to form the lateral walls of the urethral groove on the ventral aspect of the penis. A proliferation of endodermal cells lines the urethral groove and is referred to as the urethral plate, and it extends from the phallic portion of the urogenital sinus.

The urethral fold fuse with each other to form the ‘”spongy urethra”’ on the ventral surface of the penis. As the surface endoderm fuses in the median plane of the penis it encloses the spongy urethra- this fusion is called the “’penile raphe”’.
At the tip of the penis, the an endodermal ingrowth forms a cellular endodermal chord which grows inside the penis towards the base. This cord canalizes and the lumen joins the previously formed spongy urethra, thus completing the terminal part of the urethra, mobbing the external urethral orifice to the tip of the penis.

During the twelfth week of development, an ectodermal circular ingrowth develops around the periphery of the penis and sits like a cap. The ingrowth breaks down and forms the ‘”prepuce”’ (foreskin) which remains as a fold of skin covering the tip of a penis. The mesenchyme of the phallus gives rise to the corpus cavernosum and the corpus spongiosum. The labioscrotal swellings grow toward eachother and fuse in the center to form the “’scrotum”’, this line of fusion is eferred to as the “’scrotal raphe”’.

“’Female”’
Much like the male genitalia, the genital tubercle swells and elongates to form the “’glans clitoris”’. At eighteen weeks, the clitoris is still a prominent swelling. In females, the urethral folds only fuse at the posterior aspect and form the ‘”labia minora’’. The labioscrotal folds fuse only at two points, posteriorly to form the posterior labial commissure, and anteriorly to form the “’mons pubis”’, the remain unfused portions remain as the “’labia majora”’.

'''References'''

[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

===Current Research and Findings===
====Male====
----

[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

----

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

----

'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.

====Female====
----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

----

'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research findings and interesting reads:'''
|-
| * A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-22T01:23:53Z

Z3416697:

{{ANAT2341Project2014header}}
=Genital=
==System Development==

[[File:SexualDifferentation.jpg|300px|left|thumb|The stages in sexual differentiation of the female and male reproductive system]]

Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis
---?
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
|bgcolor="aliceblue"| The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

| bgcolor="lavenderblush"| The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males.
|-
|- style="height:10px"
| style="width:50%"|
|}

===Development of the External Genitalia ===

Until the seventh week of development, the external genitalia of both XX and XY embryos is indistinguishable,. Sexual characteristics only become apparent after the ninth week, however are only clearly different between male and female after the twelfth week of development. In the fourth week of the embryonic phase of development, the cranial end of the cloacal membrane begins to swell and proliferate and produce a protrusion called the ‘”genital tubercle”’. This protrusion acts as a precursor for the major sexual organs, the glans penis in males and the glands clitoris in females.

Also in the forth week, swellings begin to form around the cloacal membrane called the labioscrotal swellings and urogenital folds. The genital tubercle elongates in both sexes and forms a primordial phallus. The urogenital membrane which lies on the floor of the cleft formed by the urethral folds

“’Male”’
Testosterone produced by the interstitial Leydig cells of the fetal testes stimulates the masculinization of this indifferent genitalia. It stimulates the phallus to enlarges and elongates to form the “’glans penis”’, and the urethral folds begin to form the lateral walls of the urethral groove on the ventral aspect of the penis. A proliferation of endodermal cells lines the urethral groove and is referred to as the urethral plate, and it extends from the phallic portion of the urogenital sinus.

The urethral fold fuse with each other to form the ‘”spongy urethra”’ on the ventral surface of the penis. As the surface endoderm fuses in the median plane of the penis it encloses the spongy urethra- this fusion is called the “’penile raphe”’.
At the tip of the penis, the an endodermal ingrowth forms a cellular endodermal chord which grows inside the penis towards the base. This cord canalizes and the lumen joins the previously formed spongy urethra, thus completing the terminal part of the urethra, mobbing the external urethral orifice to the tip of the penis.

During the twelfth week of development, an ectodermal circular ingrowth develops around the periphery of the penis and sits like a cap. The ingrowth breaks down and forms the ‘”prepuce”’ (foreskin) which remains as a fold of skin covering the tip of a penis. The mesenchyme of the phallus gives rise to the corpus cavernosum and the corpus spongiosum. The labioscrotal swellings grow toward eachother and fuse in the center to form the “’scrotum”’, this line of fusion is eferred to as the “’scrotal raphe”’.

“’Female”’
Much like the male genitalia, the genital tubercle swells and elongates to form the “’glans clitoris”’. At eighteen weeks, the clitoris is still a prominent swelling. In females, the urethral folds only fuse at the posterior aspect and form the ‘”labia minora’’. The labioscrotal folds fuse only at two points, posteriorly to form the posterior labial commissure, and anteriorly to form the “’mons pubis”’, the remain unfused portions remain as the “’labia majora”’.

'''References'''

[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

===Current Research and Findings===
====Male====
----

[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

----

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

----

'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.

====Female====
----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

----

'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research findings and interesting reads:'''
|-
| * A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-22T00:58:50Z

Z3416697: /* Genital */

{{ANAT2341Project2014header}}
=Genital=
==System Development==

[[File:SexualDifferentation.jpg|300px|left|thumb[[Media:|The stages in sexual differentiation of the female and male reproductive system]]

Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis
---?
===2. Development of the internal genitalia===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
'''Male'''
The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

'''Female'''

The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males.

{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
|bgcolor="aliceblue"| The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

| bgcolor="lavenderblush"| The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males.
|-
|- style="height:10px"
| style="width:50%"|
|}

===3. Development of the external genitalia===

[[File:External genitalia current model.jpg|400px|right|thumb|Current model of external genitalia of male and female fetuses]]

Until the seventh week of development, the external genitalia of both XX and XY embryos is indistinguishable,. Sexual characteristics only become apparent after the ninth week, however are only clearly different between male and female after the twelfth week of development. In the fourth week of the embryonic phase of development, the cranial end of the cloacal membrane begins to swell and proliferate and produce a protrusion called the ‘”genital tubercle”’. This protrusion acts as a precursor for the major sexual organs, the glans penis in males and the glands clitoris in females.

Also in the forth week, swellings begin to form around the cloacal membrane called the labioscrotal swellings and urogenital folds. The genital tubercle elongates in both sexes and forms a primordial phallus. The urogenital membrane which lies on the floor of the cleft formed by the urethral folds

“’Male”’
Testosterone produced by the interstitial Leydig cells of the fetal testes stimulates the masculinization of this indifferent genitalia. It stimulates the phallus to enlarges and elongates to form the “’glans penis”’, and the urethral folds begin to form the lateral walls of the urethral groove on the ventral aspect of the penis. A proliferation of endodermal cells lines the urethral groove and is referred to as the urethral plate, and it extends from the phallic portion of the urogenital sinus.

The urethral fold fuse with each other to form the ‘”spongy urethra”’ on the ventral surface of the penis. As the surface endoderm fuses in the median plane of the penis it encloses the spongy urethra- this fusion is called the “’penile raphe”’.
At the tip of the penis, the an endodermal ingrowth forms a cellular endodermal chord which grows inside the penis towards the base. This cord canalizes and the lumen joins the previously formed spongy urethra, thus completing the terminal part of the urethra, mobbing the external urethral orifice to the tip of the penis.

During the twelfth week of development, an ectodermal circular ingrowth develops around the periphery of the penis and sits like a cap. The ingrowth breaks down and forms the ‘”prepuce”’ (foreskin) which remains as a fold of skin covering the tip of a penis. The mesenchyme of the phallus gives rise to the corpus cavernosum and the corpus spongiosum. The labioscrotal swellings grow toward eachother and fuse in the center to form the “’scrotum”’, this line of fusion is eferred to as the “’scrotal raphe”’.

“’Female”’
Much like the male genitalia, the genital tubercle swells and elongates to form the “’glans clitoris”’. At eighteen weeks, the clitoris is still a prominent swelling. In females, the urethral folds only fuse at the posterior aspect and form the ‘”labia minora’’. The labioscrotal folds fuse only at two points, posteriorly to form the posterior labial commissure, and anteriorly to form the “’mons pubis”’, the remain unfused portions remain as the “’labia majora”’.

|-
|- style="height:10px"
| style="width:50%"|
|}
'''References'''

[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''

{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''
|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|-
|- style="height:10px"
| style="width:50%"|
|}

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

===Current Research and Findings===
====Male====
----

[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

----

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

----

'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.

====Female====
----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

----

'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research findings and interesting reads:'''
|-
| * A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

User:Z3416697

2014-10-22T00:51:33Z

Z3416697:

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:45, 6 August 2014 (EST)
==lab attendance==
Lab 1
http://www.ncbi.nlm.nih.gov/pubmed

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

<pubmed>2508416</pubmed>

----

==Lab Assessment 1==
===ARTICLE 1===
<pubmed>25071849</pubmed>

In Vitro Fertilization (IVF) is a popular method of Assisted Reproduction which allows for fertilization to occur under optimal conditions (which may not be achieved in those that are having trouble conceiving), with monitored hormone levels and calculated growth of the embryo so as to maximize implantation, and ideally, successful pregnancy. This research article endeavors to assess the different variables available in IVF to determine which method yields the most successful amount of pregnancies. The variables in question are whether the embryo should be fresh (within a hours of fertilization), or frozen-thawed (embryo frozen a few days after fertilization and thawed when the mother is ready to receive an embryo). Another variable considered is the developmental stage at which the embryo is implanted; some embryos are implanted at the cleavage stage (hours after fertilization) and others are implanted at the blastocyst stage (5 days after fertilization), this study also considered implants at the cleavage stage extended blastocyst stage however it did not clarify what this term means, and I was unable to find elsewhere what this means.

This study observed IVF cycles of 1891 women at the Wuhan Union Hospital between January and December of 2012. Of the 1891 women observed, 1150 had fresh embryo transfers and 741 had frozen thawed embryo transfers. Of the Fresh embryo transfers 993 were implanted at the cleavage stage (799 of them women were less than 35 years old and 194 were greater than or equal to 35 years old), and 157 were implanted at the blastocyst stage (131 were less than 35 years old, 26 greater than or equal to 35 years old). Of the 741 women with frozen thawed embryo transfers, 212 were implanted at the cleavage stage of embryonic development (159 women were less than 35 and 53 were greater than or equal to 35), 137 were implanted at the cleavage stage extended blastocyst stage (111 were less than 35, 26 were greater than or equal to 35) and 328 were implanted at the blastocyst stage (276 were less than 35, 52 were greater than or equal to 35). All of these women underwent traditional methods of IVF- that is they were initially treated with Gonadotropin Releasing Hormone to stimulate follicular development. When two or more follicles were greater than 18mm Human Chorionic Gonadotropin was injected to assist follicular maturation. 24-26 hours later the ova were collected (Ovum Pick Up/OPU) and 4-6 hours after OPU IVF or Intracytoplasmic Sperm Injection (ICSI) were performed on the ova. The embryos were assessed by morphology and rate of development and at day three they are transferred onto a blastocyst medium and cultured for 2-3 days until it forms a blastocyst. The blastocysts are socred according to the Gardner standard and usually 1-2 good embryos are implanted. The remaining viable embryos are cryopreserved via vitrification and may be used if the current IVF cycle is unsuccessful. The Estrogen and Progesterone levels are monitored and regulated throughout the process according to the characteristics of the patient. Clinical pregnancy was defined by the presence of a gestational sac with or without a heart beat 30 days after implantation.

From this experiment it was found that there was a greater amount of successful pregnancies in women less than 35 years old resulting from implantation of fresh embryos at the cleavage stage (52.7% success) as opposed to the blastocyst stage (35.88%). There was no statistically significant differences clinically between the two types of implantation [ie- multiple pregnancies, abortion or ectopic pregnancy]. There were also a significantly higher number of pregnancies in the cleavage stage [41.24%] vs the blastocyst stage [26.92%]. However, this was not that case for those whom has frozen-thawed embryo transfers, as there was generally a much greater success rate for pregnancy in those who had blastocyst stage transfers than those who had cleavage stage transfers. Furthermore, there is a significantly greater pregnancy rate between in fresh embryo transfers compared to frozen thawed embryo transfers at the cleavage stage. Overall, there was a greater incidence of clinical pregnancy resulting from fresh cleavage stage embryo transfers compared to any other type of transfer [ie fresh blastocyst stage, frozen thawed cleavage stage and frozen thawed blastocyst stage]. These researchers concluded that this type of implantation should be used under normal conditions, and other methods should only be considered if the mother is of compromised health (eg has Ovarian Hyper Stimulation Syndrome), in which case as fresh blastocyst stage embryo is used.

===ARTICLE 2===
<pubmed>25017405 </pubmed>
This article aimed to assess the success rate of clinical pregnancy of women at differing age groups whom have undergone assisted reproductive methods such as In-Vitro Fertilzation and Intracytoplasmic Sperm Injection. Based on previous literature it was expected that the success rate would decline as the woman ages, as typically the most successful IVF cycles are seen in women whom are 25-30 years old. Also based on natural conception rates, spontaneous conception rates begin to decrease around 31-35 years old, and women tend to have difficulty conceiving around the ages of 35-39. General fecundabilty (probability of released ovum becoming fertilized and resulting in a successful pregnancy in one menstrual cycle) tend t decrease as the woman reaches menopause (around the early fifties) and at 5-10 years prior to this (40-44 years old), half of the women have reduced reproductive capacity.

This study observed 2,900 women undergoing IVF at the KK Women and Children’s hospital, of which yielded 3,412 fresh IVF cycles. The women were classifies into sub groups based only on age [< 30 years; 30–35 years; 36–37 years; 38 years; 39 years; 40–44 years; and ≥ 45 years]. The IVF cycles were monitored and the average number of occytes, average duration of stimulation and fertilization rates were observed. Furthermore, the number of cycles until successful embryo transfer, clinically successfully pregnancy rates, miscarriage rates and multiple pregnancy rates were also reported.
In this study, most of the patients undergoing IVF were between the ages of 30-35 and 36-37, and the least amount of patients belonged to the ≥ 45 years group. Of these, it was found that there was a 15% miscarriage rate in those younger than 30 years old, but this figure doubled to 30% at the age of 38 and among women aged 40-44, the miscarriage rate was as high as 55%. Only half of the women aged greater than 45 reached embryo transfer, and of those, none proceeded to successful clinical pregnancy. Furthermore, compared to other age groups, these women had the lowest amount of oocytes collected and the lowest fertilization rate with only 50% of oocytes proceeding to fertilization, compared to 95% in women less than 30 years old. However, it was found that there was no differences in mean duration of ovarian stimulation prior to ovum collection based on age. Finally, it was found that there was a general decreasing trend of successful clinical pregnancies as age increased in women undergoing IVF, as the rate of live births was highest in women who were less than 30 years old. The occurence of multiple births was highest in this age group also.

Overall it was found that the age of the woman undoubtedly has an effect on the reproductive capacity of a woman undergoing IVF. The researchers hypothesized that the general decreased success of an aging woman may be due to decreasing ovarian reserve, poorer oocyte quality, lower embryo implantation rates, altered hormonal environment resulting in ovulatory dysfunction and uterine problems. Male factors were also considered to be causative.

--[[User:Z8600021|Mark Hill]] These papers are suitable for the assessment exercise and you have included an appropriate summary. (5/5)

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==Lab Assessment 2==
[[File:Mutation of Gene Wt1 Causes Aberrant Gonadal Development.jpeg|300px]]

Mutation of Gene Wt1 Causes Aberrant Gonadal Development<ref><pubmed>23497137 </pubmed>| [http://www.biomedcentral.com/1741-7007/11/22/figure/F1]</ref>

<references/>

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:08, 20 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] This is a relevant image. I have fixed a few formatting issues in the associated file information, don't include the .jpeg in the figure legend, see the image page history for changes. (5/5)

==Lab Attendance: LAB 2==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:56, 20 August 2014 (EST)
Forgot to do my attendance at the lab of week 3 given by guest Speakers Hayden Homer and Rob Gilchrist about meiosis, oocyte quality and various technologies in assisted reproduction

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==Lab Attendance week 4==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:39, 20 August 2014 (EST)

==Lab three Online Assessment==
Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 20:10, 26 August 2014 (EST)

--[[User:Z8600021|Mark Hill]]These 3 references meet the assessment requirement, it appears that you have just included the references without a description? Your description of genital differentiation is not quite accurate and should be clarified by the future Genital Development Lecture. (4/5)

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==Lab 4 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 27 August 2014 (EST)

==Lab 4 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:23, 2 September 2014 (EST)

<pubmed>25137413</pubmed>

Hepatocellular carcinoma and other degenerative liver diseases often result in hepatic dysfunction and ultimately organ failure. To avoid this otherwise fatal diagnosis, bio-artificial livers and hepatocyte transplantation provides some leg- room whilst waiting on a full-organ transplant. However liver transplants, much like many other organs, are often hard to come by and are usually sensitive to the immune response of the host. As a result, researchers are looking towards stem cells as an answer to this problem. Mesenchymal stem cells derived from the Wharton’s Jelly of the umbilical Chord are often chosen because they have been found to have a slightly higher multipotency and immunogenicity. The umbilical stem cells were selected because they are more primitive compared to other Mesenchymal stem cells and do not express the major histocompatibility complex class II antigens- a key determinant in illiciting an immune response form the host. However, hepatocyte like cells derived from stem cells are not clinically used because they do not express enough functional proteins and do not exhibit a full level of metabolic activity.

This study aimed to identify and observe the transcription factors involved in hepatocyte differentiation from Human umbilical cord Mesenchymal Stem Cells (HuMSCs), they were particularly interested in Hepatocyte Nuclear Factor 4-alpha (HNF-4alpha) which is believed to behave like a “master gene” in driving hepatocyte differentiation and maturation. This study continued to expose the differentiating HuMSCs to excess amounts of HNF-4alpha and hypothesized a significant improvement in the differentiation status of the hepatocyte-like cells, providing a basis for future clinical application of HuMSCs in the treatment and management of liver diseases.

The research initially confirmed that the HuMSCs are of low immunogenicity- a critical issue with organ transplantation. Once this was confirmed, they observed that there was an up-regulation of functional hepatic enzymes once the differentiating hepatocyte-like stem cells were exposed to HNF-4alpha. An important finding they discovered that the time at which the stem cells were exposed to HNF-4alpha were integral in ensuring correct hepatocyte differentiation. Ultimately they concluded that the differentiation of HuMSCs could be improved by exposure to high levels of HNF-4alpha at specific times in the development of hepatocyte-like stem cells, an important discovery for the progression of the therapeutic application of stem cells.

The three shunts which are present in fetal development but are closed postnatally are:

• ductus arteriosis → channel between the pulmonary artery and aorta in the fetus which bypasses the lungs to distribute oxygenated blood from the placenta derived from the mothers circulation.

• ductus venosus → shunts a portion of the left umbilical vein blood flow which would flow directly to the inferior vena cava- allows b=oxygenated blood to bypass the liver.

• foramen ovale → allows passageway of blood from left atrium to right atrium in the fetus.

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==Lab 5 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 3 September 2014 (EST)

==Lab 5 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:10, 16 September 2014 (EST)

Congenital Lobar emphysema (CLE) is a condition of the respiratory system which results in hyperinflation of one or more pulmonary lobes and is usually diagnosed postnatally, usually in the neonatal period- however there have been cases where CLE is not diagnosed until 10 years after birth. The clinical symptoms of CLE are often at birth as dyspnea, cyanosis and recurrent respiratory tract infections, as well as generalized neonatal respiratory distress and hyperinflation and hyperaeration of the pulmonary lobes- often seen as visible enlargements or imaged through CT. CLE is a rare disorder affecting only 1 in 20,000 to 30, 000 newborns, and appears to have a slight male predominance [3:1 male to female ratio], although the cause of this gender predilection is not fully understood.

The developmental causes of CLE are often as final result of a number of bronchopulmonary disturbances during development. These result from abnormal interactions between embryonic endodermal and mesodermal components of the lung which may result in abnormalities in airway or alveoli number and size, however the exact pathogenesis of CLE is not able to be determined in approximately half of cases. Another frequently observed cause of CLE is an obstruction of the developing airway, which creates a “ball valve” resulting in an uneven distribution of air- favoring greater airflow to the affected lobe during inspiration than is able to be cleared in expiration- resulting in air trapping. There may also be vascular abnormalities which produce compression, bronchial stenosis, bronchogenic cysts and congenital cytomegaloviral infections observed.

<pubmed>PMC2141574</pubmed>

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==Lab attendance week 8==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 17 September 2014 (EST)

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==Lab Report- week 8==

==lab Attendance WEEK 9==

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==Lab attendance week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)
==lab report week 9==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)

----

==Lab assessment week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 00:56, 15 October 2014 (EST)
'''Group 1'''
This project is extremely well done. I found the overall layout of your work to be easy to read and succinct. It captured my attention throughout the entirety of the project and was engaging with the use of bullet points. I thought your use of diagrams was great in aiding the understanding of this topic, however I thought that more diagrams or pictures could be added in order to help the reader visualize exactly what’s going on. I thought that te developmental timeline was a great idea, however could benefit from some more images or diagrams to assist in understanding the developmental stages. I thought the historic findings sections was especially well done as it appears well researched and thoroughly informative. The abnormalities was also well done, however again could benefit from the addition of a few more diagrams.

I think that with the addition of more drawings needs to be some attention to detail when referencing and stating copyright. I’ve noticed that some pictures lack copyright and some don’t have a description, making it difficult to understand the context of the picture and to envisage how it relates to the content. Whilst this is mostly self explanatory- I think that because this is an informative piece it pays to spoon-feed us a bit. Also, your referencing could use a bit of a tidy, but that can easily be fixed before submission. I think that overall this has great potential to be a wonderful project and I look forward to seeing it at its completion!

'''Group 2'''
I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

'''Group 3'''
Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

'''Group 5'''
Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once.

I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

'''Group 6'''
Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

'''Group 7'''
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.
The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.
The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing.
Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

'''Group 8'''
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

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==Lab Attendance week 11==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:43, 15 October 2014 (EST)

==Lab attendance week 12==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:51, 22 October 2014 (EST)

2014 Group Project 4

2014-10-22T00:38:18Z

Z3416697: /* Genital */

{{ANAT2341Project2014header}}
=Genital=
==System Development==

[[File:Image.jpg|300px|left|thumb|The stages in sexual differentiation of the female and male reproductive system]]

Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis
---?
===2. Development of the internal genitalia===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
'''Male'''
The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

'''Female'''

The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males.

===3. Development of the external genitalia===
Until the seventh week of development, the external genitalia of both XX and XY embryos is indistinguishable,. Sexual characteristics only become apparent after the ninth week, however are only clearly different between male and female after the twelfth week of development. In the fourth week of the embryonic phase of development, the cranial end of the cloacal membrane begins to swell and proliferate and produce a protrusion called the ‘”genital tubercle”’. This protrusion acts as a precursor for the major sexual organs, the glans penis in males and the glands clitoris in females.

Also in the forth week, swellings begin to form around the cloacal membrane called the labioscrotal swellings and urogenital folds. The genital tubercle elongates in both sexes and forms a primordial phallus. The urogenital membrane which lies on the floor of the cleft formed by the urethral folds

“’Male”’
Testosterone produced by the interstitial Leydig cells of the fetal testes stimulates the masculinization of this indifferent genitalia. It stimulates the phallus to enlarges and elongates to form the “’glans penis”’, and the urethral folds begin to form the lateral walls of the urethral groove on the ventral aspect of the penis. A proliferation of endodermal cells lines the urethral groove and is referred to as the urethral plate, and it extends from the phallic portion of the urogenital sinus.

The urethral fold fuse with each other to form the ‘”spongy urethra”’ on the ventral surface of the penis. As the surface endoderm fuses in the median plane of the penis it encloses the spongy urethra- this fusion is called the “’penile raphe”’.
At the tip of the penis, the an endodermal ingrowth forms a cellular endodermal chord which grows inside the penis towards the base. This cord canalizes and the lumen joins the previously formed spongy urethra, thus completing the terminal part of the urethra, mobbing the external urethral orifice to the tip of the penis.

During the twelfth week of development, an ectodermal circular ingrowth develops around the periphery of the penis and sits like a cap. The ingrowth breaks down and forms the ‘”prepuce”’ (foreskin) which remains as a fold of skin covering the tip of a penis. The mesenchyme of the phallus gives rise to the corpus cavernosum and the corpus spongiosum. The labioscrotal swellings grow toward eachother and fuse in the center to form the “’scrotum”’, this line of fusion is eferred to as the “’scrotal raphe”’.

“’Female”’
Much like the male genitalia, the genital tubercle swells and elongates to form the “’glans clitoris”’. At eighteen weeks, the clitoris is still a prominent swelling. In females, the urethral folds only fuse at the posterior aspect and form the ‘”labia minora’’. The labioscrotal folds fuse only at two points, posteriorly to form the posterior labial commissure, and anteriorly to form the “’mons pubis”’, the remain unfused portions remain as the “’labia majora”’.

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'''References'''

[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

[[File:External genitalia current model.jpg|400px|right|thumb|Current model of external genitalia of male and female fetuses]]

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

----

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''

{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''
|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|-
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===Current Research and Findings===
====Male====
----

[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

----

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

----

'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.

====Female====
----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

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'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research findings and interesting reads:'''
|-
| * A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-21T23:02:25Z

Z3416697: /* 2. Development of the internal genitalia */

{{ANAT2341Project2014header}}
=Genital=
==System Development==

[[File:Image.jpg|300px|left|thumb|The stages in sexual differentiation of the female and male reproductive system]]

Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis
---?
===2. Development of the internal genitalia===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-

'''Male'''

The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the '''epididymis'''. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the '''ductus deferens'''.

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

'''Female'''

The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males.

===3. Development of the external genitalia===

|-
|- style="height:10px"
| style="width:50%"|
|}
'''References'''

[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

[[File:External genitalia current model.jpg|400px|right|thumb|Current model of external genitalia of male and female fetuses]]

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

----

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''

{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''
|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|-
|- style="height:10px"
| style="width:50%"|
|}
===Current Research and Findings===
====Male====
----

[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

----

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

----

'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.

====Female====
----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

----

'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research and findings and interesting reads:'''
|-
| *A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-21T22:58:59Z

Z3416697: /* 2. Development of the internal genitalia */

{{ANAT2341Project2014header}}
=Genital=
==System Development==

[[File:Image.jpg|300px|left|thumb|The stages in sexual differentiation of the female and male reproductive system]]

Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis
---?
===2. Development of the internal genitalia===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
'''Male'''
The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.

''Fetal Male Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

'''Female'''

The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. The paramesonephric ducts give rise to most of the female internal genital system- the unfused cranial aspects of the ducts give rise to a primitive '''fallopian tubes''', whilst the caudally fused portions form the uterovaginal primordium which will develop into a '''uterus''' and '''superior vagina'''. The splanchnic mesenchyme gives rise to the endometrial stromal tissue and the myometrium.

Female genital development during the fetal period is not dependant on endocrine contributions from the foetus. Later in fetal development, maternal oestrogen's and oestrogen derived from the placenta contribute to the development of the fallopian tubes, uterus and the superior vagina.

''Female Glandular Development''

* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.
* outgrowths from the urogenital sinus form the '''greater vestibular glands''' in the lower third of the Labia Majora. These glands are also mucous secreting and are comparative to the bulbourethral glands in males.

===3. Development of the external genitalia===

|-
|- style="height:10px"
| style="width:50%"|
|}
'''References'''

[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

[[File:External genitalia current model.jpg|400px|right|thumb|Current model of external genitalia of male and female fetuses]]

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

----

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''

{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''
|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|-
|- style="height:10px"
| style="width:50%"|
|}
===Current Research and Findings===
====Male====
----

[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

----

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

----

'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.

====Female====
----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

----

'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research and findings and interesting reads:'''
|-
| *A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-21T22:24:24Z

Z3416697: /* 2. Development of the internal genitalia */

{{ANAT2341Project2014header}}
=Genital=
==System Development==

[[File:Image.jpg|300px|left|thumb|The stages in sexual differentiation of the female and male reproductive system]]

Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis
---?
===2. Development of the internal genitalia===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
'''Male'''
The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.

''Fetal Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

'''Female'''
The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. Thus, female genital development during the fetal period is not dependant on endocrine involvement.

3. Development of the external genitalia

|-
|- style="height:10px"
| style="width:50%"|
|}
'''References'''

[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

[[File:External genitalia current model.jpg|400px|right|thumb|Current model of external genitalia of male and female fetuses]]

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

----

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''

{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''
|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|-
|- style="height:10px"
| style="width:50%"|
|}
===Current Research and Findings===
====Male====
----

[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

----

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

----

'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.

====Female====
----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

----

'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research and findings and interesting reads:'''
|-
| *A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-21T22:21:50Z

Z3416697: /* 2. Development of the internal genitalia */

{{ANAT2341Project2014header}}
=Genital=
==System Development==

[[File:Image.jpg|300px|left|thumb|The stages in sexual differentiation of the female and male reproductive system]]

Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis
---?
===2. Development of the internal genitalia===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
'''Male'''
The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.

''Fetal Glandular Development''
* the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
* the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme. This acts as a base of the proliferation of the glandular epithelium of the prostate to differentiate- the associated mesenchyme will differentiate into dense stroma and the smooth muscle of the prostate.
* The bulbourethral glands are pea-sized and developed from paired outgrowths that originate from the spongy pat of the urethra. The adjacent mesenchyme gives rise to the stroma and smooth muscle fibres which will ultimately produce secretions which contribute to the semen.

'''Female'''
The absence of testosterone production in XX embryos results in the regression of the mesonephric duct, and conversely the absence of MIH results in the development and progression of the paramesonephric ducts. Thus, female genital development during the fetal period is not dependant on endocrine involvement.

3. Development of the external genitalia

|-
|- style="height:10px"
| style="width:50%"|
|}
'''References'''

[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

[[File:External genitalia current model.jpg|400px|right|thumb|Current model of external genitalia of male and female fetuses]]

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

----

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''

{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''
|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|-
|- style="height:10px"
| style="width:50%"|
|}
===Current Research and Findings===
====Male====
----

[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

----

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

----

'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

[[File:Schematic representation of the various treatment windows and experimental design..jpg|400px|thumb|left|Schematic representation of the various treatment windows and experimental design]]

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.

====Female====
----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

----

'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research and findings and interesting reads:'''
|-
| *A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-21T11:58:35Z

Z3416697:

{{ANAT2341Project2014header}}
=Genital=
==System Development==

[[File:Image.jpg|300px|left|thumb|The stages in sexual differentiation of the female and male reproductive system]]

Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis
---?
===2. Development of the internal genitalia===
{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE'''
|bgcolor="violet"|'''FEMALE'''
|-
'''Male'''
The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.

''Fetal Glandular Development''
# the seminal glands develop from lateral outgrowths from that caudal end of each mesonephric duct which nourishes the sperm and constitutes most of the fluid in the ejaculate
# the endodermal outgrowths arise from the prostatic part of the urethra which grow into the surrounding mesenchyme.
3. Development of the external genitalia

|-
|- style="height:10px"
| style="width:50%"|
|}
'''References'''

[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

[[File:External genitalia current model.jpg|400px|right|thumb|Current model of external genitalia of male and female fetuses]]

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

----

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''

{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''
|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|-
|- style="height:10px"
| style="width:50%"|
|}
===Current Research and Findings===
====Male====
----

[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

----

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

----

'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.

====Female====
----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

----

'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research and findings and interesting reads:'''
|-
| *A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-21T11:44:49Z

Z3416697:

{{ANAT2341Project2014header}}
=Genital=
==System Development==

[[File:Image.jpg|300px|left|thumb|The stages in sexual differentiation of the female and male reproductive system]]

Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis
---?
=2. Development of he internal genitalia=

'''Male'''
The fetal development of internal genitalia is largely dependent on the endocrine functions of the fetal testes. The fetal testes produce masculinizing hormones such as '''testosterone''' which begins its release from the interstitial Leydig cells of the primitive seminiferous tubules during the 8th week of development, and also the release of '''Mullerian Inhibiting Hormone (MIS)''' which is released at the sixth and seventh weeks by the Sertoli Cells. Testosterone acts primarily on the mesonephric ducts to stimulate the formation of the male genital ducts, whereas the MIS acts on the paramesonephric duct to stimulate its regression.

By the eighth week of fetal development in XY embryos, the testosterone produced in the testes results in the convolution of the proximal ends of the mesonephric ducts to form the 'epididymis. The mesonephros begins to degenerate, however some of the mesonephric tubules remain and develop into efferent ductules, which then open into the duct of the epididymis. Distal to this end, the mesonephric duct begins to develop a thick lining of smooth muscle and progresses to become the ductus deferens.

''Fetal Glandular develeopment'''Bold text'''''

3. Development of the external genitalia

'''References'''

[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

[[File:External genitalia current model.jpg|400px|right|thumb|Current model of external genitalia of male and female fetuses]]

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

----

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''

{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''
|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|-
|- style="height:10px"
| style="width:50%"|
|}
===Current Research and Findings===
====Male====
----

[[File:Hypospadias.jpg|200px|thumb|right|Different types of hypospadias]]

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

----

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

----

'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.

====Female====
----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

----

'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research and findings and interesting reads:'''
|-
| *A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-21T11:11:27Z

Z3416697: /* System Development */

{{ANAT2341Project2014header}}
=Genital=
==System Development==

[[File:Image.jpg|300px|left|thumb|The stages in sexual differentiation of the female and male reproductive system]]

Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis

2. Development of he internal genitalia
3. Development of the external genitalia

'''References'''

[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

[[File:External genitalia current model.jpg|400px|right|thumb|Current model of external genitalia of male and female fetuses]]

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.<ref name=PMID21710394><pubmed>21710394</pubmed></ref>

----

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''

{| style="width:100%"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''
|-
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

[[File:Cross section of genital tubercle male.jpg|270px|right|thumb|Cross section of the male genital tubercle]][[File:Anatomical diagram of testes.jpg|300px|left|thumb|Anatomical drawing of adult male testes]]

* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.

* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|-
|- style="height:10px"
| style="width:50%"|
|}
===Current Research and Findings===
====Male====
----

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

----

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

----

'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2012)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.

====Female====
----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

----

'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

{| class="wikitable mw-collapsible mw-collapsed"
! '''Other current research and findings and interesting reads:'''
|-
| *A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>

2014 Group Project 4

2014-10-21T10:17:12Z

Z3416697: /* System Development */

{{ANAT2341Project2014header}}
=Genital=
==System Development==

Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis

2. Development of he internal genitalia
3. Development of the external genitalia

'''References'''

[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

[[File:Image.jpg|300px|left|thumb|The stages in sexual differentiation of the female and male reproductive system]]

===Related video===

<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media>

==Current Research, Models and Findings==

===Current Models===

[[File:External genitalia current model.jpg|400px|right|thumb|Current model of external genitalia of male and female fetuses]]

Most current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

When observing the morphology and cell biology of the developing testis, it is important to note that most of the research conducted on the subject involves the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy. <ref name=PMID17237341><pubmed>17237341</pubmed></ref>

Some examples of different animal models used in research involving fetal development of male and female genital systems are:

* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref>
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref>
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref>
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref>
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref>
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref>
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref>

Different models are used for different research topics; for example, research involving Polycystic ovary syndrome (PCOS) uses murine models preferable due to the developmental time frame that allows studies of inherited PCOS to be examined within an appropriate time frame. The sheep model is also beneficial to use for PCOS research as it is cost effective and their size allows them to be subjected to certain procedures such as ultrasound and neurotransmitter measures. Primates are examples of an optimal model however are limited in their accessibility and long time frame of development.

It is important to note that any findings associated with an animal model should be translated appropriately to the human model, as animals differ in their anatomy and regulatory mechanisms, as well as placentation. That is, sheep, rats and mice display different placentation and ovarian development that occurs in utero in sheep, primates and humans differs to the ex utero development in murine models.

----

'''The current model for embryonic development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

'''The current model for fetal development of the external genitalia in humans and mice:'''

{| style="width:100%; height:150px"
|bgcolor="lightskyblue"|'''MALE MODEL'''|center
|bgcolor="violet"|'''FEMALE MODEL'''|center
|-
|- style="height:150px"
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''
# Only minor changes occur from the embryonic ambisexual stage in the female, beginning with the minimal growth of the genital tubercle to form the clitoris.
# The urogenital folds remain apart and unfused to form the labia majora.
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|-
|- style="height:150px"
| style="width:50%"|[[File:Cross section of genital tubercle male.jpg|300px|center]]
| hfflffluftuftlufulfy
|-
|- style="height:150px"
|bgcolor="aliceblue"|
* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.
* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|bgcolor="lavenderblush"|
* Together, these bilateral labial structures and the clitoris located proximally form the border for the urogenital ostium, thus forming the vestibule of the vagina, with vaginal and urethral openings.
|-
|- style="height:150px"
| [[File:Anatomical diagram of testes.jpg|300px|center]]
| Third Row Column 2
|-
|- style="height:150px"
|bgcolor="aliceblue"|Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|bgcolor="lavenderblush"|
* Sexual dimorphism of the external genitalia in female humans is determined by the absence of androgenic pathways, however the female genital tubercle can be ‘masculinised’ as 5a-reductase and androgen recpetors are present.
* The genital tubercle can not go on to form a penis as testosterone is not produced, however in some instances it is abnormally produced in excess by the suprarenal gland resulting in different degrees of masculinsation of the clitoris.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|}

----

===Current Research and Findings===

====Male====
----

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

----

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

----

'''The Effect of Dihydrotestosterone Exposure During or Prior to the Masculinisation Programming Window on Reproductive Development in Male and Female Rats (2011)'''<ref name=PMID22248293><pubmed>22248293</pubmed></ref>

<pubmed>22248293</pubmed>

Whilst it is evident that some of the most common reproductive abnormalities in males occurs within the fetal stage, it is believed that disorders that affect young men later in life (such as low sperm count or testicular cancer) could also occur within this stage. Previous studies have demonstrated a critical period (masculinisation programming window - MPW) during fetal development that must transpire in order for masculinisation of the male fetus to occur. If the androgenic pathways do not occur in the correct manner, testicular dysgenisis (TD) may result. Although androgen production can be difficult to measure in humans, it can be measured by examining the anogenital distance, which is shorter in females versus males.

Therefore, it can be established that the MPW is important in setting up normal male development and it is triggered to open by either the presence or absence of both androgens and their receptors. The aim of the present study was to investigate whether or not availability of excess androgens available to their receptors before or during the MPW could increase masculinisation and therefore, development of male and female rats.

This study uses the highly potent dihydrotestosterone (DHT) androgen in comparison to other studies, which used testosterone, with the potential to convert to oestradiol and cause pregnancy disorders. The study used pregnant Wister rats and exposed them to DHT in two time frames: either before the MPW or during it. Relevant tissues were then extracted from the animals and certain procedures such as spectrophotometry, immunohistochemistry for AR proteins and RNA analysis were used to measure masculinisation and obtain results.

Results showed that exposing male fetuses to a dosage of DHT that would result in masculinisation of the female fetus had no effect on the male. More specifically, the results indicated that exposure to DHT before or during the MPW did not stimulate any male reproductive development, and female masculinisation may begin much prior to the MPW. The results also support previous evidence demonstrating the potential for testosterone and oestrogen treatment to cause adverse pregnancy effects.

Overall, the study concludes that genital development in male rats is not enhanced by DHT exposure before or during the MPW and that sensitivity of the female fetus to androgens can not only be refined to occurring during the MPW but also prior to. This has implications in that the female fetus is more susceptible to androgens and masculinisation of the genital system much before the male is, therefore suggesting a wider window.

====Female====
----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

----

'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

{|class="wikitable mw-collapsible mw-collapsed"
! '''Other current research and findings and interesting reads:'''
|
*A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>
*<pubmed>21584884</pubmed>
*<pubmed>18367374</pubmed>
*<pubmed>15086026</pubmed>
*<pubmed>14641326</pubmed>
*<pubmed>11684660</pubmed>
*<pubmed>22127979</pubmed>
*<pubmed>24631756</pubmed>
*<pubmed>23192465</pubmed>
|}

----

==Historic Finding==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==Abnormalities==

[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]

==References==
<references/>
<ref name=PMID18431748><pubmed>18431748</pubmed></ref>
<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>

2014 Group Project 4

2014-10-21T01:34:27Z

Z3416697:

{{ANAT2341Project2014header}}
=Genital=
==System Development==
(NB: having formatting issues trying to put the following information into a table, an attempt at the table is included below)
Prior to discussing the fetal development of the genital system, it is important to briefly appreciate the embryonic development of the genital tracts. Up until the seventh week of development, male and female genital tracts are '''indifferent'''. The genital system begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally in the coelomic cavity. The proliferation of this coelomic epithelium leads to an outgrowth known as the '''genital ridge'''. The genital ridge continues in outgrowth due to the ingression of the polemic epithelium, proliferation and recruitment of adjacent mesonephric cells. This bipotential genital ridge is indifferent in XX and XY embryos, however due to chromosomal and genetic influences differentiate into the testis and ovary respectively. [1]

Fetal genital development occurs in three main stages
1. Differentiation of gonad into Ovary or Testis
2. Development of he internal genitalia
3. Development of the external genitalia

'''References'''
[1] <pubmed>PMC3841730</pubmed>
<pubmed>11315960</pubmed>

<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>

[[File:Image.jpg|300px|left|thumb|The stages in sexual differentiation of the female and male reproductive system]]

===Related video===

==Current Research, Models and Findings==

===Current Research and Findings===

====Male====

Extensive research into organogenesis of the external genitalia, mainly in males, is driven by the increasing incidence of hypospadias. Hypospadias are a result of the defect of fusion of the urethral folds of the lower part of the penis to fold and form the tubular penile urethra. The result of this in humans is the presence of an abnormal ventral urethral meatus, incomplete formation of the prepuce and an abnormal penile curvature.

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>

'''Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.''' '''(2013)'''<ref name=PMID24030937><pubmed>24030937</pubmed></ref>

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

The development of the male reproductive system requires the action of different hormones and is highly susceptible for development to be altered due to endocrine disruptions.

Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.
Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are some of the most widely used drugs used. These drugs have recently been identified as potential endocrine disruptors (ED) in humans. A number of epidemiological studies have reported that exposure to NSAIDs and analgesics during pregnancy showed an increased risk of cryptorchidism.

This study used 62 fetuses from the first trimester between 7-12 weeks in gestation (GW) from pregnant women who obtained an abortion legally and with were given information and verbal consent was obtained according to national guidelines. The terminations were not motivated by abnormalities. The testes were cut in approximately 1mm3 pieces and drugs were used in the same concentration compared to recommended dosages in the body. The drugs used were paracetamol, aspirin, indomethacin, ketoconazole (antifungal).

Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.
The results showed no changes in the architecture of the testis with the analgesic treatment whereas the ketoconazole caused the boundaries of the testis cords to become unrecognisable. The analgesics did not significantly modify the number of germ cells or sertoli cells.
Ketoconazole reduced testosterone levels in contrast to indomethacin, which stimulated testosterone production. Paracetamol had no significant effect on testosterone while aspirin produced a dose response relationship with an increase in testosterone after 72 hours in the youngest fetuses (8-9.86 GW) but not the older testes (10-12GW). None of the analgesics significantly affect the number of interstitial cells.

The results showed a consistent trend for lower INSL3 production after 48-72 hours of exposure to mild analgesics and ketoconazole. This was the first study to measure direct production of INSL3 by the testis.
Aspirin strongly stimulated AMH production, whereas as paracetamol and indomethacin increased production but not significantly. The analgesics did not significantly alter the sertoli cells and Ketoconazole significantly inhibited AMH production. Aspirin and paracetamol showed significant inhibition of Prostaglandin E2 production while indomethacin had no effect.

In conclusion, the study shows that painkillers have a direct effect on various hormones, which are crucial for endocrine function and development of the human testis. The study shows that there is a direct effect with the dosages which are currently found with most medications.

====FEMALE====

----

'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref>

<pubmed>21584884</pubmed>

In the past, magnetic resonance imaging (MRI) has been used in conjunction with ultrasound to diagnose prenatal complications, including urogenital abnormalities. However, no previous research yielded any data regarding normal development of female external genitalia using MRI. As a result, this study investigated labial growth and correlated it with gestational age using prenatal MRI.

This study included fetal MRI results from 197 female fetuses of Caucasian background, with either normal anatomy or minor congenital abnormalities. Fetuses with major congenital abnormalities, especially with urogenital abnormalities were omitted from the study. The MRI results were used to confirm if suspected anomalies during ultrasound screening were correct. Axial and coronal images of the fetus’ lower body were used to visualise the external female genitalia, including labia and clitoris and statistical analyses were performed on all MR images.

Results showed a linear relationship between bilabial diameter and gestational age, and the morphology on the MRI showed a statistically significant difference between the 20-23 weeks age group and the rest (24-36 weeks) in the visual differentiation of the clitoris and the labial structures. Between 20-23 weeks, differentiation of the clitoris from the labia was not possible. Similar to what can be identified in ultrasounds, from 24 weeks onwards, in 12% of fetuses the clitoris and labia could be differentiated as 3-5 protuberances emerging from the pelvis, with the clitoris lying in the midline.

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.<ref name=PMID18431748><pubmed>18431748</pubmed></ref>

In conclusion, this study examines the morphological development of the female external genitalia in utero using MRI, proving its effectiveness as a visualiser of the female phenotype and diagnosis of genital abnormalities, and should be used in conjunction with ultrasound.

----

'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref>

<pubmed>21584884</pubmed>

As sexual differentiation of the external genitalia is an event that occurs within the fetal period, it is highly important to maintain the correct intrauterine environment in terms of hormonal content. In humans, differentiation and growth of the external genitalia is triggered by the release of androgens from the fetal testis such as dihydrotestosterone. Exposure of the female fetus to these androgens results in the female developing more male sexual characteristics at birth. This results from congenital adrenal hyperplasia, due to a deficiency of cytochrome P450 21-hydroxylase (CYP21), an enzyme involved in the biosynthesis of cortisol.

A deficiency of CYP21 results in a decrease in cortisol levels, and this is believed to alleviate negative feedback at the fetal anterior pituitary. As a result, increased adrenocorticotropic hormone (ACTH) shifts steroid precursor formation towards androgen biosynthesis and therefore a balance between cortisol biosynthesis and androgen production is important for normal female external genitalia development. Therefore, this article illustrates the potential of utilising early cortisol biosynthesis to uphold normal female sexual development.

The study used gas chromatography and mass spectrometry to observe a 9-18 fold increase in cortisol levels within the adrenal gland during the first trimester. The capacity of the adrenal gland in the fetus to secrete androgens was also determined using assays.

By the time differentiation of the external genitalia occurs in the second trimester, the female fetus is well protected by high levels of placental aromatase enzymes, which convert androgens to oestrogens. Also, in order to prevent virilisation in CYP21 deficiency, dexamethasone needs to be administered at week 6.

----

'''Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)'''<ref name=PMID23585338><pubmed>23585338</pubmed></ref>

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life<ref name=PMID20970500><pubmed>20970500</pubmed></ref>. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

This study obtained 29 samples of ovarian tissue from humans in first or second trimester fetuses and 6 non-PCOS adults. Fetal bovine ovaries were also obtained. mRNA expression analyses were performed, as well as PCR and indirect immunofluorescence immunochemistry.

Results showed that in both human and bovine ovaries, fibrillin-3 mRNA is mostly expressed during the first trimester, with little to none being expressed in the adult ovaries. Localised expression of fibrillin-3 surrounding primordial and primary follicles results in fetal oocyte and adult follicle expansion within the stroma, as the ECM remodeling is necessary to support the growth of these follicles. Therefore, the fibrillin-3 gene in PCOS women displays potential for altering fetal ovarian follicle development, and since it is expressed in ECM throughout the fetus, it may result in altered development in non-ovarian organ systems in human fetuses.

In conclusion, the study suggests that since the stroma within the ovaries is hyper developed in PCOS women, different alleles of the same fibrillin-3 gene could be expressed within the fetal ovary to overcommit the polycystic ovary to follicular growth that is unlikely to mature into preovulatory follicles.

----

'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref>

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development <ref name=PMID19027189><pubmed>19027189</pubmed></ref>

Some critical genes involved in the testicular and ovarian pathways include:
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref>
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref>
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref>
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Such genes are expressed in the support cells of the fetal gonads, for example, the Sertoli cells in the testis and the granulosa cells in the ovary.<ref name=PMID18250098><pubmed>18250098</pubmed></ref>

Small non-coding RNA molecules, called miRNAs are RNAs that regulate gene expression and function within many different tissue types. Whilst studies have shown that miRNAs are important for growth and development of the gonads, none have yet indicated which miRNAs.

Not much is known regarding the expression of miRNAs during fetal genital development in mammals and the purpose of this study was to identify this expression of miRNAs using the ovine as a model. Expression levels were examined and the importance of such research is to provide further understanding of human genital development on a genetic level, as well as the reproductive development of ovine, which may have economical implications as livestock.

This study used sheep breeding methods and collected fetal gonads, which then underwent PCR genotyping. RNA was isolated, and miRNAs were treated with reverse transcriptase and then hybridised. These techniques were all used to detect expression levels of the relevant genes.

From the study, it is evident that miRNAs are indeed present during fetal genital development in sheep. It is believed that miRNAs are important regulators of gene expression and function and based upon the results, the genes Let7 and miR-22 regulate oestrogen signaling during fetal genital development. Further, miR-22 may be needed for suppression of the oestrogen-signaling pathway during fetal development of the testes, as localisation of the gene in the testicular cords suggested that Sertoli cell development required such suppression of the oestrogen-signaling pathway.

----

'''Other current research and findings:'''

*A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. <ref name=PMID19379463><pubmed>19379463</pubmed></ref>Additionally, the study showed that the longer a culture of fetal gonads was kept (>14 days), follicular and development and oocyte growth in vivo was affected, as well as the maturation of the oocytes in vitro following transplantation into kidney capsules (the capsules are an ectopic site, however have all the necessary conditions for growth of the oocytes). <ref name=PMID8882299><pubmed>8882299</pubmed></ref>

===Current Models===

Current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

Also, when observing the morphology and cell biology of the developing testis, it is important to note that much of the research conducted on the subject involved the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy.<ref name=PMID17237341><pubmed>17237341</pubmed></ref>

[[File:External genitalia current model.jpg|800px|center]]

'''The current model for fetal development of the external genitalia in humans and mice:'''

{|class="wikitable mw-collapsible mw-collapsed"
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''
|- bgcolor="purple"
|- bgcolor="lavender"
|
# The external genitalia initially begin in the perineal region as three primordia, being the genital tubercle in the midline and the bilateral genital swellings. These three primordia arise together with the differentiation of the cloacal part of the hindgut into the urogenital sinus, rectum and anal canal. The cloacal membrane extends from the perineum cranially to the root of the umbilical cord and during development, this bilayered cloacal membrane retracts into the perineum. This is due to cranial and medial migration of mesodermal cells into the ventral body wall between the ectoderm and endoderm of the cloacal membrane. These migrating mesodermal cells line around the membrane and accumulate, forming the three primordial swellings.
# These external features are internally related to the cloaca, which becomes divided coronally by the urorectal septum into the urogenital sinus anteriorly, and the rectum and anus posteriorly.
# This division of the cloaca occurs in a specific way so the allantois, Mullerian and Wolffian ducts and ureters all empty into the urogenital sinus.
# When the cloacal membrane becomes divided into the urogenital and anal membranes, the urogenital membrane is bound cranially by the genital tubercle in the midline and laterally by the urogenital folds and genital swellings.
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.
|}

----

{| style="width:100%; height:150px"
|bgcolor="lightskyblue"|'''MALE MODEL'''
|bgcolor="violet"|'''FEMALE MODEL'''
|-
|- style="height:150px"
|bgcolor="aliceblue"|''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION''
# Initially, the female and male fetuses’ external genitalia are identical and include the genital tubercle in the midline, urogenital folds (forming the urogenital ostium) and genital swellings (laterally).
# In males, the genital tubercle will eventually form the penis and the genital swellings migrate caudally and a fusion event in the midline occurs, thus forming the scrotum.
# As the genital tubercle elongates to form the penis, a groove forms on the ventral surface known as the urethral groove. The urethral folds that are continuous with the urogenital folds surrounding the urogenital ostium define the urethral groove laterally.
# At first, the urethral groove and folds extend only part of the along the shaft of the elongating genital tubercle (known as the phallus at this stage).
# Distally, the urethral groove terminates at the urethral plate, consisting of epithelial cells, and then extends into the glans of the penis, forming a channel.
# As the phallus elongates, the urethral folds grow toward each other and fuse in the midline forming the midline epithelial seam, converting the urethral groove into a tubular penile urethra. The fusion of the urethral folds begins proximally in the perineal region and extends distally towards the glans of the penis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|bgcolor="lavenderblush"|''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION''
|-
|- style="height:150px"
| style="width:50%"|[[File:Cross section of genital tubercle male.jpg|300px|center]]
| hfflffluftuftlufulfy
|-
|- style="height:150px"
|bgcolor="aliceblue"|
* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
* During development, the mesoderm separates into connective tissues and dermis.
* Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.
* Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
* Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|bgcolor="lavenderblush"|HFYKDFUFFYLGUP
|-
|- style="height:150px"
| [[File:Anatomical diagram of testes.jpg|300px|center]]
| Third Row Column 2
|-
|- style="height:150px"
|bgcolor="aliceblue"|Development of the external genitalia is highly regulated by the endocrine system. Sexual differentiation of the external genitalia is determined by the presence or absence of androgen receptor signaling. The fetal testes produce testosterone, which travels to the genital tubercle via the bloodstream, where it is converted into 5a-dihydrotestosterone by the enzyme 5a-reductase. This formation of the highly potent 5a-dihydrotestosterone masculinizes the developing external genitalia, as binding of the 5a-dihydrotestosterone to its androgen receptor leads to the regulation of downstream signaling genes.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
*: Sonic Hedgehog (SHH) acts as an endodermal signal that normally regulates patterning of the hindgut and is expressed in the epithelium of the cloaca, urogenital sinus and urethral plate epithelium. However this has an important signaling pathway role in development of external genitalia. The SHH gene codes for a particular protein that has important roles in organogenesis as well as structures that are dependent upon mesenchymal-epithelial interactions, such as limbs, teeth and prostate.<ref name=PMID14641326><pubmed>14641326</pubmed></ref>
|bgcolor="lavenderblush"|HFYKDFUFFYLGUP
|}

----

====Female====

* In females, the genital tubercle will eventually form the clitoris and the genital swellings remain apart and will eventually form the labia majora. The urogenital folds forming the border for the urogenital ostium will eventually form the labia minora in the female, thus forming the vestibule of the vagina. <ref name=PMID14641326><pubmed>14641326</pubmed></ref>

===Future Research===
Future research can work to decrease the incidence of hypospadias, which has more than doubled from 1973-2003.

<ref name=PMID18431748><pubmed>18431748</pubmed></ref>
<pubmed>21584884</pubmed>
<pubmed>18367374</pubmed>
<pubmed>15086026</pubmed>
<pubmed>14641326</pubmed>
<pubmed>11684660</pubmed>
<pubmed>22127979</pubmed>
<pubmed>24631756</pubmed>
<pubmed>23192465</pubmed>

==Historic Finding==
===Female Genital Development===

Female genital system development has been a subject of many historical literatures dating to the 17th century. Certain research articles aimed to focus on the female genital system as a whole, whereas others delved into specific areas such as the epithelium or specific organs such as the vagina. With the development of technology and research skills over the years, the understanding of the female genital system has improved substantially from the understanding of origin, the structure of the organs and even the nomenclature of the system. <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232984><pubmed>17232984</pubmed></ref>

Majority of the findings lead to a proposal of a theory of that organ or the system, with some of these theories still accepted today and others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref>

# The origin of the vagina and inner genital organs is the Mullerian duct.
# Part of the Wolffian ducts give rise to some or all of the vaginal epithelium.
# Contribution of the vagina is from the epithelium of the urogenital sinus.

Prior to the discovery of the importance of the Mullerian ducts, the origin of the vagina was considered to be the urogenital sinus. It was not until later that century, roughly in 1864 that the Mullerian ducts and their fusion pattern and foetal development was introduced. This realisation was later supported by many academics in their published work, particularly in the early 1900s (1912, 1927, 1930, and 1939). <ref name=PMID13475148><pubmed>13475148</pubmed></ref>

[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]

According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the timeframe of 1868 to 1939, concluded that the mullerian (paramesonephric) ducts, found laterally to the wolffian ducts, are the original structures of the female reproductive system. Female sexual organs (the fallopian tubes, uterus and vagina) originate from the mullerian ducts, which differentiates within the foetal developmental phase. Initially the foetus contains two mullerian ducts, however by the ninth week, fusion of the lower portion of the ducts is complete, creating the fundamental structure of the uterus and the vagina, however the these two organs are not continuous with the vagina being solid. The non-fused upper part of the ducts emerge into the fallopian tubes. It is not until the fourth and fifth month of development that the uterus becomes continuous with the vagina, with both organs developing a hollow lumen. The muscular layers of the uterus is also present by this stage. The cervix begins to form within the fifth month in between the continuous vagina and uterus. Also within the same month, the formation of the hymen occurs. The hymen is described as a pouting vertical slit and represents the remains of the mullerian eminence. <ref><pubmed>17232227</pubmed></ref> <ref><pubmed>13230915</pubmed></ref>

===Male Genital Development===
'''The Prostate'''

The mechanism behind prostate foetal development and modern understanding has been continuously reshaping since the 16th century. Throughout this period, various anatomical classifications have been proposed via dissection procedures, hormone responses and histological methods, attributing to the current understanding of prostate development. The rate of research into the structure and development of the prostate steeply increased in the 20th century, where each decade saw an improvement of the understanding of the development of the gland. <ref><pubmed>18462432</pubmed></ref> <ref><pubmed>13948442</pubmed></ref>

{| class="wikitable"
|-
! Date !! Description
|-
| 1543 || Andreas Vesalius published the first illustrations of the prostate gland.
|-
| 1674 || Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.
|-
| 1901 || Pallin thoroughly investigated the prostate gland and its origin.
|-
| 1912 || Oswald S Lowsley constructed the first detailed drawing of the anatomy of the prostate by dissecting and researching on a 13-week old foetus, 30-week old foetus, and one at full-term. He proposed the concept of separating the gland into five lobes, and that the prostate originates from the urogenital sinus.
|-
| 1920 || Johnson reshaped the anatomical illustration after being unable to replicate Lowsley’s results. He preserved the use of the term ‘lobe’ in describing the prostatic divisions.
|-
| 1954 || Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.
|-
| 1983 || McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.
|}

'''Testicular descent'''

Testicular descent begins during the early foetal period, 8-10 weeks, and takes approximately 5 weeks for the testes to reach the inguinal region. The second phase of descent, when the testes reach the scrotum, is not complete until the 35th to 40th week. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections during the eighteenth and nineteenth centuries, then enhancing with endocrinological discoveries during the twentieth century.

The Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles in the late 1700s. In his research, Hunter claimed that descent occurred during the 8th foetal month and was directed by the gubernaculum testis, a ligament attaching the foetal testis to the abdominal wall and the scrotum. He further proposed that the processus vaginalis closes subsequent to the decent of the testis. This is contrary to the findings of Albrecht von Haller who illustrated that foetal testis is intra-abdominal and the processus vaginalis is not closed.

Hunter described the gubernaculum as a vascular and fibrous foetal structure covered by the cremaster muscle, a muscle of unknown function. This led to more research focused on the cremaster muscle. In 1777, Palletta questioned the importance of the cremaster muscle because of its under developed state during the time of descent. This however did not stop Pancera, who in the following year, considered the muscle as the key factor in the process. Pancera’s conclusion was confirmed by Lobsetin in 1801.

The second phase of testicular descent to the scrotum has also seen many theories. Lobsetin suggested that this phase is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth. The concept of increased abdominal pressure was reiterated by Robin in 1849, however he also introduced the theory that descent into the scrotum occurs due to the weight of the testes and muscles associated. Both Lobsetin and Robin’s work was refuted by Weber who highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.

In 1841, Curling detailed the structure of the gubernaculum and the cremaster muscle. Curling believed that during the foetal period, the cremaster muscle was important in descending the testis, however subsequent to the descent, the fibres of the muscle everted resulting in it’s new functions of elevating, supporting and compressing of the developed testis. The eversion of the muscle fibres were denied by Cleland, who in 1856 performed dissections on foetal specimens ranging from 5-6 gestational months old. In his experiment he found that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. In terms of the testicular descent process, Cleland presented a similar theory as Weber, in terms that the cremaster was not the primary source of descent, second to the gubernaculum, that led the descent of the testes. In 1888, Lockwood published a completely unique theory claiming that the testes remained stationary and that it was in fact the surrounding structures that developed, resulting in the changing of the testicular location. Lockwood’s hypothesis was disagreed on by many anatomists and embryologists.

With the introduction of endocrinology and hormonal testing, the previous theories were tested on a cellular basis. Male androgen, controlled by the pituitary gland, was the first hormonal theory believed to influence testicular descent. It has been evidently proven that androgens are important in the descent however it is unclear if it is important in both stages. It is currently accepted that testosterone influences the gubernaculum during the second phase in which the testes reach the scrotum, however the exact method is currently debatable. The first phase theories are under high scrutiny, with theories ranging from the development of the gubernaculum and hormones such as the Mullerian inhibiting substance. <sup>[4]</sup>

===References===
4. Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent.''' Pediatric Surgery International: 1991, 6(3):180-184 [http://link.springer.com/article/10.1007/BF00176064 The history of ideas about testicular descent]

<pubmed>18462432</pubmed>
<pubmed>17232227</pubmed>

==Abnormalities==

We discuss both male and female genital abnormalities internally or externally, that may occur during fetal development. The abnormalities have been identified as disorders of sex differentiation(DSD), associated with congenital conditions in the atypical development of chromosomal, gonadal or phenotypical sex <ref><pubmed>16882788</pubmed></ref>, <ref><pubmed>25248670</pubmed></ref>.
The content will cover most common abnormalities and then also the rare cases. Most genital abnormalities have a high risk in affecting fertility of both sexes. Currently there are a variety of methods applied to ensure that infertility can be treated and this will be mentioned.

===FEMALE===

[[File:Uterus and Vagina Abnormalities.jpg|400px|right|thumb|Abnormalities of the Uterus and Vagina]]
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;

*double uterus and double vagina
*double uterus
*bicornate uterus
*septated uterus
*unicornate uterus
*cervical atresia

====Mullerian agenesis====

Mullerian agenesis also known as ‘Mayer-Rokitansky-Kuster-Hauser’ syndrome, vaginal agenesis or Mullerian aplasia, is presented in the absence of the uterus or vagina or in some case even both. This is due to the unsuccessful development of the Mullerian ducts which then causes certain parts of the reproductive system to be underdeveloped. It is present in 1 of 4000-10 000 women. This condition also uses dilation therapy and following the neovaginal approach with the reconstruction of the vagina in its treatment strategies <ref><pubmed>23635766</pubmed></ref>.

====Vaginal agenesis====

Vaginal agenesis is a rare condition involving the underdevelopment of the vagina. It is commonly cause by a combination of Rokitansky (Mullerian agenesis) and androgen insensitivity syndromes <ref><pubmed>21872517</pubmed></ref>. To ensure effectiveness in treatment, it’s advised after or during adolescence, procedures consist of vaginal dilation shown a success rate of 80% and low risks. In cases where such methods are ineffective then vaginal reconstruction is implemented as a final option for patients <ref><pubmed>17995494</pubmed></ref>.

====Turners syndrome====

A chromosomal disorder occurring among women due to the absence of the whole or part of the sex chromosome (X). The condition is characterized by short stature, cardiovascular malformations, amenorrhea and estrogen insufficiency <ref><pubmed>16849410</pubmed></ref>. It is prevalent in 1 of 2000 live births among females <ref><pubmed>2037286</pubmed></ref>. Management of the syndrome depends on the extent of the condition the individual will present. Therefore treatment will vary, for short stature biosynthetic growth hormone is utalised in growth hormone. The most common cardiac malformations are bicuspid aortic valve, coarctation of the aorta and aortic stenosis that are all surgically treated. Generally patients are advised to see pediatricians, endocrinologists and many other clinicians depending on the severity of the condition, to discuss strategies to manage the syndrome <ref><pubmed>16714725</pubmed></ref>.
====Swyer Syndrome====

Swyer syndrome (46 XY, gonadal dysgenesis) is a type of hypogonadism disorder in which an individual from birth is phenotypically female with unambiguous genital form and normal mullerian structures. The condition is usually observed during adolescence since the gonads have no hormonal or reproductive function amenorrhea occurs and puberty is delayed <ref><pubmed>3182960</pubmed></ref>. It has been found that 10-20% of women with this condition have a deletion of the SRY gene in the DNA-binding site. In other cases the SRY gene is normal however mutations may present in different determining factors. Managing the syndrome consists of hormone replacement therapy (including estrogen and progesterone), to ensure bone mineral density is maintained and uterine size and shape is improved <ref><pubmed>18410658</pubmed></ref>.

'''Also related include;'''

====Polycystic Ovarian Syndrome====
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]

A metabolic endocrine disorder with an immense variety of phenotypes presented. The disorder has an imbalance in female sex hormones and a resistance to insulin.
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities.
The treatments implemented depend on the clinical manifestations each patient develops.
Insulin-sensitizing agents are among the treatments used these include Metformin, Rosiglitazone and Piglitazone all have shown to be effective <ref><pubmed>23435473</pubmed></ref>.

===MALE===

====Cryptorchidism====

[[File:Cryptorchidism.jpg|400px|right|thumb|The sites where Cryptorchidism may occur]]

Involves the absence of both or single testis to descend into the scrotum, the testes can be ectopic, incompletely descended, absent or atrophic. It is possible that sometimes the cryptrodism may be spontaneously corrected by 3 months of age. The abnormality can occur as a result of a number of factors including maternal, genetic or environmental <ref><pubmed>24683948</pubmed></ref>.
The descendence of testis occur in two stages; in the first stage insulin like hormone attaches the testis to the inguinal ring this is through gubernaculum development.
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.

Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach.
Surgical repair is intended to apply the safest and least invasive methods, focusing on repositioning the undescended testicle/s to their normal position in the scrotum. Such surgeries are recommended in early life and have proved to be most effective, with 75%+ success. The therapy used to relocate the testis into the scrotum is known as ‘Orchiopexy’, others include one-stage Fowler Stephens and two-stage FS Orchidopecy. However there are concerns with long-term effects which include infertility and testicular cancer later in life as a result of the procedure <ref><pubmed>24857650</pubmed></ref>.

====Hypospadias====
In males the most common congenital malformation of the external genitalia is hypospadias, it’s also the second most common developmental disorder. It occurs due to the midline fusion of the male urethra, as a result the urethral meatus is misplaced. There are several sites where this abnormality may occur: granular, penile, penoscrotal, scrotal and perineal. <ref><pubmed>16006950</pubmed></ref> Its believed that genetic factors contribute to the presence of the disorder, however endocrine and environmental factors are also of significance.
<ref><pubmed>24936573</pubmed></ref>
Treatment
The surgical methods currently used to treat distal hypospadias, include tabularized incised plate and meatal advancement and glansplasty intergrated repair. For proximal forms two staged procedures are employed. <ref><pubmed>25023236</pubmed></ref>

====Klinefelter====
Klinefelter is a genetic disorder caused by the addition of an X chromosome among males (47, XXY, XXY,XXXXY, XXYY), due to the inability of the extra chromosomes to detach throughout meiosis. It is believed to have an origin from either parent. The abnormality has a wide range of phenotypic variations, that typically include infertility, small testes, gynecomastia and hypergonadotropic hypogonadism <ref><pubmed>16342850</pubmed></ref>. An early diagnosis is important in order for treatment to be commenced right away. The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. The fertility options consist of IVF, where males undergo testicular sperm extraction, cryopreservation of sperm containing semen or testicular tissue during adolescence <ref><pubmed>24563893</pubmed></ref>.

====Peyronie’s Disease====

The acquired disease occurs due to fibrotic plaque formations in the tunica albuginea of the penis. This leads to sexual dysfunction, a loss in penile flexibility, shortening and penile malformations <ref><pubmed>20497306</pubmed></ref>. The penis is curved upward as a result of the plaque structure. Adult males are at risk of the condition where about 3.2-8.9% are affected among the population <ref><pubmed>3826933</pubmed></ref>. Strategies applied vary in the extent of the deformities; some procedures involve grafting in the lengthening of the penis, plaque removal and prosthesis implantation in erectile dysfunction <ref><pubmed>23435473</pubmed></ref>.

===BOTH===

====Congenital adrenal hyperplasia====

The condition is caused by a deficiency in 21-Hydroxylase, a genetic disorder of steroidogenesis. Occurs due to mutations in genes that encode enzymes that take part in adrenal steroid synthesis therefore there is a loss of function <ref><pubmed>18844712</pubmed></ref>. The deficiency is from mutations in CYP21A2, thus the clinical characteristics may vary. In females it results in the ambiguity of the female genitalia, fused labia majora, larger clitoris and common urogenital sinus <ref><pubmed>15964450</pubmed></ref>. Steroid 21-OHD deficiency is examined in-utero and then prenatal treatment with dexamethasone is administered. This is a safe method used and decreases the risk of ambiguous genitalia in females <ref><pubmed>20392211</pubmed></ref>. Among males symptoms aren’t present at birth a side from possible penile enlargement and slight hyperpigmentation <ref><pubmed>15964450</pubmed></ref>. Generally male patients also require the administration of glucocorticoid and mineralocorticoid therapies <ref><pubmed>18446680</pubmed></ref>.

====Hydrocele====

Hydrocele occurs when the space between parietal and visceral layers of tunica vaginalis accumulates an abnormal amount of serous fluid. Normally caused by an imbalance in the processes of production and reabsorption of fluid or varicocelectomy. To manage the condition treatments focus on ensuring draining any excess fluid and inhibiting reaccumulation. Techniques used involve sclerotherapy and hydrocelectomy <ref><pubmed>20548330</pubmed></ref>. In females it is a very rare condition, occurs in the ‘Canal of Nuck’, a part of the inguinal canal containing a section of the processus vaginalis. A swelling is present on the labia major or inguinal ring. Techniques applied to treat the condition in females involve ligation of the processus vaginalis neck and the hydrocele is surgically resected <ref><pubmed>16416273</pubmed></ref>.

'''Also related include;'''

====Kallmann syndrome====

Kallmann’s syndrome is a heterogenous disease expressed during puberty due to a combination of hypogonadotropic hypogonadism and anosmia. The genetic disease is responsible for infertility and the inability to smell. Seems to have affects on 1 in 10 000 males and 1 in 50 000 females <ref><pubmed>16952059</pubmed></ref>. It occurs during embryonic development at a time in which hypothalamic neurons (gonadotropin-releasing hormones) are unable to migrate into the hypothalamus. Currently there are no available treatments for the olfactory deficit, however among males hormone replacement therapy is implemented with human chorionic gonadotropin, human menopause gonnadotropin and testosterone undecanoate <ref><pubmed>24432625</pubmed></ref>. In females treatment focuses on maintaining and inducing secondary sex characteristics <ref><pubmed>23368665</pubmed></ref>.

====Hypogonadotropic hypogonadism====

The condition results in a failure to secrete gonadotropin such as luteinizing (LH) and follicular stimulating hormones (FSH), which then reduce the gonadotropin levels <ref>http://www.ncbi.nlm.nih.gov/books/NBK1334/</ref> . This indicates possible issues with the hypothalamus or the pituitary gland. It may occur in conjunction with Kallmann’s syndrome or a decreased gonadotropin-releasing hormone (GnRH). In males treatment methods depend on how the condition is presented and whether it’s associated with another abnormality. Generally the therapies may require testosterone in cases with micropenis and to generate spermatogenesis gonadotropin replacement is utalised. Hypogonadotropic Hypogonadism is rare among females, however it may be presented thus similar treatment options are available. Treatments consist of gonadotropins administration of FSH and LH, to ensure successful occyte formation <ref><pubmed>17260221</pubmed></ref>.

==References==
<references/>

User:Z3416697

2014-10-15T00:43:12Z

Z3416697:

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:45, 6 August 2014 (EST)
==lab attendance==
Lab 1
http://www.ncbi.nlm.nih.gov/pubmed

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

<pubmed>2508416</pubmed>

----

==Lab Assessment 1==
===ARTICLE 1===
<pubmed>25071849</pubmed>

In Vitro Fertilization (IVF) is a popular method of Assisted Reproduction which allows for fertilization to occur under optimal conditions (which may not be achieved in those that are having trouble conceiving), with monitored hormone levels and calculated growth of the embryo so as to maximize implantation, and ideally, successful pregnancy. This research article endeavors to assess the different variables available in IVF to determine which method yields the most successful amount of pregnancies. The variables in question are whether the embryo should be fresh (within a hours of fertilization), or frozen-thawed (embryo frozen a few days after fertilization and thawed when the mother is ready to receive an embryo). Another variable considered is the developmental stage at which the embryo is implanted; some embryos are implanted at the cleavage stage (hours after fertilization) and others are implanted at the blastocyst stage (5 days after fertilization), this study also considered implants at the cleavage stage extended blastocyst stage however it did not clarify what this term means, and I was unable to find elsewhere what this means.

This study observed IVF cycles of 1891 women at the Wuhan Union Hospital between January and December of 2012. Of the 1891 women observed, 1150 had fresh embryo transfers and 741 had frozen thawed embryo transfers. Of the Fresh embryo transfers 993 were implanted at the cleavage stage (799 of them women were less than 35 years old and 194 were greater than or equal to 35 years old), and 157 were implanted at the blastocyst stage (131 were less than 35 years old, 26 greater than or equal to 35 years old). Of the 741 women with frozen thawed embryo transfers, 212 were implanted at the cleavage stage of embryonic development (159 women were less than 35 and 53 were greater than or equal to 35), 137 were implanted at the cleavage stage extended blastocyst stage (111 were less than 35, 26 were greater than or equal to 35) and 328 were implanted at the blastocyst stage (276 were less than 35, 52 were greater than or equal to 35). All of these women underwent traditional methods of IVF- that is they were initially treated with Gonadotropin Releasing Hormone to stimulate follicular development. When two or more follicles were greater than 18mm Human Chorionic Gonadotropin was injected to assist follicular maturation. 24-26 hours later the ova were collected (Ovum Pick Up/OPU) and 4-6 hours after OPU IVF or Intracytoplasmic Sperm Injection (ICSI) were performed on the ova. The embryos were assessed by morphology and rate of development and at day three they are transferred onto a blastocyst medium and cultured for 2-3 days until it forms a blastocyst. The blastocysts are socred according to the Gardner standard and usually 1-2 good embryos are implanted. The remaining viable embryos are cryopreserved via vitrification and may be used if the current IVF cycle is unsuccessful. The Estrogen and Progesterone levels are monitored and regulated throughout the process according to the characteristics of the patient. Clinical pregnancy was defined by the presence of a gestational sac with or without a heart beat 30 days after implantation.

From this experiment it was found that there was a greater amount of successful pregnancies in women less than 35 years old resulting from implantation of fresh embryos at the cleavage stage (52.7% success) as opposed to the blastocyst stage (35.88%). There was no statistically significant differences clinically between the two types of implantation [ie- multiple pregnancies, abortion or ectopic pregnancy]. There were also a significantly higher number of pregnancies in the cleavage stage [41.24%] vs the blastocyst stage [26.92%]. However, this was not that case for those whom has frozen-thawed embryo transfers, as there was generally a much greater success rate for pregnancy in those who had blastocyst stage transfers than those who had cleavage stage transfers. Furthermore, there is a significantly greater pregnancy rate between in fresh embryo transfers compared to frozen thawed embryo transfers at the cleavage stage. Overall, there was a greater incidence of clinical pregnancy resulting from fresh cleavage stage embryo transfers compared to any other type of transfer [ie fresh blastocyst stage, frozen thawed cleavage stage and frozen thawed blastocyst stage]. These researchers concluded that this type of implantation should be used under normal conditions, and other methods should only be considered if the mother is of compromised health (eg has Ovarian Hyper Stimulation Syndrome), in which case as fresh blastocyst stage embryo is used.

===ARTICLE 2===
<pubmed>25017405 </pubmed>
This article aimed to assess the success rate of clinical pregnancy of women at differing age groups whom have undergone assisted reproductive methods such as In-Vitro Fertilzation and Intracytoplasmic Sperm Injection. Based on previous literature it was expected that the success rate would decline as the woman ages, as typically the most successful IVF cycles are seen in women whom are 25-30 years old. Also based on natural conception rates, spontaneous conception rates begin to decrease around 31-35 years old, and women tend to have difficulty conceiving around the ages of 35-39. General fecundabilty (probability of released ovum becoming fertilized and resulting in a successful pregnancy in one menstrual cycle) tend t decrease as the woman reaches menopause (around the early fifties) and at 5-10 years prior to this (40-44 years old), half of the women have reduced reproductive capacity.

This study observed 2,900 women undergoing IVF at the KK Women and Children’s hospital, of which yielded 3,412 fresh IVF cycles. The women were classifies into sub groups based only on age [< 30 years; 30–35 years; 36–37 years; 38 years; 39 years; 40–44 years; and ≥ 45 years]. The IVF cycles were monitored and the average number of occytes, average duration of stimulation and fertilization rates were observed. Furthermore, the number of cycles until successful embryo transfer, clinically successfully pregnancy rates, miscarriage rates and multiple pregnancy rates were also reported.
In this study, most of the patients undergoing IVF were between the ages of 30-35 and 36-37, and the least amount of patients belonged to the ≥ 45 years group. Of these, it was found that there was a 15% miscarriage rate in those younger than 30 years old, but this figure doubled to 30% at the age of 38 and among women aged 40-44, the miscarriage rate was as high as 55%. Only half of the women aged greater than 45 reached embryo transfer, and of those, none proceeded to successful clinical pregnancy. Furthermore, compared to other age groups, these women had the lowest amount of oocytes collected and the lowest fertilization rate with only 50% of oocytes proceeding to fertilization, compared to 95% in women less than 30 years old. However, it was found that there was no differences in mean duration of ovarian stimulation prior to ovum collection based on age. Finally, it was found that there was a general decreasing trend of successful clinical pregnancies as age increased in women undergoing IVF, as the rate of live births was highest in women who were less than 30 years old. The occurence of multiple births was highest in this age group also.

Overall it was found that the age of the woman undoubtedly has an effect on the reproductive capacity of a woman undergoing IVF. The researchers hypothesized that the general decreased success of an aging woman may be due to decreasing ovarian reserve, poorer oocyte quality, lower embryo implantation rates, altered hormonal environment resulting in ovulatory dysfunction and uterine problems. Male factors were also considered to be causative.

--[[User:Z8600021|Mark Hill]] These papers are suitable for the assessment exercise and you have included an appropriate summary. (5/5)

----

==Lab Assessment 2==
[[File:Mutation of Gene Wt1 Causes Aberrant Gonadal Development.jpeg|300px]]

Mutation of Gene Wt1 Causes Aberrant Gonadal Development<ref><pubmed>23497137 </pubmed>| [http://www.biomedcentral.com/1741-7007/11/22/figure/F1]</ref>

<references/>

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:08, 20 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] This is a relevant image. I have fixed a few formatting issues in the associated file information, don't include the .jpeg in the figure legend, see the image page history for changes. (5/5)

==Lab Attendance: LAB 2==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:56, 20 August 2014 (EST)
Forgot to do my attendance at the lab of week 3 given by guest Speakers Hayden Homer and Rob Gilchrist about meiosis, oocyte quality and various technologies in assisted reproduction

----

==Lab Attendance week 4==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:39, 20 August 2014 (EST)

==Lab three Online Assessment==
Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 20:10, 26 August 2014 (EST)

--[[User:Z8600021|Mark Hill]]These 3 references meet the assessment requirement, it appears that you have just included the references without a description? Your description of genital differentiation is not quite accurate and should be clarified by the future Genital Development Lecture. (4/5)

----

==Lab 4 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 27 August 2014 (EST)

==Lab 4 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:23, 2 September 2014 (EST)

<pubmed>25137413</pubmed>

Hepatocellular carcinoma and other degenerative liver diseases often result in hepatic dysfunction and ultimately organ failure. To avoid this otherwise fatal diagnosis, bio-artificial livers and hepatocyte transplantation provides some leg- room whilst waiting on a full-organ transplant. However liver transplants, much like many other organs, are often hard to come by and are usually sensitive to the immune response of the host. As a result, researchers are looking towards stem cells as an answer to this problem. Mesenchymal stem cells derived from the Wharton’s Jelly of the umbilical Chord are often chosen because they have been found to have a slightly higher multipotency and immunogenicity. The umbilical stem cells were selected because they are more primitive compared to other Mesenchymal stem cells and do not express the major histocompatibility complex class II antigens- a key determinant in illiciting an immune response form the host. However, hepatocyte like cells derived from stem cells are not clinically used because they do not express enough functional proteins and do not exhibit a full level of metabolic activity.

This study aimed to identify and observe the transcription factors involved in hepatocyte differentiation from Human umbilical cord Mesenchymal Stem Cells (HuMSCs), they were particularly interested in Hepatocyte Nuclear Factor 4-alpha (HNF-4alpha) which is believed to behave like a “master gene” in driving hepatocyte differentiation and maturation. This study continued to expose the differentiating HuMSCs to excess amounts of HNF-4alpha and hypothesized a significant improvement in the differentiation status of the hepatocyte-like cells, providing a basis for future clinical application of HuMSCs in the treatment and management of liver diseases.

The research initially confirmed that the HuMSCs are of low immunogenicity- a critical issue with organ transplantation. Once this was confirmed, they observed that there was an up-regulation of functional hepatic enzymes once the differentiating hepatocyte-like stem cells were exposed to HNF-4alpha. An important finding they discovered that the time at which the stem cells were exposed to HNF-4alpha were integral in ensuring correct hepatocyte differentiation. Ultimately they concluded that the differentiation of HuMSCs could be improved by exposure to high levels of HNF-4alpha at specific times in the development of hepatocyte-like stem cells, an important discovery for the progression of the therapeutic application of stem cells.

The three shunts which are present in fetal development but are closed postnatally are:

• ductus arteriosis → channel between the pulmonary artery and aorta in the fetus which bypasses the lungs to distribute oxygenated blood from the placenta derived from the mothers circulation.

• ductus venosus → shunts a portion of the left umbilical vein blood flow which would flow directly to the inferior vena cava- allows b=oxygenated blood to bypass the liver.

• foramen ovale → allows passageway of blood from left atrium to right atrium in the fetus.

----

==Lab 5 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 3 September 2014 (EST)

==Lab 5 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:10, 16 September 2014 (EST)

Congenital Lobar emphysema (CLE) is a condition of the respiratory system which results in hyperinflation of one or more pulmonary lobes and is usually diagnosed postnatally, usually in the neonatal period- however there have been cases where CLE is not diagnosed until 10 years after birth. The clinical symptoms of CLE are often at birth as dyspnea, cyanosis and recurrent respiratory tract infections, as well as generalized neonatal respiratory distress and hyperinflation and hyperaeration of the pulmonary lobes- often seen as visible enlargements or imaged through CT. CLE is a rare disorder affecting only 1 in 20,000 to 30, 000 newborns, and appears to have a slight male predominance [3:1 male to female ratio], although the cause of this gender predilection is not fully understood.

The developmental causes of CLE are often as final result of a number of bronchopulmonary disturbances during development. These result from abnormal interactions between embryonic endodermal and mesodermal components of the lung which may result in abnormalities in airway or alveoli number and size, however the exact pathogenesis of CLE is not able to be determined in approximately half of cases. Another frequently observed cause of CLE is an obstruction of the developing airway, which creates a “ball valve” resulting in an uneven distribution of air- favoring greater airflow to the affected lobe during inspiration than is able to be cleared in expiration- resulting in air trapping. There may also be vascular abnormalities which produce compression, bronchial stenosis, bronchogenic cysts and congenital cytomegaloviral infections observed.

<pubmed>PMC2141574</pubmed>

----

==Lab attendance week 8==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 17 September 2014 (EST)

----

==Lab Report- week 8==

==lab Attendance WEEK 9==

----

==Lab attendance week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)
==lab report week 9==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)

----

==Lab assessment week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 00:56, 15 October 2014 (EST)
'''Group 1'''
This project is extremely well done. I found the overall layout of your work to be easy to read and succinct. It captured my attention throughout the entirety of the project and was engaging with the use of bullet points. I thought your use of diagrams was great in aiding the understanding of this topic, however I thought that more diagrams or pictures could be added in order to help the reader visualize exactly what’s going on. I thought that te developmental timeline was a great idea, however could benefit from some more images or diagrams to assist in understanding the developmental stages. I thought the historic findings sections was especially well done as it appears well researched and thoroughly informative. The abnormalities was also well done, however again could benefit from the addition of a few more diagrams.

I think that with the addition of more drawings needs to be some attention to detail when referencing and stating copyright. I’ve noticed that some pictures lack copyright and some don’t have a description, making it difficult to understand the context of the picture and to envisage how it relates to the content. Whilst this is mostly self explanatory- I think that because this is an informative piece it pays to spoon-feed us a bit. Also, your referencing could use a bit of a tidy, but that can easily be fixed before submission. I think that overall this has great potential to be a wonderful project and I look forward to seeing it at its completion!

'''Group 2'''
I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

'''Group 3'''
Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

'''Group 5'''
Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once.

I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

'''Group 6'''
Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

'''Group 7'''
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.
The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.
The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing.
Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

'''Group 8'''
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

----

==Lab Attendance week 11==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:43, 15 October 2014 (EST)

User:Z3416697

2014-10-14T13:58:52Z

Z3416697: /* Lab assessment week 10 */

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:45, 6 August 2014 (EST)
==lab attendance==
Lab 1
http://www.ncbi.nlm.nih.gov/pubmed

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

<pubmed>2508416</pubmed>

==Lab Assessment 1==
===ARTICLE 1===
<pubmed>25071849</pubmed>

In Vitro Fertilization (IVF) is a popular method of Assisted Reproduction which allows for fertilization to occur under optimal conditions (which may not be achieved in those that are having trouble conceiving), with monitored hormone levels and calculated growth of the embryo so as to maximize implantation, and ideally, successful pregnancy. This research article endeavors to assess the different variables available in IVF to determine which method yields the most successful amount of pregnancies. The variables in question are whether the embryo should be fresh (within a hours of fertilization), or frozen-thawed (embryo frozen a few days after fertilization and thawed when the mother is ready to receive an embryo). Another variable considered is the developmental stage at which the embryo is implanted; some embryos are implanted at the cleavage stage (hours after fertilization) and others are implanted at the blastocyst stage (5 days after fertilization), this study also considered implants at the cleavage stage extended blastocyst stage however it did not clarify what this term means, and I was unable to find elsewhere what this means.

This study observed IVF cycles of 1891 women at the Wuhan Union Hospital between January and December of 2012. Of the 1891 women observed, 1150 had fresh embryo transfers and 741 had frozen thawed embryo transfers. Of the Fresh embryo transfers 993 were implanted at the cleavage stage (799 of them women were less than 35 years old and 194 were greater than or equal to 35 years old), and 157 were implanted at the blastocyst stage (131 were less than 35 years old, 26 greater than or equal to 35 years old). Of the 741 women with frozen thawed embryo transfers, 212 were implanted at the cleavage stage of embryonic development (159 women were less than 35 and 53 were greater than or equal to 35), 137 were implanted at the cleavage stage extended blastocyst stage (111 were less than 35, 26 were greater than or equal to 35) and 328 were implanted at the blastocyst stage (276 were less than 35, 52 were greater than or equal to 35). All of these women underwent traditional methods of IVF- that is they were initially treated with Gonadotropin Releasing Hormone to stimulate follicular development. When two or more follicles were greater than 18mm Human Chorionic Gonadotropin was injected to assist follicular maturation. 24-26 hours later the ova were collected (Ovum Pick Up/OPU) and 4-6 hours after OPU IVF or Intracytoplasmic Sperm Injection (ICSI) were performed on the ova. The embryos were assessed by morphology and rate of development and at day three they are transferred onto a blastocyst medium and cultured for 2-3 days until it forms a blastocyst. The blastocysts are socred according to the Gardner standard and usually 1-2 good embryos are implanted. The remaining viable embryos are cryopreserved via vitrification and may be used if the current IVF cycle is unsuccessful. The Estrogen and Progesterone levels are monitored and regulated throughout the process according to the characteristics of the patient. Clinical pregnancy was defined by the presence of a gestational sac with or without a heart beat 30 days after implantation.

From this experiment it was found that there was a greater amount of successful pregnancies in women less than 35 years old resulting from implantation of fresh embryos at the cleavage stage (52.7% success) as opposed to the blastocyst stage (35.88%). There was no statistically significant differences clinically between the two types of implantation [ie- multiple pregnancies, abortion or ectopic pregnancy]. There were also a significantly higher number of pregnancies in the cleavage stage [41.24%] vs the blastocyst stage [26.92%]. However, this was not that case for those whom has frozen-thawed embryo transfers, as there was generally a much greater success rate for pregnancy in those who had blastocyst stage transfers than those who had cleavage stage transfers. Furthermore, there is a significantly greater pregnancy rate between in fresh embryo transfers compared to frozen thawed embryo transfers at the cleavage stage. Overall, there was a greater incidence of clinical pregnancy resulting from fresh cleavage stage embryo transfers compared to any other type of transfer [ie fresh blastocyst stage, frozen thawed cleavage stage and frozen thawed blastocyst stage]. These researchers concluded that this type of implantation should be used under normal conditions, and other methods should only be considered if the mother is of compromised health (eg has Ovarian Hyper Stimulation Syndrome), in which case as fresh blastocyst stage embryo is used.

===ARTICLE 2===
<pubmed>25017405 </pubmed>
This article aimed to assess the success rate of clinical pregnancy of women at differing age groups whom have undergone assisted reproductive methods such as In-Vitro Fertilzation and Intracytoplasmic Sperm Injection. Based on previous literature it was expected that the success rate would decline as the woman ages, as typically the most successful IVF cycles are seen in women whom are 25-30 years old. Also based on natural conception rates, spontaneous conception rates begin to decrease around 31-35 years old, and women tend to have difficulty conceiving around the ages of 35-39. General fecundabilty (probability of released ovum becoming fertilized and resulting in a successful pregnancy in one menstrual cycle) tend t decrease as the woman reaches menopause (around the early fifties) and at 5-10 years prior to this (40-44 years old), half of the women have reduced reproductive capacity.

This study observed 2,900 women undergoing IVF at the KK Women and Children’s hospital, of which yielded 3,412 fresh IVF cycles. The women were classifies into sub groups based only on age [< 30 years; 30–35 years; 36–37 years; 38 years; 39 years; 40–44 years; and ≥ 45 years]. The IVF cycles were monitored and the average number of occytes, average duration of stimulation and fertilization rates were observed. Furthermore, the number of cycles until successful embryo transfer, clinically successfully pregnancy rates, miscarriage rates and multiple pregnancy rates were also reported.
In this study, most of the patients undergoing IVF were between the ages of 30-35 and 36-37, and the least amount of patients belonged to the ≥ 45 years group. Of these, it was found that there was a 15% miscarriage rate in those younger than 30 years old, but this figure doubled to 30% at the age of 38 and among women aged 40-44, the miscarriage rate was as high as 55%. Only half of the women aged greater than 45 reached embryo transfer, and of those, none proceeded to successful clinical pregnancy. Furthermore, compared to other age groups, these women had the lowest amount of oocytes collected and the lowest fertilization rate with only 50% of oocytes proceeding to fertilization, compared to 95% in women less than 30 years old. However, it was found that there was no differences in mean duration of ovarian stimulation prior to ovum collection based on age. Finally, it was found that there was a general decreasing trend of successful clinical pregnancies as age increased in women undergoing IVF, as the rate of live births was highest in women who were less than 30 years old. The occurence of multiple births was highest in this age group also.

Overall it was found that the age of the woman undoubtedly has an effect on the reproductive capacity of a woman undergoing IVF. The researchers hypothesized that the general decreased success of an aging woman may be due to decreasing ovarian reserve, poorer oocyte quality, lower embryo implantation rates, altered hormonal environment resulting in ovulatory dysfunction and uterine problems. Male factors were also considered to be causative.

--[[User:Z8600021|Mark Hill]] These papers are suitable for the assessment exercise and you have included an appropriate summary. (5/5)

==Lab Assessment 2==
[[File:Mutation of Gene Wt1 Causes Aberrant Gonadal Development.jpeg|300px]]

Mutation of Gene Wt1 Causes Aberrant Gonadal Development<ref><pubmed>23497137 </pubmed>| [http://www.biomedcentral.com/1741-7007/11/22/figure/F1]</ref>

<references/>

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:08, 20 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] This is a relevant image. I have fixed a few formatting issues in the associated file information, don't include the .jpeg in the figure legend, see the image page history for changes. (5/5)

==Lab Attendance: LAB 2==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:56, 20 August 2014 (EST)
Forgot to do my attendance at the lab of week 3 given by guest Speakers Hayden Homer and Rob Gilchrist about meiosis, oocyte quality and various technologies in assisted reproduction

==Lab Attendance week 4==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:39, 20 August 2014 (EST)

==Lab three Online Assessment==
Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 20:10, 26 August 2014 (EST)

--[[User:Z8600021|Mark Hill]]These 3 references meet the assessment requirement, it appears that you have just included the references without a description? Your description of genital differentiation is not quite accurate and should be clarified by the future Genital Development Lecture. (4/5)

==Lab 4 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 27 August 2014 (EST)

==Lab 4 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:23, 2 September 2014 (EST)

<pubmed>25137413</pubmed>

Hepatocellular carcinoma and other degenerative liver diseases often result in hepatic dysfunction and ultimately organ failure. To avoid this otherwise fatal diagnosis, bio-artificial livers and hepatocyte transplantation provides some leg- room whilst waiting on a full-organ transplant. However liver transplants, much like many other organs, are often hard to come by and are usually sensitive to the immune response of the host. As a result, researchers are looking towards stem cells as an answer to this problem. Mesenchymal stem cells derived from the Wharton’s Jelly of the umbilical Chord are often chosen because they have been found to have a slightly higher multipotency and immunogenicity. The umbilical stem cells were selected because they are more primitive compared to other Mesenchymal stem cells and do not express the major histocompatibility complex class II antigens- a key determinant in illiciting an immune response form the host. However, hepatocyte like cells derived from stem cells are not clinically used because they do not express enough functional proteins and do not exhibit a full level of metabolic activity.

This study aimed to identify and observe the transcription factors involved in hepatocyte differentiation from Human umbilical cord Mesenchymal Stem Cells (HuMSCs), they were particularly interested in Hepatocyte Nuclear Factor 4-alpha (HNF-4alpha) which is believed to behave like a “master gene” in driving hepatocyte differentiation and maturation. This study continued to expose the differentiating HuMSCs to excess amounts of HNF-4alpha and hypothesized a significant improvement in the differentiation status of the hepatocyte-like cells, providing a basis for future clinical application of HuMSCs in the treatment and management of liver diseases.

The research initially confirmed that the HuMSCs are of low immunogenicity- a critical issue with organ transplantation. Once this was confirmed, they observed that there was an up-regulation of functional hepatic enzymes once the differentiating hepatocyte-like stem cells were exposed to HNF-4alpha. An important finding they discovered that the time at which the stem cells were exposed to HNF-4alpha were integral in ensuring correct hepatocyte differentiation. Ultimately they concluded that the differentiation of HuMSCs could be improved by exposure to high levels of HNF-4alpha at specific times in the development of hepatocyte-like stem cells, an important discovery for the progression of the therapeutic application of stem cells.

The three shunts which are present in fetal development but are closed postnatally are:

• ductus arteriosis → channel between the pulmonary artery and aorta in the fetus which bypasses the lungs to distribute oxygenated blood from the placenta derived from the mothers circulation.

• ductus venosus → shunts a portion of the left umbilical vein blood flow which would flow directly to the inferior vena cava- allows b=oxygenated blood to bypass the liver.

• foramen ovale → allows passageway of blood from left atrium to right atrium in the fetus.

==Lab 5 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 3 September 2014 (EST)

==Lab 5 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:10, 16 September 2014 (EST)

Congenital Lobar emphysema (CLE) is a condition of the respiratory system which results in hyperinflation of one or more pulmonary lobes and is usually diagnosed postnatally, usually in the neonatal period- however there have been cases where CLE is not diagnosed until 10 years after birth. The clinical symptoms of CLE are often at birth as dyspnea, cyanosis and recurrent respiratory tract infections, as well as generalized neonatal respiratory distress and hyperinflation and hyperaeration of the pulmonary lobes- often seen as visible enlargements or imaged through CT. CLE is a rare disorder affecting only 1 in 20,000 to 30, 000 newborns, and appears to have a slight male predominance [3:1 male to female ratio], although the cause of this gender predilection is not fully understood.

The developmental causes of CLE are often as final result of a number of bronchopulmonary disturbances during development. These result from abnormal interactions between embryonic endodermal and mesodermal components of the lung which may result in abnormalities in airway or alveoli number and size, however the exact pathogenesis of CLE is not able to be determined in approximately half of cases. Another frequently observed cause of CLE is an obstruction of the developing airway, which creates a “ball valve” resulting in an uneven distribution of air- favoring greater airflow to the affected lobe during inspiration than is able to be cleared in expiration- resulting in air trapping. There may also be vascular abnormalities which produce compression, bronchial stenosis, bronchogenic cysts and congenital cytomegaloviral infections observed.

<pubmed>PMC2141574</pubmed>

==Lab attendance week 8==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 17 September 2014 (EST)

==Lab Report- week 8==

==lab Attendance WEEK 9==

==Lab attendance week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)
==lab report week 9==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)

==Lab assessment week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 00:56, 15 October 2014 (EST)
'''Group 1'''
This project is extremely well done. I found the overall layout of your work to be easy to read and succinct. It captured my attention throughout the entirety of the project and was engaging with the use of bullet points. I thought your use of diagrams was great in aiding the understanding of this topic, however I thought that more diagrams or pictures could be added in order to help the reader visualize exactly what’s going on. I thought that te developmental timeline was a great idea, however could benefit from some more images or diagrams to assist in understanding the developmental stages. I thought the historic findings sections was especially well done as it appears well researched and thoroughly informative. The abnormalities was also well done, however again could benefit from the addition of a few more diagrams.

I think that with the addition of more drawings needs to be some attention to detail when referencing and stating copyright. I’ve noticed that some pictures lack copyright and some don’t have a description, making it difficult to understand the context of the picture and to envisage how it relates to the content. Whilst this is mostly self explanatory- I think that because this is an informative piece it pays to spoon-feed us a bit. Also, your referencing could use a bit of a tidy, but that can easily be fixed before submission. I think that overall this has great potential to be a wonderful project and I look forward to seeing it at its completion!

'''Group 2'''
I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

'''Group 3'''
Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

'''Group 5'''
Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once.

I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

'''Group 6'''
Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

'''Group 7'''
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.
The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.
The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing.
Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

'''Group 8'''
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

User:Z3416697

2014-10-14T13:57:56Z

Z3416697: /* Lab assessment week 10 */

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:45, 6 August 2014 (EST)
==lab attendance==
Lab 1
http://www.ncbi.nlm.nih.gov/pubmed

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

<pubmed>2508416</pubmed>

==Lab Assessment 1==
===ARTICLE 1===
<pubmed>25071849</pubmed>

In Vitro Fertilization (IVF) is a popular method of Assisted Reproduction which allows for fertilization to occur under optimal conditions (which may not be achieved in those that are having trouble conceiving), with monitored hormone levels and calculated growth of the embryo so as to maximize implantation, and ideally, successful pregnancy. This research article endeavors to assess the different variables available in IVF to determine which method yields the most successful amount of pregnancies. The variables in question are whether the embryo should be fresh (within a hours of fertilization), or frozen-thawed (embryo frozen a few days after fertilization and thawed when the mother is ready to receive an embryo). Another variable considered is the developmental stage at which the embryo is implanted; some embryos are implanted at the cleavage stage (hours after fertilization) and others are implanted at the blastocyst stage (5 days after fertilization), this study also considered implants at the cleavage stage extended blastocyst stage however it did not clarify what this term means, and I was unable to find elsewhere what this means.

This study observed IVF cycles of 1891 women at the Wuhan Union Hospital between January and December of 2012. Of the 1891 women observed, 1150 had fresh embryo transfers and 741 had frozen thawed embryo transfers. Of the Fresh embryo transfers 993 were implanted at the cleavage stage (799 of them women were less than 35 years old and 194 were greater than or equal to 35 years old), and 157 were implanted at the blastocyst stage (131 were less than 35 years old, 26 greater than or equal to 35 years old). Of the 741 women with frozen thawed embryo transfers, 212 were implanted at the cleavage stage of embryonic development (159 women were less than 35 and 53 were greater than or equal to 35), 137 were implanted at the cleavage stage extended blastocyst stage (111 were less than 35, 26 were greater than or equal to 35) and 328 were implanted at the blastocyst stage (276 were less than 35, 52 were greater than or equal to 35). All of these women underwent traditional methods of IVF- that is they were initially treated with Gonadotropin Releasing Hormone to stimulate follicular development. When two or more follicles were greater than 18mm Human Chorionic Gonadotropin was injected to assist follicular maturation. 24-26 hours later the ova were collected (Ovum Pick Up/OPU) and 4-6 hours after OPU IVF or Intracytoplasmic Sperm Injection (ICSI) were performed on the ova. The embryos were assessed by morphology and rate of development and at day three they are transferred onto a blastocyst medium and cultured for 2-3 days until it forms a blastocyst. The blastocysts are socred according to the Gardner standard and usually 1-2 good embryos are implanted. The remaining viable embryos are cryopreserved via vitrification and may be used if the current IVF cycle is unsuccessful. The Estrogen and Progesterone levels are monitored and regulated throughout the process according to the characteristics of the patient. Clinical pregnancy was defined by the presence of a gestational sac with or without a heart beat 30 days after implantation.

From this experiment it was found that there was a greater amount of successful pregnancies in women less than 35 years old resulting from implantation of fresh embryos at the cleavage stage (52.7% success) as opposed to the blastocyst stage (35.88%). There was no statistically significant differences clinically between the two types of implantation [ie- multiple pregnancies, abortion or ectopic pregnancy]. There were also a significantly higher number of pregnancies in the cleavage stage [41.24%] vs the blastocyst stage [26.92%]. However, this was not that case for those whom has frozen-thawed embryo transfers, as there was generally a much greater success rate for pregnancy in those who had blastocyst stage transfers than those who had cleavage stage transfers. Furthermore, there is a significantly greater pregnancy rate between in fresh embryo transfers compared to frozen thawed embryo transfers at the cleavage stage. Overall, there was a greater incidence of clinical pregnancy resulting from fresh cleavage stage embryo transfers compared to any other type of transfer [ie fresh blastocyst stage, frozen thawed cleavage stage and frozen thawed blastocyst stage]. These researchers concluded that this type of implantation should be used under normal conditions, and other methods should only be considered if the mother is of compromised health (eg has Ovarian Hyper Stimulation Syndrome), in which case as fresh blastocyst stage embryo is used.

===ARTICLE 2===
<pubmed>25017405 </pubmed>
This article aimed to assess the success rate of clinical pregnancy of women at differing age groups whom have undergone assisted reproductive methods such as In-Vitro Fertilzation and Intracytoplasmic Sperm Injection. Based on previous literature it was expected that the success rate would decline as the woman ages, as typically the most successful IVF cycles are seen in women whom are 25-30 years old. Also based on natural conception rates, spontaneous conception rates begin to decrease around 31-35 years old, and women tend to have difficulty conceiving around the ages of 35-39. General fecundabilty (probability of released ovum becoming fertilized and resulting in a successful pregnancy in one menstrual cycle) tend t decrease as the woman reaches menopause (around the early fifties) and at 5-10 years prior to this (40-44 years old), half of the women have reduced reproductive capacity.

This study observed 2,900 women undergoing IVF at the KK Women and Children’s hospital, of which yielded 3,412 fresh IVF cycles. The women were classifies into sub groups based only on age [< 30 years; 30–35 years; 36–37 years; 38 years; 39 years; 40–44 years; and ≥ 45 years]. The IVF cycles were monitored and the average number of occytes, average duration of stimulation and fertilization rates were observed. Furthermore, the number of cycles until successful embryo transfer, clinically successfully pregnancy rates, miscarriage rates and multiple pregnancy rates were also reported.
In this study, most of the patients undergoing IVF were between the ages of 30-35 and 36-37, and the least amount of patients belonged to the ≥ 45 years group. Of these, it was found that there was a 15% miscarriage rate in those younger than 30 years old, but this figure doubled to 30% at the age of 38 and among women aged 40-44, the miscarriage rate was as high as 55%. Only half of the women aged greater than 45 reached embryo transfer, and of those, none proceeded to successful clinical pregnancy. Furthermore, compared to other age groups, these women had the lowest amount of oocytes collected and the lowest fertilization rate with only 50% of oocytes proceeding to fertilization, compared to 95% in women less than 30 years old. However, it was found that there was no differences in mean duration of ovarian stimulation prior to ovum collection based on age. Finally, it was found that there was a general decreasing trend of successful clinical pregnancies as age increased in women undergoing IVF, as the rate of live births was highest in women who were less than 30 years old. The occurence of multiple births was highest in this age group also.

Overall it was found that the age of the woman undoubtedly has an effect on the reproductive capacity of a woman undergoing IVF. The researchers hypothesized that the general decreased success of an aging woman may be due to decreasing ovarian reserve, poorer oocyte quality, lower embryo implantation rates, altered hormonal environment resulting in ovulatory dysfunction and uterine problems. Male factors were also considered to be causative.

--[[User:Z8600021|Mark Hill]] These papers are suitable for the assessment exercise and you have included an appropriate summary. (5/5)

==Lab Assessment 2==
[[File:Mutation of Gene Wt1 Causes Aberrant Gonadal Development.jpeg|300px]]

Mutation of Gene Wt1 Causes Aberrant Gonadal Development<ref><pubmed>23497137 </pubmed>| [http://www.biomedcentral.com/1741-7007/11/22/figure/F1]</ref>

<references/>

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:08, 20 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] This is a relevant image. I have fixed a few formatting issues in the associated file information, don't include the .jpeg in the figure legend, see the image page history for changes. (5/5)

==Lab Attendance: LAB 2==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:56, 20 August 2014 (EST)
Forgot to do my attendance at the lab of week 3 given by guest Speakers Hayden Homer and Rob Gilchrist about meiosis, oocyte quality and various technologies in assisted reproduction

==Lab Attendance week 4==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:39, 20 August 2014 (EST)

==Lab three Online Assessment==
Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 20:10, 26 August 2014 (EST)

--[[User:Z8600021|Mark Hill]]These 3 references meet the assessment requirement, it appears that you have just included the references without a description? Your description of genital differentiation is not quite accurate and should be clarified by the future Genital Development Lecture. (4/5)

==Lab 4 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 27 August 2014 (EST)

==Lab 4 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:23, 2 September 2014 (EST)

<pubmed>25137413</pubmed>

Hepatocellular carcinoma and other degenerative liver diseases often result in hepatic dysfunction and ultimately organ failure. To avoid this otherwise fatal diagnosis, bio-artificial livers and hepatocyte transplantation provides some leg- room whilst waiting on a full-organ transplant. However liver transplants, much like many other organs, are often hard to come by and are usually sensitive to the immune response of the host. As a result, researchers are looking towards stem cells as an answer to this problem. Mesenchymal stem cells derived from the Wharton’s Jelly of the umbilical Chord are often chosen because they have been found to have a slightly higher multipotency and immunogenicity. The umbilical stem cells were selected because they are more primitive compared to other Mesenchymal stem cells and do not express the major histocompatibility complex class II antigens- a key determinant in illiciting an immune response form the host. However, hepatocyte like cells derived from stem cells are not clinically used because they do not express enough functional proteins and do not exhibit a full level of metabolic activity.

This study aimed to identify and observe the transcription factors involved in hepatocyte differentiation from Human umbilical cord Mesenchymal Stem Cells (HuMSCs), they were particularly interested in Hepatocyte Nuclear Factor 4-alpha (HNF-4alpha) which is believed to behave like a “master gene” in driving hepatocyte differentiation and maturation. This study continued to expose the differentiating HuMSCs to excess amounts of HNF-4alpha and hypothesized a significant improvement in the differentiation status of the hepatocyte-like cells, providing a basis for future clinical application of HuMSCs in the treatment and management of liver diseases.

The research initially confirmed that the HuMSCs are of low immunogenicity- a critical issue with organ transplantation. Once this was confirmed, they observed that there was an up-regulation of functional hepatic enzymes once the differentiating hepatocyte-like stem cells were exposed to HNF-4alpha. An important finding they discovered that the time at which the stem cells were exposed to HNF-4alpha were integral in ensuring correct hepatocyte differentiation. Ultimately they concluded that the differentiation of HuMSCs could be improved by exposure to high levels of HNF-4alpha at specific times in the development of hepatocyte-like stem cells, an important discovery for the progression of the therapeutic application of stem cells.

The three shunts which are present in fetal development but are closed postnatally are:

• ductus arteriosis → channel between the pulmonary artery and aorta in the fetus which bypasses the lungs to distribute oxygenated blood from the placenta derived from the mothers circulation.

• ductus venosus → shunts a portion of the left umbilical vein blood flow which would flow directly to the inferior vena cava- allows b=oxygenated blood to bypass the liver.

• foramen ovale → allows passageway of blood from left atrium to right atrium in the fetus.

==Lab 5 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 3 September 2014 (EST)

==Lab 5 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:10, 16 September 2014 (EST)

Congenital Lobar emphysema (CLE) is a condition of the respiratory system which results in hyperinflation of one or more pulmonary lobes and is usually diagnosed postnatally, usually in the neonatal period- however there have been cases where CLE is not diagnosed until 10 years after birth. The clinical symptoms of CLE are often at birth as dyspnea, cyanosis and recurrent respiratory tract infections, as well as generalized neonatal respiratory distress and hyperinflation and hyperaeration of the pulmonary lobes- often seen as visible enlargements or imaged through CT. CLE is a rare disorder affecting only 1 in 20,000 to 30, 000 newborns, and appears to have a slight male predominance [3:1 male to female ratio], although the cause of this gender predilection is not fully understood.

The developmental causes of CLE are often as final result of a number of bronchopulmonary disturbances during development. These result from abnormal interactions between embryonic endodermal and mesodermal components of the lung which may result in abnormalities in airway or alveoli number and size, however the exact pathogenesis of CLE is not able to be determined in approximately half of cases. Another frequently observed cause of CLE is an obstruction of the developing airway, which creates a “ball valve” resulting in an uneven distribution of air- favoring greater airflow to the affected lobe during inspiration than is able to be cleared in expiration- resulting in air trapping. There may also be vascular abnormalities which produce compression, bronchial stenosis, bronchogenic cysts and congenital cytomegaloviral infections observed.

<pubmed>PMC2141574</pubmed>

==Lab attendance week 8==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 17 September 2014 (EST)

==Lab Report- week 8==

==lab Attendance WEEK 9==

==Lab attendance week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)
==lab report week 9==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)

==Lab assessment week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 00:56, 15 October 2014 (EST)
'''Group 1'''
This project is extremely well done. I found the overall layout of your work to be easy to read and succinct. It captured my attention throughout the entirety of the project and was engaging with the use of bullet points. I thought your use of diagrams was great in aiding the understanding of this topic, however I thought that more diagrams or pictures could be added in order to help the reader visualize exactly what’s going on. I thought that te developmental timeline was a great idea, however could benefit from some more images or diagrams to assist in understanding the developmental stages. I thought the historic findings sections was especially well done as it appears well researched and thoroughly informative. The abnormalities was also well done, however again could benefit from the addition of a few more diagrams.

I think that with the addition of more drawings needs to be some attention to detail when referencing and stating copyright. I’ve noticed that some pictures lack copyright and some don’t have a description, making it difficult to understand the context of the picture and to envisage how it relates to the content. Whilst this is mostly self explanatory- I think that because this is an informative piece it pays to spoon-feed us a bit. Also, your referencing could use a bit of a tidy, but that can easily be fixed before submission. I think that overall this has great potential to be a wonderful project and I look forward to seeing it at its completion!

'''Group 2'''
I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

'''Group 3'''
Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

'''Group 5'''
Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once.

I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

'''Group 6'''
Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

'''Group 7'''
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.
The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.
The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing.
Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

'''Group 8'''
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

User:Z3416697

2014-10-14T13:56:46Z

Z3416697:

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:45, 6 August 2014 (EST)
==lab attendance==
Lab 1
http://www.ncbi.nlm.nih.gov/pubmed

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

<pubmed>2508416</pubmed>

==Lab Assessment 1==
===ARTICLE 1===
<pubmed>25071849</pubmed>

In Vitro Fertilization (IVF) is a popular method of Assisted Reproduction which allows for fertilization to occur under optimal conditions (which may not be achieved in those that are having trouble conceiving), with monitored hormone levels and calculated growth of the embryo so as to maximize implantation, and ideally, successful pregnancy. This research article endeavors to assess the different variables available in IVF to determine which method yields the most successful amount of pregnancies. The variables in question are whether the embryo should be fresh (within a hours of fertilization), or frozen-thawed (embryo frozen a few days after fertilization and thawed when the mother is ready to receive an embryo). Another variable considered is the developmental stage at which the embryo is implanted; some embryos are implanted at the cleavage stage (hours after fertilization) and others are implanted at the blastocyst stage (5 days after fertilization), this study also considered implants at the cleavage stage extended blastocyst stage however it did not clarify what this term means, and I was unable to find elsewhere what this means.

This study observed IVF cycles of 1891 women at the Wuhan Union Hospital between January and December of 2012. Of the 1891 women observed, 1150 had fresh embryo transfers and 741 had frozen thawed embryo transfers. Of the Fresh embryo transfers 993 were implanted at the cleavage stage (799 of them women were less than 35 years old and 194 were greater than or equal to 35 years old), and 157 were implanted at the blastocyst stage (131 were less than 35 years old, 26 greater than or equal to 35 years old). Of the 741 women with frozen thawed embryo transfers, 212 were implanted at the cleavage stage of embryonic development (159 women were less than 35 and 53 were greater than or equal to 35), 137 were implanted at the cleavage stage extended blastocyst stage (111 were less than 35, 26 were greater than or equal to 35) and 328 were implanted at the blastocyst stage (276 were less than 35, 52 were greater than or equal to 35). All of these women underwent traditional methods of IVF- that is they were initially treated with Gonadotropin Releasing Hormone to stimulate follicular development. When two or more follicles were greater than 18mm Human Chorionic Gonadotropin was injected to assist follicular maturation. 24-26 hours later the ova were collected (Ovum Pick Up/OPU) and 4-6 hours after OPU IVF or Intracytoplasmic Sperm Injection (ICSI) were performed on the ova. The embryos were assessed by morphology and rate of development and at day three they are transferred onto a blastocyst medium and cultured for 2-3 days until it forms a blastocyst. The blastocysts are socred according to the Gardner standard and usually 1-2 good embryos are implanted. The remaining viable embryos are cryopreserved via vitrification and may be used if the current IVF cycle is unsuccessful. The Estrogen and Progesterone levels are monitored and regulated throughout the process according to the characteristics of the patient. Clinical pregnancy was defined by the presence of a gestational sac with or without a heart beat 30 days after implantation.

From this experiment it was found that there was a greater amount of successful pregnancies in women less than 35 years old resulting from implantation of fresh embryos at the cleavage stage (52.7% success) as opposed to the blastocyst stage (35.88%). There was no statistically significant differences clinically between the two types of implantation [ie- multiple pregnancies, abortion or ectopic pregnancy]. There were also a significantly higher number of pregnancies in the cleavage stage [41.24%] vs the blastocyst stage [26.92%]. However, this was not that case for those whom has frozen-thawed embryo transfers, as there was generally a much greater success rate for pregnancy in those who had blastocyst stage transfers than those who had cleavage stage transfers. Furthermore, there is a significantly greater pregnancy rate between in fresh embryo transfers compared to frozen thawed embryo transfers at the cleavage stage. Overall, there was a greater incidence of clinical pregnancy resulting from fresh cleavage stage embryo transfers compared to any other type of transfer [ie fresh blastocyst stage, frozen thawed cleavage stage and frozen thawed blastocyst stage]. These researchers concluded that this type of implantation should be used under normal conditions, and other methods should only be considered if the mother is of compromised health (eg has Ovarian Hyper Stimulation Syndrome), in which case as fresh blastocyst stage embryo is used.

===ARTICLE 2===
<pubmed>25017405 </pubmed>
This article aimed to assess the success rate of clinical pregnancy of women at differing age groups whom have undergone assisted reproductive methods such as In-Vitro Fertilzation and Intracytoplasmic Sperm Injection. Based on previous literature it was expected that the success rate would decline as the woman ages, as typically the most successful IVF cycles are seen in women whom are 25-30 years old. Also based on natural conception rates, spontaneous conception rates begin to decrease around 31-35 years old, and women tend to have difficulty conceiving around the ages of 35-39. General fecundabilty (probability of released ovum becoming fertilized and resulting in a successful pregnancy in one menstrual cycle) tend t decrease as the woman reaches menopause (around the early fifties) and at 5-10 years prior to this (40-44 years old), half of the women have reduced reproductive capacity.

This study observed 2,900 women undergoing IVF at the KK Women and Children’s hospital, of which yielded 3,412 fresh IVF cycles. The women were classifies into sub groups based only on age [< 30 years; 30–35 years; 36–37 years; 38 years; 39 years; 40–44 years; and ≥ 45 years]. The IVF cycles were monitored and the average number of occytes, average duration of stimulation and fertilization rates were observed. Furthermore, the number of cycles until successful embryo transfer, clinically successfully pregnancy rates, miscarriage rates and multiple pregnancy rates were also reported.
In this study, most of the patients undergoing IVF were between the ages of 30-35 and 36-37, and the least amount of patients belonged to the ≥ 45 years group. Of these, it was found that there was a 15% miscarriage rate in those younger than 30 years old, but this figure doubled to 30% at the age of 38 and among women aged 40-44, the miscarriage rate was as high as 55%. Only half of the women aged greater than 45 reached embryo transfer, and of those, none proceeded to successful clinical pregnancy. Furthermore, compared to other age groups, these women had the lowest amount of oocytes collected and the lowest fertilization rate with only 50% of oocytes proceeding to fertilization, compared to 95% in women less than 30 years old. However, it was found that there was no differences in mean duration of ovarian stimulation prior to ovum collection based on age. Finally, it was found that there was a general decreasing trend of successful clinical pregnancies as age increased in women undergoing IVF, as the rate of live births was highest in women who were less than 30 years old. The occurence of multiple births was highest in this age group also.

Overall it was found that the age of the woman undoubtedly has an effect on the reproductive capacity of a woman undergoing IVF. The researchers hypothesized that the general decreased success of an aging woman may be due to decreasing ovarian reserve, poorer oocyte quality, lower embryo implantation rates, altered hormonal environment resulting in ovulatory dysfunction and uterine problems. Male factors were also considered to be causative.

--[[User:Z8600021|Mark Hill]] These papers are suitable for the assessment exercise and you have included an appropriate summary. (5/5)

==Lab Assessment 2==
[[File:Mutation of Gene Wt1 Causes Aberrant Gonadal Development.jpeg|300px]]

Mutation of Gene Wt1 Causes Aberrant Gonadal Development<ref><pubmed>23497137 </pubmed>| [http://www.biomedcentral.com/1741-7007/11/22/figure/F1]</ref>

<references/>

--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:08, 20 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] This is a relevant image. I have fixed a few formatting issues in the associated file information, don't include the .jpeg in the figure legend, see the image page history for changes. (5/5)

==Lab Attendance: LAB 2==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:56, 20 August 2014 (EST)
Forgot to do my attendance at the lab of week 3 given by guest Speakers Hayden Homer and Rob Gilchrist about meiosis, oocyte quality and various technologies in assisted reproduction

==Lab Attendance week 4==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:39, 20 August 2014 (EST)

==Lab three Online Assessment==
Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen
<pubmed>24240231</pubmed>
<pubmed>24928207</pubmed>
<pubmed>24741072</pubmed>
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 20:10, 26 August 2014 (EST)

--[[User:Z8600021|Mark Hill]]These 3 references meet the assessment requirement, it appears that you have just included the references without a description? Your description of genital differentiation is not quite accurate and should be clarified by the future Genital Development Lecture. (4/5)

==Lab 4 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:07, 27 August 2014 (EST)

==Lab 4 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:23, 2 September 2014 (EST)

<pubmed>25137413</pubmed>

Hepatocellular carcinoma and other degenerative liver diseases often result in hepatic dysfunction and ultimately organ failure. To avoid this otherwise fatal diagnosis, bio-artificial livers and hepatocyte transplantation provides some leg- room whilst waiting on a full-organ transplant. However liver transplants, much like many other organs, are often hard to come by and are usually sensitive to the immune response of the host. As a result, researchers are looking towards stem cells as an answer to this problem. Mesenchymal stem cells derived from the Wharton’s Jelly of the umbilical Chord are often chosen because they have been found to have a slightly higher multipotency and immunogenicity. The umbilical stem cells were selected because they are more primitive compared to other Mesenchymal stem cells and do not express the major histocompatibility complex class II antigens- a key determinant in illiciting an immune response form the host. However, hepatocyte like cells derived from stem cells are not clinically used because they do not express enough functional proteins and do not exhibit a full level of metabolic activity.

This study aimed to identify and observe the transcription factors involved in hepatocyte differentiation from Human umbilical cord Mesenchymal Stem Cells (HuMSCs), they were particularly interested in Hepatocyte Nuclear Factor 4-alpha (HNF-4alpha) which is believed to behave like a “master gene” in driving hepatocyte differentiation and maturation. This study continued to expose the differentiating HuMSCs to excess amounts of HNF-4alpha and hypothesized a significant improvement in the differentiation status of the hepatocyte-like cells, providing a basis for future clinical application of HuMSCs in the treatment and management of liver diseases.

The research initially confirmed that the HuMSCs are of low immunogenicity- a critical issue with organ transplantation. Once this was confirmed, they observed that there was an up-regulation of functional hepatic enzymes once the differentiating hepatocyte-like stem cells were exposed to HNF-4alpha. An important finding they discovered that the time at which the stem cells were exposed to HNF-4alpha were integral in ensuring correct hepatocyte differentiation. Ultimately they concluded that the differentiation of HuMSCs could be improved by exposure to high levels of HNF-4alpha at specific times in the development of hepatocyte-like stem cells, an important discovery for the progression of the therapeutic application of stem cells.

The three shunts which are present in fetal development but are closed postnatally are:

• ductus arteriosis → channel between the pulmonary artery and aorta in the fetus which bypasses the lungs to distribute oxygenated blood from the placenta derived from the mothers circulation.

• ductus venosus → shunts a portion of the left umbilical vein blood flow which would flow directly to the inferior vena cava- allows b=oxygenated blood to bypass the liver.

• foramen ovale → allows passageway of blood from left atrium to right atrium in the fetus.

==Lab 5 Attendance==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 3 September 2014 (EST)

==Lab 5 Online Assessment==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 14:10, 16 September 2014 (EST)

Congenital Lobar emphysema (CLE) is a condition of the respiratory system which results in hyperinflation of one or more pulmonary lobes and is usually diagnosed postnatally, usually in the neonatal period- however there have been cases where CLE is not diagnosed until 10 years after birth. The clinical symptoms of CLE are often at birth as dyspnea, cyanosis and recurrent respiratory tract infections, as well as generalized neonatal respiratory distress and hyperinflation and hyperaeration of the pulmonary lobes- often seen as visible enlargements or imaged through CT. CLE is a rare disorder affecting only 1 in 20,000 to 30, 000 newborns, and appears to have a slight male predominance [3:1 male to female ratio], although the cause of this gender predilection is not fully understood.

The developmental causes of CLE are often as final result of a number of bronchopulmonary disturbances during development. These result from abnormal interactions between embryonic endodermal and mesodermal components of the lung which may result in abnormalities in airway or alveoli number and size, however the exact pathogenesis of CLE is not able to be determined in approximately half of cases. Another frequently observed cause of CLE is an obstruction of the developing airway, which creates a “ball valve” resulting in an uneven distribution of air- favoring greater airflow to the affected lobe during inspiration than is able to be cleared in expiration- resulting in air trapping. There may also be vascular abnormalities which produce compression, bronchial stenosis, bronchogenic cysts and congenital cytomegaloviral infections observed.

<pubmed>PMC2141574</pubmed>

==Lab attendance week 8==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 11:54, 17 September 2014 (EST)

==Lab Report- week 8==

==lab Attendance WEEK 9==

==Lab attendance week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)
==lab report week 9==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 12:27, 8 October 2014 (EST)

==Lab assessment week 10==
--[[User:Z3416697|Z3416697]] ([[User talk:Z3416697|talk]]) 00:56, 15 October 2014 (EST)
'''Group 1'''
This project is extremely well done. I found the overall layout of your work to be easy to read and succinct. It captured my attention throughout the entirety of the project and was engaging with the use of bullet points. I thought your use of diagrams was great in aiding the understanding of this topic, however I thought that more diagrams or pictures could be added in order to help the reader visualize exactly what’s going on. I thought that te developmental timeline was a great idea, however could benefit from some more images or diagrams to assist in understanding the developmental stages. I thought the historic findings sections was especially well done as it appears well researched and thoroughly informative. The abnormalities was also well done, however again could benefit from the addition of a few more diagrams.

I think that with the addition of more drawings needs to be some attention to detail when referencing and stating copyright. I’ve noticed that some pictures lack copyright and some don’t have a description, making it difficult to understand the context of the picture and to envisage how it relates to the content. Whilst this is mostly self explanatory- I think that because this is an informative piece it pays to spoon-feed us a bit. Also, your referencing could use a bit of a tidy, but that can easily be fixed before submission. I think that overall this has great potential to be a wonderful project and I look forward to seeing it at its completion!

'''Group 2'''
I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

'''Group 3'''
Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section.

The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

'''Group 5'''
Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once.

I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

'''Group 6'''
Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

'''Group 7'''
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.
The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.
The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing.
Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

'''Group 8'''
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

Talk:2014 Group Project 8

2014-10-14T13:53:52Z

Z3416697: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==
===1===
Let me start by saying that the “Muscle Gains” section is funny but obviously very irrelevant to the project. Looking at the contents of this page, there seem to be a lot of focus on the development and very little on the other sections. The development section is well-researched and great job on the in-text citations! Some parts look a bit bulky though so maybe try to break some of them down into bulletpoints if possible. A timeline of development is also very helpful in this project.

On abnormalities, very concise and detailed. Try to write about 3-4 abnormalities and find information on how they’re treated or managed presently. As for historic findings, there is a section on the Wikipage that has old books on embryology. It’s under the “Explore” tab and you’ll see “Historic embryo”. Those books have a lot of information regarding that section. Don’t forget to write about current findings as well. Another thing, try to use images since these really help with understanding the content of the page. Overall, a lot of work has to be done before the due date. I do understand why because there are only two people in this group. Goodluck and I wish you the best in finishing this project!

===2===

The key points of musculoskeletal development appear as headings however there is still much that needs to be clearly discussed beneath each of these points. The main headings are good and specific but some are way too specific and should be under much larger headings, for example, 1.2-1.9 could be subheadings that come under the heading ‘System Development’. ‘Background embryonic development’ is useful to understand but perhaps it is better to not have so much detail, or summarise it in a table. The ‘Abnormalities’ heading is done well, with one disease listed (Duchenne Muscular Dystrophy). It might be better to have more than one abnormality listed and clearly described as well. I particularly like the use of statistics and genetic references. It seems most of the key points relating to system development have been clearly described, but some tidying up in terms of editing needs to be done.

Also, more work needs to be done on historic findings, current research, models and findings. Once all the research parts are completed, the timeline can be correctly constructed. Also like the idea of putting a timeline and the heading shows that this is intended. More subheadings could be used to make the page look more organised and pleasing to the eye.

There are also no graphs or tables as well as pictures. A table could be used to make the timeline or highlight the differences between the second, third trimesters and neonatal periods of fetal muscular development. Maybe the initial heading of the page should be changed to ‘Muscular Fetal Development’ to indicate that muscular development is actually being covered instead of both muscular and skeletal. There also isn’t much information regarding limb fetal development, so maybe it would be good to go through that on a deeper level.

It could also help to have images loaded onto the page or to draw flow diagrams to assist in the description of how the muscles develop in the fetal period. For example, upload an image showing the difference between slow twitch and fast twitch muscle fibres or draw a flow chart to show better understanding of the molecular and cellular regulation of fetal myogenesis.

References need to be in one larger section at the end under the heading ‘References’, not two and scattered throughout as is seen. The major section of references appears to be referenced correctly and in-cite references are done very well. There are also many references which are good and show that this group has thoroughly researched their topic.

Overall, this group has done very well and just needs to add more information for certain headings, as well as organise the page a bit better in neater headings and subheadings. Pictures should be added, as well as graphs, tables and own student-drawn images.

===4===

Overall the Group project page seems to be set out quite well with its headings and sub headings. Just needs a bit more info for some of the sub headings particularly from ‘second trimester muscular development’ onwards and a few formatting adjustments. The use of timelines, tables and dot points might help in those sections. The content provided is written well and in a detailed manner, which is still understood. There is a significant amount of research presented and this is seen through the in text citations and then further identified in the reference list. A good use of referencing is seen supporting the content info provided. The content uses examples of past and current research to help develop and establish ideas that are presented well. The abnormalities section on ‘Duchenne muscular dystrophy’ is described really well, maybe other abnormalities could also be added later.

To improve the page some suggestions include the use of diagrams and images, would help to add a bit more vibrancy to the page. Images and drawings are a great way to help in understanding the content. They are also a great way to make the content clearer especially if there are a number of processes involved in the development. Some of the longer paragraphs of content may also be formatted into dot points just to avoid lengthy paragraphs of info. It might also be useful to include some of the headings mentioned on the assessment page (identify current research models and findings, historic findings etc.).
Finally, the page so far is done well however it will need a little bit more work to be completely finished. Try to just gather as much info as you can to ensure you have enough content and then add images and any other visual aids later. Keep up the good work and good luck :).

===5===
Firstly, I thought the “Making Gains” bit was great- and I can guess who came up with that. I know you’ll take it our prior to submission though haha. The structure of your project is quite good, and the subheadings would make it much easier to read- the only thing is you need to add more content! I think because your system encompasses quite a lot, it would be a better idea for you to put as much information as you can into tables and include diagrams- I saw that musculoskeletal development has quite a few visual resources so it you should use them!
There are some areas where the content is really sparse, yet others where it is extremely heavy. In these areas, you may benefit from putting your information into bullet points so as to alleviate any confusion that may arise and overall enhance the clarity of your work. The references you have done are quite good, but there appears to be some missing.

Overall, I think your project would greatly benefit from the incorporation of images and diagrams. Because you are describing so much, a visual aid will help you immensely and also assist in retaining the attention of the reader throughout the entirety of the piece. Also, I see that you have deviated from the recommended headings. This may be a good idea to individualise your project- but make sure all topics are covered. I think it’s a good start considering you only have two team members, and I’m sure you will be able to pull it all together by the time it is due.

==4==
This page needs a lot of work; there are sections with little to no information, while others have just slabs of text, some of which have no references. Of those that have info presented, the topic is well covered with the large amount of content. You should use some dot points for some areas where you have a lot of info. You also need to use some images!! They will help to alleviate the slabs of content you have and add some colour to the page. Make sure you caption and reference them correctly, and add the correct copyright info.

Overall, there isn’t much I can say except add content, reference is correctly both in text and at the bottom of the page, and images and use some dot points and/or tables; don’t write everything in large slabs of text. Also, maybe get rid of that 'Muscle Gains' section, unless you actually plan to write something relevant in there haha. Otherwise, Good luck!

==5==
Let me start by saying, for only having two people in the group, well done. The page should have an introduction though, and this is missing. Just by simply summarizing all the information that will be covered in the page and adding it to the introduction, will improve the overall presentation significantly, you may wish to leave this to last, or edit as you go along.

The section “Making gains” is amusing, but inappropriate and should be omitted from the final submission. The timeline for the page I believe should be put into a table to save time and add to the presentation of the page, it can be easily done if you follow the steps outlined in the ‘editing basics’ page

The background information is comprehensive, however, the page is in desperate need of some images as there are just slabs of text. Images will really help break up the contents of the page and make it visually appealing.

The abnormalities section also seems to be coming along quite well. Keep up the good work.

==6==

This is great work so far from a group consisting of only 2 people. Keep up the good work and continue to work hard in finishing this page. Very admirable.

Overall, I would suggest reformatting and adding pictures to enhance the presentation of this page. Consider the use of lists and tables, throughout this wiki.

Instead of the rather hilarious (but rather inappropriate) ‘Making gains’ subheading, I believe an introduction should be added. Remember to clearly indicate the outcomes that the page hopes to achieve.

I also believe that the development/timeline section of this page is informative, with a very good use of headings and sub-headings. There is excellent evidence of significant scientific research and is correctly referenced and cited. However, this section could be further summarised or improved through the use of a table I believe- just a suggestion however. Adding pictures would also add to the overall understanding of this section.

This page has no information for the “recent findings” or “historic findings” section. Remember to include relevant information/pictures and references to these sections.

The abnormalities section is also looking very promising. Include more varying abnormalities. The abnormality included, DMD, is well written and informative. It needs to be correctly referenced however.

==7==
In this review I hope to highlight the merits of your project and suggest some areas for improvement in line with the marking criteria.

I see that you have conducted a great amount of research on the fetal development of the musculoskeletal system. The content clearly goes beyond the material covered in the lectures. It was interesting to read about the different transcriptions factors involved in induction and regulation of myoblast differentiation. I think it will be good to see a summary of all this information in a timeline format. I suggest simply highlighting the main developments at each stage.

You have made a good start on abnormalities. I suggest that you begin by selecting one abnormality include Description; Epidemiology; Cause and Treatment. You can add more later.

The page needs a little more structure. Make sure you include appropriate sub-heading and organise the information before you submit the project. Remember we were asked specifically to address the topics of current research and historic findings.

Finally it would be good see some images to support the text. Perhaps diagrams on tendon development would help summarise the process.

Great work so far!! Hope this feed back helps.

==8==

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

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

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

Week 5

--[[User:Z3418989|Z3418989]] ([[User talk:Z3418989|talk]]) 22:34, 26 August 2014 (EST)
Hi guys
After discussing in lab last week we tried to divide the categories and work as following;
* skeletal and cartilaginous development - Joel
* muscular development - Gowtem
* overall skeletal and muscular arrangement macroscopically - Danny
What do you guys think about addressing these topics as well
* Historical findings
* Abnormalities
* New findings

--[[User:Z3418779|Z3418779]] ([[User talk:Z3418779|talk]]) 12:44, 27 August 2014 (EST)
Great idea m8 Danny can probably also do abnormalities, remember to post any articles of particular relevance to New/historical findings. To complete after main content assembled

--[[User:Z3418779|Z3418779]] ([[User talk:Z3418779|talk]]) 01:02, 28 August 2014 (EST)
I would suggest that we narrow down the topic to focusing on the appendicular musculoskeletal system, so that;
*To make work load more managable
*To avoid the multiple highly specialised and irregular muscles/bones of the head
*The muscles I would suggest to include in are all muscles which have attachments to the appendicular skeleton including axioappendicular muscles (petoralis major, pectoralis minor, subclavious, serratus anterior, Latissimus Dorsi, Traps, levator scap, rhomboid major and minor.
*Joints and tendons are included in the musculoskeletal system, we should about wether we want to have a section for them.

--[[User:Z3418779|Z3418779]] ([[User talk:Z3418779|talk]]) 09:05, 31 August 2014 (EST)

Hi guys just posted the topics of abnormalities of muscle and skeletal system im gonna talk bout and references of relevant articles to the topics. Sorry for being late btw

--[[User:Z3418779|Z3418779]] ([[User talk:Z3418779|talk]]) 14:57, 9 September 2014 (EST)
Disregard the rest of the stuff I said in earlier discussions, I believe that to make it significantly easier we just do muscular system. I will Reformat everything to make it make sense.

--[[User:Z3418989|Z3418989]] ([[User talk:Z3418989|talk]]) 01:51, 10 September 2014 (EST)
Yeah completely agree, I think focusing on the muscular system would be much easier than doing both. Appendicular muscles sounds good - so muscles of limbs. Could divide it into upper and lower limbs. May have to talk about bone/cartilage a bit to describe how the muscle forms around it. Maybe how developing of muscles in embryonic development is important and eventually affects origin and insertions and actions of muscles when fully developed.

--[[User:Z3418779|Z3418779]] ([[User talk:Z3418779|talk]]) 12:56, 17 September 2014 (EST) This link shows a very good description of myogenesis; http://books.google.com.au/books?id=1ZRCMRXbbwoC&pg=PA38&lpg=PA38&dq=primary+secondary+myofibers&source=bl&ots=RSRcVVe5xr&sig=eDJBF_3qkYzA8WSin1tnbzT2xYY&hl=en&sa=X&ei=OegYVL_UHpOB8gWMxoDYAw&ved=0CCoQ6AEwAw#v=onepage&q&f=false

--[[User:Z3418989|Z3418989]] ([[User talk:Z3418989|talk]]) 12:27, 20 September 2014 (EST)
Ill add a bit more on embryonic muscle development guys

--[[User:Z3418779|Z3418779]] ([[User talk:Z3418779|talk]]) 22:30, 6 October 2014 (EST)
Here are some article which would probably be helpful
Nrk2b-mediated NAD+ production regulates cell adhesion and is required for muscle morphogenesis in vivo: Nrk2b and NAD+ in muscle morphogenesis
Coexpression of two distinct muscle acetylcholine receptor a-subunits during development

At the moment I have a general structure for tendon development and abnormalities will add to wiki tommorrow.

the good indepth morphogenesis studies focus on gluteus maxximus, extrenal urethra spincter, tensor veli palatini very little are done of the other muscles, so will try to apply the conclusions from these studies to related skeltal muscles

Talk:2014 Group Project 7

2014-10-14T13:40:26Z

Z3416697: /* 10 */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==
===1===
Good introduction but I would move what happens in the embryonic development to the “development” section. Also, don’t forget any references and in-text citations for this section. Maybe add more on what the page is about and what the readers should be expecting. Nonetheless, it gives a good background of the key organs in this system. The diagram for the timeline of development is quite complex. Try to explain what is happening in this diagram within the “development” section. For example, maybe try to have the same headings (cell multiplication, cell migration, etc.) as the diagram for the “development” subheadings. Or, if you’re willing, make a timeline of your own. At least, you can make a simpler diagram where only relevant information is included. Good job on the “Visible Anatomical Details” table.

On current findings, good choice on research articles. They’re very relevant to the topic and to the project as well. Maybe try to add some images if possible. Also, try to add some dates or anything to show how recent these studies are. There is a bit of imbalance in terms of the amount of content for each study but nonetheless, this section was written well. Good job! As for “abnormalities”, this section was done well. Each disease was written with lots of detail but very concisely. I do suggest adding more images that show the clinical manifestation of each disease. Also, don’t just focus on the manifestations of each defects. Try to look for current treatments or techniques on managing the abnormality. Also, maybe look for more references.

On historic findings, where is it? There is a section on the Wikipage that has old books on embryology. It’s under the “Explore” tab and you’ll see “Historic embryo”.

I’ve check all the images and there are no issues with them in terms of copyright. I can see that you tried to add captions to each photo, which is good but you can format the image in a way so that the caption is framed with the photo. Check out the [[https://embryology.med.unsw.edu.au/embryology/index.php/Help:Image_Tutorial#Image_Formatting| Image Formatting]] guide to do this. Overall, this page is very detailed and written very well. Just try to edit the page and make it look cleaner.

===2===

This project page is very nicely organised with the group clearly specifying what aspect of neural development they are covering, being the CNS. The use of headings and subheadings is done very neatly, however sections 1.1-1.5 could be subheadings for the larger title ‘system development’. The key points have been clearly described but there is no referencing throughout the ‘Introduction’, ‘Brain development’ and ‘Abnormalities’ sections. Most key points have at least some information on them which is good for this stage of the project; however some of the headings without could use some more work.

The choice of content is highly appropriate and the use of diagrams and pictures help show the groups understanding of the project thus far. I particularly like the use of subheadings in this project as they make the page look neater and organised. The image showing the timeline of fetal neural development is good however perhaps it would be better to draw or make a timeline on the computer in order to show better understanding of the time course of fetal development. Most images that have been uploaded are also well referenced and when clicking onto them, it takes the reader to a page that has more information related to the image. The table to describe anatomical details is also done well and is important that such a key point is mentioned seeing as this is an anatomy course.

I also really like how the ‘Current research, models and findings’ section is split into ‘Current research’ and ‘Future Research’, however it seems future research needs to be further looked into. The ‘Abnormalities’ section is done very well, with multiple abnormalities listed with images used to show each one. The bolding of several key words is seen and is helpful in showing understanding of some of the key points. There are also no historic findings so try and find some information on that.

Referencing is correctly done with most references being in one main section at the end, and ordered correctly. In-cite referencing is also done correctly. All images are correctly referenced with copyright information present and the student image template. I also like the way the current research findings sources have been referenced with the use of dot points assisting learning by not just presenting to the reader as a blob of information.

Overall, well done group 7! Keep up the great work!

===3===
The content looks well organized. The introduction could use a bit of work; it does a good job of introducing the CNS, but it should also mention all the other sections this page will cover regarding the topic. You might want to get rid of the using bold for brain and spinal cord, it just makes it look a little weird. Otherwise, a good embryonic developmental background is provided, it’s a good way to set the stage for when fetal development will commence from.

The information is organized well, no chunky slabs of texts. But the use of dot points is a bit extensive; almost every section of the page has dot points or makes up the complete majority of the info presented. You might want to present some of it in paragraph form e.g. the abnormalities part, as that section can still be kept quite short and not be packed with text. As long as you mention what it is, how you get it/how it forms, some statistics and use a picture, the section can be still visually appealing.
The images are captioned ok, but there is a better way of doing it. In the command to input the image, continue the command with: |thumb|’whatever you want to write’], and the section in the apostrophes will be the caption under the picture (go into edit mode on another project page for a better idea, I might not have explained well).

The use of the table is well done, makes all that info easily presentable, though I see the meninges development still needs to be done. The current research models and findings looks kind of messy with just the referenced PubMed article there. It might look better if you had the article name written in bold and a couple sentences underneath each to describe what the article was trying to achieve, like what has been done under current research. A couple pictures may be included to make it all more visually appealing and colourful.

Overall, this was done well. You have a good amount of information, just try not to present it all in dot points. Make sure all your info is referenced in text, will all references displayed at the bottom of the page. Another note, try to organise your pictures in different areas of the page as well, as they are all currently on the left hand side.

===4===

This group page shows a good amount of work completed however there are quite a few sections that clearly still need some more info. A good introduction to the neural development and a accurate description of what will be covered. Although it seems to be missing the in text citations. The section on ‘development during fetal period’ is presented clearly and structured really well. The info is not too overwhelming and the use of dot points for this section is great as neural development is quite complex. There’s a good identification of images and the use of in text citations. The brain development section is written really well with enough detail and it’s nice to see a table for the timeline of changes during each week. It does however seem to be a bit short, maybe that’s because it’s all in dot point form. It would be useful if the ‘brain, spinal cord and meninges development’ were combined under one heading, this might be a better way to structure it. Otherwise just keep each section separate but format the info into paragraph form. In the ‘current research’ section a thorough amount of info was provided. It seems as though it hasn’t been finished and more info will be added later that will be great. The abnormalities content is sufficient and well organised. Just consider using more in text citations in this section, add some more images and complete all the sub headings.

Finally a good effort in this project page, it is structured well and the info provided is easy to understand. However it needs some more research and content to fill all the sub headings in order for it to be finished. Some suggestions that may be considered include; having all the references under one main heading at the end of the page. The use of more in text citations in some of the paragraphs throughout the whole page would be effective. There is an adequately amount of images already shown, so maybe the use of videos or drawings would also be good especially in the abnormalities section and current research. The key is to focus on filing the info and then just making a few adjustments in terms of formatting. Otherwise the page is set out well , just needs a little more work. The page will look really great once completed. Good luck ☺

===5===
This page is organized well, all the headings and subheadings are thought through. Although, I’m unsure while the sections brain and spinal cord are in bold? The development during fetal period image lacks the necessary “student template” at the bottom of the description summary and I was unable to open the link http://www.nichd.nih.gov/publications/pubs/acute/images/p44.gif.
Otherwise, all the other images uploaded on the page look really good and are referenced correctly.

The table under the section brain development is very brief, and expansions on the content will allow for a better understanding of the content. Adding images to appear after the table will also add to the appearance of the page and give it a cleaner look.

The spinal cord and menegies development have been left untouched and the current research models have no content, just pubmed references. I understand the current research models are probably the hardest part of the assignment, but the content appears to be quite good, the formatting of the section could be improved by following the structure Mark uses. You could look at the other group projects as examples.

In regards to referencing, there are no in-text citations for the first two subheadings. I would also like to recommend just adding a final list of references at the bottom of the page, as it looks much neater.

The abnormalities section is done well. But try to minimise the use of dot points as this section lacks any structured paragraphs. It use of images are great, although there is an image that appear to have been removed and as a result, there is a broken link.

Overall, great job so far!

===6===
This is a really good project so far. The introduction is really well done and I especially like that you have included a diagrams in it. The brain development is good, however I’m not completely sure about the dot points. It would look better if they were not there.

Well done with the images that you have got there they all appear to be well described and referenced when you click on them. Only problem with the images is that there is a lack of them. It appears that there is an imbalance between written information and images tipping in favor of the information. I think it would be a good idea to add some more images to elicit more excitement in the page. Student images are a good idea as they highlight that it is a student project and make it more interesting for the viewer.

The current research models and findings shouldn’t be left like it is at the moment. You will need to go into more detail and reference properly. While on referencing it is important that you put all your references at the bottom of the page. You only have 20 at the bottom at the moment and it is clear that you have used many more than twenty. Also you need to add in text citations so that we know exactly where you have got your information from.

The current research part is good with plenty of information, but again look at adding more images to make it a bit more interesting. There are obviously some parts that you need to finish off which I’m sure your aware of.

Overall it is a really good project with the potential to be excellent because of the amount of effort you have put into the research. Just make sure you change your references so that they are all down the bottom and have in text citations, add more images and maybe student images as well to make your page more presentable. Very well done so far and good luck with finishing the project off.

===7===

In this review I intend to highlight the merits of your project and suggest some areas for improvement in light of the marking criterial provided.

The introduction provides the perfect preface for your project, it serves to summarise the topic and highlight the areas that you will be addressing.

In the first section you have discussed fetal development of the neural system in great detail. I feel that a lot of research has gone into the collection and presentation of this date. The diagrams have been appropriately selected. Each image really ties in with the content and helps explain that stage development; I particularly like the diagram summarising the cell migration. In addition the images are well referenced. In the link you provide a brief description of the image and effectively explain the meaning of all the abbreviations.

The topics addressed under the heading of current seem quite interesting. The project really succeeds in providing insight into this new MIR technology, a technology that will certainly allow us to build on current knowledge of fetal neural development. I see that the heading of future research has not been completed. However I feel that this is a very interesting sub heading and shows a clear aspiration to go beyond the scope of the course.

A number of abnormalities have been addressed. I only suggest that you ensure that each of these subheading is addressed for each abnormality. Description; Epidemiology; Cause and possible Treatments, an image would be good too.

All the content on this page is well written. I feel that all the subheadings are relevant, though some sections are not complete. The only major drawback of your project is that, at this point the area of historic findings has not been addressed at all. Make sure you address this area.

===8===

I believe the introduction of this page is excellent. A good choice of appropriate headings and subheadings. The addition of images would just add to the presentation of the introduction.

The development section of this page is excellent! There is very informative, easy to follow and well-presented. There is clear evidence of significant scientific research and correct referencing. The choice and use of graphs and diagrams is excellent and does indeed add to the overall understanding of this section. I do believe, however, that this section could be included with the use of more tables? (Eg. The first four bolded subheadings)- but this is only a suggestion. Excellent nevertheless. Really enjoyed the ‘Visible anatomical details’ table.

The current research section is a bit lacking in detail and appropriate choice of pictures. There is a good choice of subheadings and references though. The first included study is excellent though and should serve as a benchmark for the other remaining studies.

The historic findings section is not presented on the page yet? I cant seem to find this section on your page.

The abnormalities section is excellent, well presented and well researched. There is a very good use of subheadings and an excellent varying amount of abnormalities/defects included. The use of dot-points is effective, as well as, the accompanying pictures- really aids in understanding. This section, however, needs to be correctly referenced and cited. The other remaining abnormalities should be finalised (although I believe not all of the abnormalities should be discussed in great detail!). Great work, overall.

===9===

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

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

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

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

===10===
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.

The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.

The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing. Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 14:21, 16 August 2014 (EST) Hey everyone,

What's everyone's ideas about doing the neural system for our project? there are lots of interesting Neurologic deficits that we could talk about!!!

--[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 23:25, 16 August 2014 (EST) That's a good idea. Neural system is a complex structure and it should be fun to work on it! Any other ideas?

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 23:51, 19 August 2014 (EST)
I talked to Yas before, sorry couldnt respond faster haha. Agree that Neural system would be interesting to research :p

Do you guys have facebook as well? It might be an additional way to communicate

--[[User:Z3422484|Z3422484]] ([[User talk:Z3422484|talk]])
I also agree on this topic being quite interesting as well
--[[User:Z3418981|Z3418981]]

--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 10:54, 25 August 2014 (EST) hey guys it's yas! so we each need to choose one of the following:
Review the neural system development during the fetal period.
Identify current research models and finding.
Identify historic findings.
Identify abnormalities that can occur in this system during fetal period.

--[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 21:07, 25 August 2014 (EST) Thanks! This is vivian. Can I do "the review of the neural system development during the fetal period"? Or if anyone wants to do this section?

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 12:07, 26 August 2014 (EST)
Hey guys, Can i do historic findings for fetal neutral system development :) - Sean

--[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 17:47, 26 August 2014 (EST)I have put some subtitles to give a brief structure to our webpage, feel free to change them if you want!

--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 17:51, 26 August 2014 (EST) sure and I'll do the abnormalities - Yas

--[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 18:25, 26 August 2014 (EST) hey Yas, see if this helps. <pubmed>25007063</pubmed>

--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 21:14, 26 August 2014 (EST) Thanks Vivian!! the article is very helpful! and the page looks really good too :)

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 20:18, 26 August 2014 (EST)
Hey guys, I think the last entry from my section will help alot in the ''Development'' section for our project :) - Sean

<pubmed>17848161</pubmed>

--[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 23:14, 26 August 2014 (EST) That's true! thanks Sean :) - vivian

--[[User:Z3422484|Z3422484]]--[[User:Z3422484|Z3422484]] ([[User talk:Z3422484|talk]]) 12:50, 27 August 2014 (EST)
Hey guys, this is a useful article for the abnormalities area

<pubmed>24664314</pubmed>

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 23:55, 1 September 2014 (EST) nice one :D
How are you guys going with your sections?

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 12:58, 17 September 2014 (EST) <pubmed>10226791</pubmed> maybe for development

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 21:12, 20 September 2014 (EST) http://www.ehd.org/cache/pdf/fd7e47f291dded855c38ffb3418fbdc8/timeline.pdf

something which might help us figure out a timeline structure

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 11:56, 24 September 2014 (EST) http://discovery.lifemapsc.com/library/review-of-medical-embryology
A textbook which has great information on the development of the CNS during the fetal period

--[[User:Z3422484|Z3422484]] ([[User talk:Z3422484|talk]]) 11:35, 8 October 2014 (EST)
Hey guys i will be adding a few extra research articles to the current research tab

--[[User:Z3422484|Z3422484]] ([[User talk:Z3422484|talk]]) 11:35, 8 October 2014 (EST)
Also is there anything else anyone needs help on as well?

--[[User:Z3422484|Z3422484]] ([[User talk:Z3422484|talk]]) 12:09, 8 October 2014 (EST)
Forgot to mention that I'll also be adding spinal cord abnormalities

For Historial Research and Findings
<pubmed>19339620</pubmed>
<pubmed>8005032</pubmed>
<pubmed>9311417</pubmed>
<pubmed>17848161</pubmed>
<pubmed>12768653</pubmed>
<pubmed>17060425</pubmed>
<pubmed>21042938</pubmed> for brain de

abnormalities
<pubmed>12454899</pubmed>
<pubmed>25007063</pubmed>
<pubmed>16530991</pubmed>
<pubmed>7504639</pubmed>
<pubmed>19651588</pubmed>
<pubmed>25135350</pubmed>
<pubmed>25128525</pubmed>
<pubmed>24397701</pubmed>

----

*Good start on the introduction. Maybe have it used to explicitly state what your entire page will be covering rather than just a background on what the CNS is.
*You're missing references for the huge chunks of information in the introduction section
*The image of the timeline of development seems overly complex and I can't tell if you've explained it. If it's not relevant, maybe just come up with your own concise table of what happens during the course of development
*Maybe think of re-creating some simpler images by hand and uploading them. That way you can choose to focus on what you actually need from the image to show what you're explaining
*Include the years of when your current findings were discovered
*For the "abnormalities" section, as there are many, maybe the amount of detail you've included for the first couple of ones isn't needed, but of course, use your own discretion to how much is relevant. Otherwise, the bullet points are a good way to simplify information
*Collate all your references in the bottom from all the separate sections

Talk:2014 Group Project 7

2014-10-14T13:39:14Z

Z3416697: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==
===1===
Good introduction but I would move what happens in the embryonic development to the “development” section. Also, don’t forget any references and in-text citations for this section. Maybe add more on what the page is about and what the readers should be expecting. Nonetheless, it gives a good background of the key organs in this system. The diagram for the timeline of development is quite complex. Try to explain what is happening in this diagram within the “development” section. For example, maybe try to have the same headings (cell multiplication, cell migration, etc.) as the diagram for the “development” subheadings. Or, if you’re willing, make a timeline of your own. At least, you can make a simpler diagram where only relevant information is included. Good job on the “Visible Anatomical Details” table.

On current findings, good choice on research articles. They’re very relevant to the topic and to the project as well. Maybe try to add some images if possible. Also, try to add some dates or anything to show how recent these studies are. There is a bit of imbalance in terms of the amount of content for each study but nonetheless, this section was written well. Good job! As for “abnormalities”, this section was done well. Each disease was written with lots of detail but very concisely. I do suggest adding more images that show the clinical manifestation of each disease. Also, don’t just focus on the manifestations of each defects. Try to look for current treatments or techniques on managing the abnormality. Also, maybe look for more references.

On historic findings, where is it? There is a section on the Wikipage that has old books on embryology. It’s under the “Explore” tab and you’ll see “Historic embryo”.

I’ve check all the images and there are no issues with them in terms of copyright. I can see that you tried to add captions to each photo, which is good but you can format the image in a way so that the caption is framed with the photo. Check out the [[https://embryology.med.unsw.edu.au/embryology/index.php/Help:Image_Tutorial#Image_Formatting| Image Formatting]] guide to do this. Overall, this page is very detailed and written very well. Just try to edit the page and make it look cleaner.

===2===

This project page is very nicely organised with the group clearly specifying what aspect of neural development they are covering, being the CNS. The use of headings and subheadings is done very neatly, however sections 1.1-1.5 could be subheadings for the larger title ‘system development’. The key points have been clearly described but there is no referencing throughout the ‘Introduction’, ‘Brain development’ and ‘Abnormalities’ sections. Most key points have at least some information on them which is good for this stage of the project; however some of the headings without could use some more work.

The choice of content is highly appropriate and the use of diagrams and pictures help show the groups understanding of the project thus far. I particularly like the use of subheadings in this project as they make the page look neater and organised. The image showing the timeline of fetal neural development is good however perhaps it would be better to draw or make a timeline on the computer in order to show better understanding of the time course of fetal development. Most images that have been uploaded are also well referenced and when clicking onto them, it takes the reader to a page that has more information related to the image. The table to describe anatomical details is also done well and is important that such a key point is mentioned seeing as this is an anatomy course.

I also really like how the ‘Current research, models and findings’ section is split into ‘Current research’ and ‘Future Research’, however it seems future research needs to be further looked into. The ‘Abnormalities’ section is done very well, with multiple abnormalities listed with images used to show each one. The bolding of several key words is seen and is helpful in showing understanding of some of the key points. There are also no historic findings so try and find some information on that.

Referencing is correctly done with most references being in one main section at the end, and ordered correctly. In-cite referencing is also done correctly. All images are correctly referenced with copyright information present and the student image template. I also like the way the current research findings sources have been referenced with the use of dot points assisting learning by not just presenting to the reader as a blob of information.

Overall, well done group 7! Keep up the great work!

===3===
The content looks well organized. The introduction could use a bit of work; it does a good job of introducing the CNS, but it should also mention all the other sections this page will cover regarding the topic. You might want to get rid of the using bold for brain and spinal cord, it just makes it look a little weird. Otherwise, a good embryonic developmental background is provided, it’s a good way to set the stage for when fetal development will commence from.

The information is organized well, no chunky slabs of texts. But the use of dot points is a bit extensive; almost every section of the page has dot points or makes up the complete majority of the info presented. You might want to present some of it in paragraph form e.g. the abnormalities part, as that section can still be kept quite short and not be packed with text. As long as you mention what it is, how you get it/how it forms, some statistics and use a picture, the section can be still visually appealing.
The images are captioned ok, but there is a better way of doing it. In the command to input the image, continue the command with: |thumb|’whatever you want to write’], and the section in the apostrophes will be the caption under the picture (go into edit mode on another project page for a better idea, I might not have explained well).

The use of the table is well done, makes all that info easily presentable, though I see the meninges development still needs to be done. The current research models and findings looks kind of messy with just the referenced PubMed article there. It might look better if you had the article name written in bold and a couple sentences underneath each to describe what the article was trying to achieve, like what has been done under current research. A couple pictures may be included to make it all more visually appealing and colourful.

Overall, this was done well. You have a good amount of information, just try not to present it all in dot points. Make sure all your info is referenced in text, will all references displayed at the bottom of the page. Another note, try to organise your pictures in different areas of the page as well, as they are all currently on the left hand side.

===4===

This group page shows a good amount of work completed however there are quite a few sections that clearly still need some more info. A good introduction to the neural development and a accurate description of what will be covered. Although it seems to be missing the in text citations. The section on ‘development during fetal period’ is presented clearly and structured really well. The info is not too overwhelming and the use of dot points for this section is great as neural development is quite complex. There’s a good identification of images and the use of in text citations. The brain development section is written really well with enough detail and it’s nice to see a table for the timeline of changes during each week. It does however seem to be a bit short, maybe that’s because it’s all in dot point form. It would be useful if the ‘brain, spinal cord and meninges development’ were combined under one heading, this might be a better way to structure it. Otherwise just keep each section separate but format the info into paragraph form. In the ‘current research’ section a thorough amount of info was provided. It seems as though it hasn’t been finished and more info will be added later that will be great. The abnormalities content is sufficient and well organised. Just consider using more in text citations in this section, add some more images and complete all the sub headings.

Finally a good effort in this project page, it is structured well and the info provided is easy to understand. However it needs some more research and content to fill all the sub headings in order for it to be finished. Some suggestions that may be considered include; having all the references under one main heading at the end of the page. The use of more in text citations in some of the paragraphs throughout the whole page would be effective. There is an adequately amount of images already shown, so maybe the use of videos or drawings would also be good especially in the abnormalities section and current research. The key is to focus on filing the info and then just making a few adjustments in terms of formatting. Otherwise the page is set out well , just needs a little more work. The page will look really great once completed. Good luck ☺

===5===
This page is organized well, all the headings and subheadings are thought through. Although, I’m unsure while the sections brain and spinal cord are in bold? The development during fetal period image lacks the necessary “student template” at the bottom of the description summary and I was unable to open the link http://www.nichd.nih.gov/publications/pubs/acute/images/p44.gif.
Otherwise, all the other images uploaded on the page look really good and are referenced correctly.

The table under the section brain development is very brief, and expansions on the content will allow for a better understanding of the content. Adding images to appear after the table will also add to the appearance of the page and give it a cleaner look.

The spinal cord and menegies development have been left untouched and the current research models have no content, just pubmed references. I understand the current research models are probably the hardest part of the assignment, but the content appears to be quite good, the formatting of the section could be improved by following the structure Mark uses. You could look at the other group projects as examples.

In regards to referencing, there are no in-text citations for the first two subheadings. I would also like to recommend just adding a final list of references at the bottom of the page, as it looks much neater.

The abnormalities section is done well. But try to minimise the use of dot points as this section lacks any structured paragraphs. It use of images are great, although there is an image that appear to have been removed and as a result, there is a broken link.

Overall, great job so far!

===6===
This is a really good project so far. The introduction is really well done and I especially like that you have included a diagrams in it. The brain development is good, however I’m not completely sure about the dot points. It would look better if they were not there.

Well done with the images that you have got there they all appear to be well described and referenced when you click on them. Only problem with the images is that there is a lack of them. It appears that there is an imbalance between written information and images tipping in favor of the information. I think it would be a good idea to add some more images to elicit more excitement in the page. Student images are a good idea as they highlight that it is a student project and make it more interesting for the viewer.

The current research models and findings shouldn’t be left like it is at the moment. You will need to go into more detail and reference properly. While on referencing it is important that you put all your references at the bottom of the page. You only have 20 at the bottom at the moment and it is clear that you have used many more than twenty. Also you need to add in text citations so that we know exactly where you have got your information from.

The current research part is good with plenty of information, but again look at adding more images to make it a bit more interesting. There are obviously some parts that you need to finish off which I’m sure your aware of.

Overall it is a really good project with the potential to be excellent because of the amount of effort you have put into the research. Just make sure you change your references so that they are all down the bottom and have in text citations, add more images and maybe student images as well to make your page more presentable. Very well done so far and good luck with finishing the project off.

===7===

In this review I intend to highlight the merits of your project and suggest some areas for improvement in light of the marking criterial provided.

The introduction provides the perfect preface for your project, it serves to summarise the topic and highlight the areas that you will be addressing.

In the first section you have discussed fetal development of the neural system in great detail. I feel that a lot of research has gone into the collection and presentation of this date. The diagrams have been appropriately selected. Each image really ties in with the content and helps explain that stage development; I particularly like the diagram summarising the cell migration. In addition the images are well referenced. In the link you provide a brief description of the image and effectively explain the meaning of all the abbreviations.

The topics addressed under the heading of current seem quite interesting. The project really succeeds in providing insight into this new MIR technology, a technology that will certainly allow us to build on current knowledge of fetal neural development. I see that the heading of future research has not been completed. However I feel that this is a very interesting sub heading and shows a clear aspiration to go beyond the scope of the course.

A number of abnormalities have been addressed. I only suggest that you ensure that each of these subheading is addressed for each abnormality. Description; Epidemiology; Cause and possible Treatments, an image would be good too.

All the content on this page is well written. I feel that all the subheadings are relevant, though some sections are not complete. The only major drawback of your project is that, at this point the area of historic findings has not been addressed at all. Make sure you address this area.

===8===

I believe the introduction of this page is excellent. A good choice of appropriate headings and subheadings. The addition of images would just add to the presentation of the introduction.

The development section of this page is excellent! There is very informative, easy to follow and well-presented. There is clear evidence of significant scientific research and correct referencing. The choice and use of graphs and diagrams is excellent and does indeed add to the overall understanding of this section. I do believe, however, that this section could be included with the use of more tables? (Eg. The first four bolded subheadings)- but this is only a suggestion. Excellent nevertheless. Really enjoyed the ‘Visible anatomical details’ table.

The current research section is a bit lacking in detail and appropriate choice of pictures. There is a good choice of subheadings and references though. The first included study is excellent though and should serve as a benchmark for the other remaining studies.

The historic findings section is not presented on the page yet? I cant seem to find this section on your page.

The abnormalities section is excellent, well presented and well researched. There is a very good use of subheadings and an excellent varying amount of abnormalities/defects included. The use of dot-points is effective, as well as, the accompanying pictures- really aids in understanding. This section, however, needs to be correctly referenced and cited. The other remaining abnormalities should be finalised (although I believe not all of the abnormalities should be discussed in great detail!). Great work, overall.

===9===

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

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

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

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

===10===
This project is coming along quite nicely! The introduction is very thorough and provides a really sound basis for the topics which you covered. I enjoyed the use of diagrams in your introduction- although I admit your flow diagram was very scary! I think you should be a bit more clear in your timeline of the human neural development – it took me a moment to figure out what was happening, so it may be a better idea to put all this information into a table.
The images that you have used are great as they are relevant and provide interest to your project page. The referencing on them appears consistent and there doesn’t appear to be any copyright issues- so I think you should include a few more diagrams, just to make your message even clearer.
The current research models could do with some reformatting. I don’t think it is a good idea to put the references at the start, and secondly it seems like your work is not so well structured. I think if you included some bullet points in your work, it would greatly aid the clarity. The abnormalities is off to a good start, I see that it is well researched but you want to consider adding some more pictures or diagrams just to make it a bit more visually appealing.
Overall this project is off to a good start, I think it may be a good idea to leave all your references until the end just to make your work more cohesive.

--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 14:21, 16 August 2014 (EST) Hey everyone,

What's everyone's ideas about doing the neural system for our project? there are lots of interesting Neurologic deficits that we could talk about!!!

--[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 23:25, 16 August 2014 (EST) That's a good idea. Neural system is a complex structure and it should be fun to work on it! Any other ideas?

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 23:51, 19 August 2014 (EST)
I talked to Yas before, sorry couldnt respond faster haha. Agree that Neural system would be interesting to research :p

Do you guys have facebook as well? It might be an additional way to communicate

--[[User:Z3422484|Z3422484]] ([[User talk:Z3422484|talk]])
I also agree on this topic being quite interesting as well
--[[User:Z3418981|Z3418981]]

--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 10:54, 25 August 2014 (EST) hey guys it's yas! so we each need to choose one of the following:
Review the neural system development during the fetal period.
Identify current research models and finding.
Identify historic findings.
Identify abnormalities that can occur in this system during fetal period.

--[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 21:07, 25 August 2014 (EST) Thanks! This is vivian. Can I do "the review of the neural system development during the fetal period"? Or if anyone wants to do this section?

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 12:07, 26 August 2014 (EST)
Hey guys, Can i do historic findings for fetal neutral system development :) - Sean

--[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 17:47, 26 August 2014 (EST)I have put some subtitles to give a brief structure to our webpage, feel free to change them if you want!

--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 17:51, 26 August 2014 (EST) sure and I'll do the abnormalities - Yas

--[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 18:25, 26 August 2014 (EST) hey Yas, see if this helps. <pubmed>25007063</pubmed>

--[[User:Z3418981|Z3418981]] ([[User talk:Z3418981|talk]]) 21:14, 26 August 2014 (EST) Thanks Vivian!! the article is very helpful! and the page looks really good too :)

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 20:18, 26 August 2014 (EST)
Hey guys, I think the last entry from my section will help alot in the ''Development'' section for our project :) - Sean

<pubmed>17848161</pubmed>

--[[User:Z3419587|Z3419587]] ([[User talk:Z3419587|talk]]) 23:14, 26 August 2014 (EST) That's true! thanks Sean :) - vivian

--[[User:Z3422484|Z3422484]]--[[User:Z3422484|Z3422484]] ([[User talk:Z3422484|talk]]) 12:50, 27 August 2014 (EST)
Hey guys, this is a useful article for the abnormalities area

<pubmed>24664314</pubmed>

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 23:55, 1 September 2014 (EST) nice one :D
How are you guys going with your sections?

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 12:58, 17 September 2014 (EST) <pubmed>10226791</pubmed> maybe for development

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 21:12, 20 September 2014 (EST) http://www.ehd.org/cache/pdf/fd7e47f291dded855c38ffb3418fbdc8/timeline.pdf

something which might help us figure out a timeline structure

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 11:56, 24 September 2014 (EST) http://discovery.lifemapsc.com/library/review-of-medical-embryology
A textbook which has great information on the development of the CNS during the fetal period

--[[User:Z3422484|Z3422484]] ([[User talk:Z3422484|talk]]) 11:35, 8 October 2014 (EST)
Hey guys i will be adding a few extra research articles to the current research tab

--[[User:Z3422484|Z3422484]] ([[User talk:Z3422484|talk]]) 11:35, 8 October 2014 (EST)
Also is there anything else anyone needs help on as well?

--[[User:Z3422484|Z3422484]] ([[User talk:Z3422484|talk]]) 12:09, 8 October 2014 (EST)
Forgot to mention that I'll also be adding spinal cord abnormalities

For Historial Research and Findings
<pubmed>19339620</pubmed>
<pubmed>8005032</pubmed>
<pubmed>9311417</pubmed>
<pubmed>17848161</pubmed>
<pubmed>12768653</pubmed>
<pubmed>17060425</pubmed>
<pubmed>21042938</pubmed> for brain de

abnormalities
<pubmed>12454899</pubmed>
<pubmed>25007063</pubmed>
<pubmed>16530991</pubmed>
<pubmed>7504639</pubmed>
<pubmed>19651588</pubmed>
<pubmed>25135350</pubmed>
<pubmed>25128525</pubmed>
<pubmed>24397701</pubmed>

----

*Good start on the introduction. Maybe have it used to explicitly state what your entire page will be covering rather than just a background on what the CNS is.
*You're missing references for the huge chunks of information in the introduction section
*The image of the timeline of development seems overly complex and I can't tell if you've explained it. If it's not relevant, maybe just come up with your own concise table of what happens during the course of development
*Maybe think of re-creating some simpler images by hand and uploading them. That way you can choose to focus on what you actually need from the image to show what you're explaining
*Include the years of when your current findings were discovered
*For the "abnormalities" section, as there are many, maybe the amount of detail you've included for the first couple of ones isn't needed, but of course, use your own discretion to how much is relevant. Otherwise, the bullet points are a good way to simplify information
*Collate all your references in the bottom from all the separate sections

Talk:2014 Group Project 6

2014-10-14T13:23:15Z

Z3416697: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==

This project would greatly benefit from an introduction, to present the contents of the project. The content is broken up into individual organs, of all the systems endocrine definitely one of the most varied in location so this approach does have some merit for initial data gathering. It does present the problem for viewers in navigation and resulting in continual repletion of timelines. Each organ is subdivided into timeline, introduction, structure, function, development and abnormalities. The content presented is solid and obviously well referenced. Placenta section should be added, because of its significant endocrine organ during fetal development. The references are mostly placed at the bottom of each organs section, these should be moved to bottom of the whole project in combination with in text citation. This will make the body of the project less cluttered and more fluid.

The table for hypothalamus hormones and associated abnormalities are mostly incomplete with “Example” filling many of the boxes. I would advise completion of hypothalamus hormone table and removal of associated abnormalities. In total there were only 3 images, addition of 2+ more images would help readers visualize the developmental organs. With at least one image per organ and preferably an additional image for an abnormality. Sufficient content is presented in this project though significant formatting changes are needed to create a completed project, additional images would be preferable.

----

Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

----

Great job on doing the endocrine system! There are lots of content for each organ of this system, which is good. I can see that this system was broken down into organs and allocated to different members. The only problem I see with this format is that presentation could be incoherent. I suggest try to follow the outline Dr. Hill gave us like development, current findings, etc. and just break each section into sub-sections for each organ. If that’s too much, then maybe just a single timeline of the development of the whole system. Also try to have a uniform layout for the tables about the hormones secreted by each gland.

There aren’t many images used in the page so maybe try to add more images. They really help with getting the readers to understand the information. In terms of referencing and citations, good job on choosing the research articles. All of them seem to be relevant to the the project. Don’t forget to use in-text citations. Not only is it important but it will make the page look a lot cleaner. Also, try to get all the references into one bulk at the bottom of the page. Overall, there aren’t a lot of problems in terms of the content but mainly about organising the page, making it coherent, and cleaning it up. I think the thyroid, parathyroid, pancreas, and adrenal sections were remarkable. Well done!

----

Group Project 6 – Endocrine Development

An introduction could be very useful to summarise what the page is going to discuss. Sections 1.2-1.11 could all be subheadings under the main heading ‘System Development’, and then each of these subheading could be further divided into smaller subheadings with timeline, introduction detailing structure/ function of the endocrine organ. It is however very well done how the headings of each organ are then further subdivided into ‘abnormalities’, ‘research findings’ and ‘timeline’. However, the fact that each section has its own references and is subdivided as such, shows that even though the page may appear more ordered, there appears to be little communication between group members at this stage. So perhaps a goal could be to make the page look like one flowing work piece as opposed to sections that each person has done.

I think the content is very well researched and I like the way each organ of the endocrine system is discussed, as all are important in fetal development. The use of images is appropriate and very well done as they are referenced correctly and when you click on an image it takes you to a new page showing the student image template, copyright information as well as extra information regarding the image. There are no student-drawn images however, so perhaps it could be possible to draw a flow chart perhaps of gonadal fetal development. The use of tables is also done very well and is frequent throughout the page, with some being used to illustrate the anatomical development of certain organs, for example, the adrenal gland and pancreas. The graphs are also useful in portraying information from research findings.

The project page is missing information regarding historic findings, and I think that if this page is going to have a main heading for Abnormalities, then the group should put all their information regarding abnormalities under this section. Although it is not an endocrine organ that grows within the developing foetus, but is an important part of the mother, there is not much information on the page regarding the placenta. This section needs to be completed as the placenta is an important source of hormones and acts as an endocrine organ during the pregnancy, sustaining the foetus.

It is good that there are many references, indicating thorough research into the endocrine system with each organ heading have its own sources, however I think these references need to be ordered better. The actual referencing is done correctly, however in-text referencing is absent, so it may be best to fix this. Most images are referenced correctly as well.

Overall, keep up the good work, but just edit the page to make it look neater and finish the sections you need to.

----

At first glance, a lot of sections seem to be incomplete. On second glance, I’ve noticed that you have added all the headings used by other groups (timeline, current findings, abnormalities) as subheadings for your own project, which I think it a really smart idea. Because you have so many glands that need to be covered, writing these sections separately can be confusing with the information quickly becoming muddled up. Doing it this way eliminates that confusion.

Make sure the use of tables is appropriate, using a table for one row of info is kind of pointless (pineal gland). The timelines used should also start with the week number, otherwise it can be quite confusing trying to work out the time (e.g. try not to say times such as ‘by the second trimester’). The information presented was concise and to the point, no long-winded explanations or slabs of text which was good. The images used were relevant and captioned.

Concerning the work completed, overall it was done well. A lot more work still needs to be completed however. References should also be made in text. If you are unsure how to do this, just go into edit mode in another group’s project and see how they have done it, instead of listing all the references at the bottom of the corresponding section. Make sure all the references are also presented at the bottom of the page, not separated into sections. It would also be nice if more images are used, if not one image for every gland then at least one for every second gland mentioned (it just needs more images).

------

There seems to be no introduction on the page, don’t forget to add content to this section before the final submission. The overall page looks disjointed by the choice of sub-headings. I think an overall timeline is needed to know which glands/organs develop when and originate from where. It would look much neater and would be easier to follow.

The parathyroid gland and pancreas seems to be the only sections that are properly completed. Both sections have good use of images and the tables provide easy readability. The images are all properly cited, good job.

The overall referencing of the page is all over the place and lacks in-text citations. I suggest you go through the contents and add these where necessary. If you are unsure how to do this, just look at the handout Mark gave out in week 2 for further reference. Or, alternatively you could look at some of the other project pages in edit mode. I would also suggest you leave all the references to the end of the page by simply putting </references> at the bottom of the page, as it looks neater to have them all in one place, rather than at the bottom of each sub-heading.

The abnormalities section is lacking content and there is only 2 diseases listed, with no description.

Overall, the page has good content, just needs to be edited to put in-text referencing. Some sections need contents such as the placenta and adding images to the page will also improve its presentation.

-----
So far you have made a good start. The introduction is a really important part of the project so it’s important that you get that down. The pineal gland part has made a good start but it would be good if some more hormones could be added. I think it would be good maybe if you all combined all of your times line and put them at the top of the page. You could maybe do this in a table form, but it’s certainly something that would make the project more succinct. Also instead of having references spread all over the page it would be a good idea to put the all of them at the page to make the page look more neat and tidy.

The hypothalamus part also needs to add extra information on the hormone part and add their illustration. I think it may be a good idea to add a student image because this makes the page more interesting and people looking at the page will be instantly attracted to this. Something that is really important and goes for the whole page is that you need to do in text referencing, as having the references at the end of the writing is tough because we don’t know which parts came from where.

Its good that there is recent findings in the hypothalamus part but I think this probably highlights the biggest issue with your project, being that It probably doesn’t link with all parts that well. I think it would be good if you could link all parts of the endocrine system together to make it easier to understand. For example, if you put the recent findings as a whole new part then everyone puts their recent findings in there it will make it easier to understand and look more collaborative. Also there is an imbalance in written information to pictures which tips in favor of the information. While it’s great to have a lot of information it becomes a bit boring just reading all the time so I think adding more images, particularly student drawn images would be something that would definitely improve the page.

Overall it has been a good start but the main points that need to be focused on are to finish off the information, make sure you correctly reference with in text citations and putting the references at the end of the page, and adding more images to make it more interesting. Good luck with the rest of the project.

-----

The page is set out really well especially since the endocrine development covers so many organs. It’s a nice clear and concise way of structuring the page. Each particular organ is addressed really well. There is good consistency with each one on the page that is great. The page contains a sufficient about of content and detail in the info for each section of an organ addressed. It is good to see the use of tables and some dot point formatting which always helps to keep the content clear. There are parts in each section that are missing info these include the abnormalities and tables. The use of images with captions containing well detailed descriptions are also constant under each section. Some suggestions to consider include adding more info to the abnormalities would be great. Focusing on discussing what each abnormality is, how it’s contracted, statistics and then treatment. Throughout the whole page in text citations have not been used at all which should be included, especially when research studies are mentioned. A way to assist with this is to use the following format; for pubmed <ref name=PMIDnumber><pubmed>pubmedIDnumber</pubmed></ref> and then for other references <ref>insert source</ref> . Then after those are inserted, add an additional referencing heading and under it write <references/> .

Overall the page does not need too many changes, just a few adjustments mostly with formatting and references. Then some sections need a little bit more info to be completed. An introduction would also be a great way to provide an overview of the content that will be covered since there is a lot discussed. So far it can be seen that a great deal of research has been conducted. It’s also understandable that not all sections are completed just yet as this is a pretty lengthy system. Try to also incorporate some graphs, drawings and even video’s, they are a great visual aids. Keep up the good and the page will be really great, good luck ☺.

----

Just must say, this must be one of the hardest topics to cover! Excellent work overall and continue to work hard in completing and finalising this page. But please don’t forget to add an introduction which clearly lists the outcomes that the page will hope to address

I really believe that this page would greatly benefit by re-structuring the entire layout by the headings suggested to us- ie. Development timeline, recent findings, current research and abnormalities. Seems a bit disjointed and is hard to follow.

Due to the manner in which you guys have subdivided the sections via organs, it is hard to comment and critique via the headings suggested. Some organs have been excellently covered (pancreas, thyroid, parathyroid), however, some organs do need a bit more development (eg. Pineal gland). Also, due to the way you guys have decided to approach this page, the writing styles and presentation of information does have notable differences amongst the oragans.

Overall, there is an excellent choice of headings and subheadings though. There is also excellent and correct citing in most of the sections. However, this page could be greatly benefited by re-structuring the entire page to follow the suggested headings. I really believe that the information and research included in this (hard) topic is excellent and demonstrates significant scientific research, however, the overall structure makes it hard to follow and understand! I believe re-structuring will address a lot of the issues mentioned. But again, excellent work so far in this very hard topic!

----

In this review I intend to highlight the merits of your project and suggest some areas for improvement in light of the marking criterial provided.

I believe that an organ-by-organ approach to this section is great. This really helps organise the information. This layout also makes the page easy to navigate allowing students to directly refer to the section that they want to learn about. However by doing so I think you may have neglected some of the areas.

Each endocrine organ has a great introduction describing the structural features and nature of the organ. I suggest including an image or a hand-drawn diagram of each gland and location, as this would really aid understanding The time line is a great way to summaries the major stages in development, I feel that this section has been completed with sufficient research and detail.

The section on abnormalities needs to be completed, even if only one abnormality is addressed make sure you include information on the following areas. Epidemiology; Description; Cause and Treatment. Furthermore ensure that the section on current research and historical findings is researched and addressed addressed.

I feel that your project is incredibly cohesive and attempts to provide a through summary of all the main endocrine organs. However a number of sections are yet to be completed. You have a great template right now. If all these areas are completed the project will be a success. In addition; I suggest placing all the references at the end of your project page, under one heading. Good Luck!

== Group Project Topic - Endocrine ==

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 11:17, 20 August 2014 (EST) We have chosen our group project to be on the endocrine system.

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 13:07, 20 August 2014 (EST) We have decided to allocate 2 topics (endocrine organs) to each group member. We will go and research each and look for research articles and then figure out the best way to structure the content.

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 12:19, 26 August 2014 (EST) This is a draft allocation for research topics for our project.
Janaki - Pineal, Hypothalamus.
Ali (z3414648)- Pituitary, thyroid.
Samrah (z3418837) - parathyroid, thymus, pancreas.
Ruth - Adrenal, gonad, placenta.
Samrah and Ruth if there is heaps to do on those three parts that i've allocated just let Janaki and I know and we can also help out. If anyones topics are sparse on info also let us know and we can reshuffle the allocations

--[[User:Z3418698|Z3418698]] ([[User talk:Z3418698|talk]]) 22:02, 26 August 2014 (EST) Hey guys, I was thinking we should maybe have a heading 'Recent findings' for maybe a few of the topics and have a short, brief summary of any new developments. I think it would be really interesting!

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 00:00, 27 August 2014 (EST) That's a good idea, should we put a separate section on recent findings, or just some information on recent findings under each section? Also we need historical findings

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 00:44, 27 August 2014 (EST)Hey guys, it's better to post student numbers to the parts allocated to each group member so it's easier for the tutor to mark. I would do this but i'm not sure about who is who :P Also I like the idea of recent findings. I think it's also better to post articles related to the recent findings and abnormalities as we go along as this will make it easier instead of leaving it to the end. For now, I think we should just post up as many articles related to each topic as possible and then figure out how to structure the content.

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 21:22, 2 September 2014 (EST) Hey guys, I've done some research on the prenatal development of the thyroid gland so I'll add that to my section. We can always change it up later.

I also found this review article that goes into a lot of detail about the pituitary gland. It explains the cellular differentiation involved to create the cells responsible for manufacturing hormones like ACTH. There is a lot of complex gene involvement but I was thinking we could condense a lot of the information into a table. I suggest you guys do that for your organs too rather than having a lot of jargon on our page that only an advanced biochemist will understand.

<pubmed>22872762</pubmed>

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 10:09, 9 September 2014 (EST) Hey i found a great article on normal and abnormal thyroid development and it's given me a lot of great information for the timeline part.
<pubmed>10.1016/j.beem.2013.08.005</pubmed>

--[[User:Z3418698|Z3418698]] ([[User talk:Z3418698|talk]]) 12:44, 10 September 2014 (EST)We are going to incorporate the Timeline and Abnormalities under each individual sub heading rather than at the end of the page. We are also going to find image links and post them in the discussion page before uploading them. We are also going to tabulate the hormones released by the glands under the subheadings. This will summarise the function of the glands in the embryo and how they contribute to fetal development.

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 00:46, 17 September 2014 (EST) Hi guys, I've added some info about adrenal development through gestation, at this stage some simple dot points which will probably be expanded upon later. There is a lot of content about the cell morphology at different weeks but I'm not sure as yet whether it's necessary to include that level of detail?

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 12:59, 17 September 2014 (EST) Hey guys, i found this link for an image that i'm thinking of using on the project. It's from PLOSone which is good because it's free to use those images. This is the link for it: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0016752

--[[User:Z3418698|Z3418698]] ([[User talk:Z3418698|talk]]) 13:06, 17 September 2014 (EST) Hey guys, I found this image I wanted to use for hypothalamus development in a rodent, it basically illustrates the different nuclei in the hypothalamus once it it fully developed but I will be focusing on those that are present during development and the role of hormones each of them releases.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2082685/figure/fig1/

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 23:50, 23 September 2014 (EST)--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 23:50, 23 September 2014 (EST) Hi guys, I think I might use this image (figure 3), it's from the PLoS too so totally fine to re-use and shows the fetal adrenal gland using 3 different techniques, like MRI, gross imaging and histological stain. I like it because it shows the gland from different perspectives. I'll upload it soon but here's the link:
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0075511

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 03:29, 24 September 2014 (EST) I might use this image for the pancreas section http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007739 . It basicallys shows the development of the islet of langerhans and the ratio of alpha & beta cells at different phases of fetal development. Also Z3418698, I don't think that image can be used as it has copyright restrictions. Try looking in Plos One =]

----

*Firstly, props on choosing the endocrine system. It seems like one of the harder ones to take on
*I don't understand why you chose to divide tasks based on endocrine organs as that has seemed to cause your research to become really disjointed. I guess now work harder to collaborate your separate findings particularly for things like having 1 united timeline overview
*Ensure uniformity throughout the page with little things like is it "fetal" or "foetal"? Choose one then go with it
*Maybe have labels for tables more distinguished as being separate to the main text
*Include the references throughout discussion, rather than a collection at the end of each section. Then have the entire reference list at the bottom like all the other pages have. You can look at the "edit" of other pages to copy and paste the codes
*Your timeline isn't really a timeline if there are no times mentioned in the "pineal gland" section. Try using a week-by-week format and separating information that way for all of your findings altogether. Then format that into a table
*Proofread for typos "Abnormalities" in "pineal gland" section
*Need more images for earlier sections
*Great formatting of images and tables for the adrenal gland, parathyroid and pancreas sections

Talk:2014 Group Project 6

2014-10-14T13:22:49Z

Z3416697: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==

This project would greatly benefit from an introduction, to present the contents of the project. The content is broken up into individual organs, of all the systems endocrine definitely one of the most varied in location so this approach does have some merit for initial data gathering. It does present the problem for viewers in navigation and resulting in continual repletion of timelines. Each organ is subdivided into timeline, introduction, structure, function, development and abnormalities. The content presented is solid and obviously well referenced. Placenta section should be added, because of its significant endocrine organ during fetal development. The references are mostly placed at the bottom of each organs section, these should be moved to bottom of the whole project in combination with in text citation. This will make the body of the project less cluttered and more fluid.

The table for hypothalamus hormones and associated abnormalities are mostly incomplete with “Example” filling many of the boxes. I would advise completion of hypothalamus hormone table and removal of associated abnormalities. In total there were only 3 images, addition of 2+ more images would help readers visualize the developmental organs. With at least one image per organ and preferably an additional image for an abnormality. Sufficient content is presented in this project though significant formatting changes are needed to create a completed project, additional images would be preferable.

----

Overall, this is quite a good project considering the complexity of the system. I think that generally, this project would benefit from some restructuring, so as to improve the cohesiveness of your work. I think that an introduction is a good idea to organize your ideas and give the reader a good background when trying to understand some of the more difficult concepts. I think that the choice of sub headings should be advised. It is interesting that you have chosen to deviate from the given subheadings, and I understand for your system that that may be necessary- however I think that some structure or regular subheadings for each part may be a bit easier to control. Also I think an overall timeline is always a great idea as it provides a visual representation and puts things into perspective.
I also think that some areas could use a bit more research, for example a large part of the pineal gland and hypothalamus appears to be missing and there are kind of “insert text here” sections- which I’m sure you’ll work on by the submission date.
I also think its important to remember that your referencing needs to be carefully done and consistent. Currently it seems quite poorly organized, and I think overall could use with a few more resources for every section. I think because you are already deviating from the normal structure of things, it would be a good idea to leave your references until last, just so your work isn’t broken up even further. The abnormalities section is severely lacking- the table is a good idea, but make sure you fill it!
Overall a good start, some places need some serious content others just need a tidy up.

---

Great job on doing the endocrine system! There are lots of content for each organ of this system, which is good. I can see that this system was broken down into organs and allocated to different members. The only problem I see with this format is that presentation could be incoherent. I suggest try to follow the outline Dr. Hill gave us like development, current findings, etc. and just break each section into sub-sections for each organ. If that’s too much, then maybe just a single timeline of the development of the whole system. Also try to have a uniform layout for the tables about the hormones secreted by each gland.

There aren’t many images used in the page so maybe try to add more images. They really help with getting the readers to understand the information. In terms of referencing and citations, good job on choosing the research articles. All of them seem to be relevant to the the project. Don’t forget to use in-text citations. Not only is it important but it will make the page look a lot cleaner. Also, try to get all the references into one bulk at the bottom of the page. Overall, there aren’t a lot of problems in terms of the content but mainly about organising the page, making it coherent, and cleaning it up. I think the thyroid, parathyroid, pancreas, and adrenal sections were remarkable. Well done!

----

Group Project 6 – Endocrine Development

An introduction could be very useful to summarise what the page is going to discuss. Sections 1.2-1.11 could all be subheadings under the main heading ‘System Development’, and then each of these subheading could be further divided into smaller subheadings with timeline, introduction detailing structure/ function of the endocrine organ. It is however very well done how the headings of each organ are then further subdivided into ‘abnormalities’, ‘research findings’ and ‘timeline’. However, the fact that each section has its own references and is subdivided as such, shows that even though the page may appear more ordered, there appears to be little communication between group members at this stage. So perhaps a goal could be to make the page look like one flowing work piece as opposed to sections that each person has done.

I think the content is very well researched and I like the way each organ of the endocrine system is discussed, as all are important in fetal development. The use of images is appropriate and very well done as they are referenced correctly and when you click on an image it takes you to a new page showing the student image template, copyright information as well as extra information regarding the image. There are no student-drawn images however, so perhaps it could be possible to draw a flow chart perhaps of gonadal fetal development. The use of tables is also done very well and is frequent throughout the page, with some being used to illustrate the anatomical development of certain organs, for example, the adrenal gland and pancreas. The graphs are also useful in portraying information from research findings.

The project page is missing information regarding historic findings, and I think that if this page is going to have a main heading for Abnormalities, then the group should put all their information regarding abnormalities under this section. Although it is not an endocrine organ that grows within the developing foetus, but is an important part of the mother, there is not much information on the page regarding the placenta. This section needs to be completed as the placenta is an important source of hormones and acts as an endocrine organ during the pregnancy, sustaining the foetus.

It is good that there are many references, indicating thorough research into the endocrine system with each organ heading have its own sources, however I think these references need to be ordered better. The actual referencing is done correctly, however in-text referencing is absent, so it may be best to fix this. Most images are referenced correctly as well.

Overall, keep up the good work, but just edit the page to make it look neater and finish the sections you need to.

----

At first glance, a lot of sections seem to be incomplete. On second glance, I’ve noticed that you have added all the headings used by other groups (timeline, current findings, abnormalities) as subheadings for your own project, which I think it a really smart idea. Because you have so many glands that need to be covered, writing these sections separately can be confusing with the information quickly becoming muddled up. Doing it this way eliminates that confusion.

Make sure the use of tables is appropriate, using a table for one row of info is kind of pointless (pineal gland). The timelines used should also start with the week number, otherwise it can be quite confusing trying to work out the time (e.g. try not to say times such as ‘by the second trimester’). The information presented was concise and to the point, no long-winded explanations or slabs of text which was good. The images used were relevant and captioned.

Concerning the work completed, overall it was done well. A lot more work still needs to be completed however. References should also be made in text. If you are unsure how to do this, just go into edit mode in another group’s project and see how they have done it, instead of listing all the references at the bottom of the corresponding section. Make sure all the references are also presented at the bottom of the page, not separated into sections. It would also be nice if more images are used, if not one image for every gland then at least one for every second gland mentioned (it just needs more images).

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There seems to be no introduction on the page, don’t forget to add content to this section before the final submission. The overall page looks disjointed by the choice of sub-headings. I think an overall timeline is needed to know which glands/organs develop when and originate from where. It would look much neater and would be easier to follow.

The parathyroid gland and pancreas seems to be the only sections that are properly completed. Both sections have good use of images and the tables provide easy readability. The images are all properly cited, good job.

The overall referencing of the page is all over the place and lacks in-text citations. I suggest you go through the contents and add these where necessary. If you are unsure how to do this, just look at the handout Mark gave out in week 2 for further reference. Or, alternatively you could look at some of the other project pages in edit mode. I would also suggest you leave all the references to the end of the page by simply putting </references> at the bottom of the page, as it looks neater to have them all in one place, rather than at the bottom of each sub-heading.

The abnormalities section is lacking content and there is only 2 diseases listed, with no description.

Overall, the page has good content, just needs to be edited to put in-text referencing. Some sections need contents such as the placenta and adding images to the page will also improve its presentation.

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So far you have made a good start. The introduction is a really important part of the project so it’s important that you get that down. The pineal gland part has made a good start but it would be good if some more hormones could be added. I think it would be good maybe if you all combined all of your times line and put them at the top of the page. You could maybe do this in a table form, but it’s certainly something that would make the project more succinct. Also instead of having references spread all over the page it would be a good idea to put the all of them at the page to make the page look more neat and tidy.

The hypothalamus part also needs to add extra information on the hormone part and add their illustration. I think it may be a good idea to add a student image because this makes the page more interesting and people looking at the page will be instantly attracted to this. Something that is really important and goes for the whole page is that you need to do in text referencing, as having the references at the end of the writing is tough because we don’t know which parts came from where.

Its good that there is recent findings in the hypothalamus part but I think this probably highlights the biggest issue with your project, being that It probably doesn’t link with all parts that well. I think it would be good if you could link all parts of the endocrine system together to make it easier to understand. For example, if you put the recent findings as a whole new part then everyone puts their recent findings in there it will make it easier to understand and look more collaborative. Also there is an imbalance in written information to pictures which tips in favor of the information. While it’s great to have a lot of information it becomes a bit boring just reading all the time so I think adding more images, particularly student drawn images would be something that would definitely improve the page.

Overall it has been a good start but the main points that need to be focused on are to finish off the information, make sure you correctly reference with in text citations and putting the references at the end of the page, and adding more images to make it more interesting. Good luck with the rest of the project.

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The page is set out really well especially since the endocrine development covers so many organs. It’s a nice clear and concise way of structuring the page. Each particular organ is addressed really well. There is good consistency with each one on the page that is great. The page contains a sufficient about of content and detail in the info for each section of an organ addressed. It is good to see the use of tables and some dot point formatting which always helps to keep the content clear. There are parts in each section that are missing info these include the abnormalities and tables. The use of images with captions containing well detailed descriptions are also constant under each section. Some suggestions to consider include adding more info to the abnormalities would be great. Focusing on discussing what each abnormality is, how it’s contracted, statistics and then treatment. Throughout the whole page in text citations have not been used at all which should be included, especially when research studies are mentioned. A way to assist with this is to use the following format; for pubmed <ref name=PMIDnumber><pubmed>pubmedIDnumber</pubmed></ref> and then for other references <ref>insert source</ref> . Then after those are inserted, add an additional referencing heading and under it write <references/> .

Overall the page does not need too many changes, just a few adjustments mostly with formatting and references. Then some sections need a little bit more info to be completed. An introduction would also be a great way to provide an overview of the content that will be covered since there is a lot discussed. So far it can be seen that a great deal of research has been conducted. It’s also understandable that not all sections are completed just yet as this is a pretty lengthy system. Try to also incorporate some graphs, drawings and even video’s, they are a great visual aids. Keep up the good and the page will be really great, good luck ☺.

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Just must say, this must be one of the hardest topics to cover! Excellent work overall and continue to work hard in completing and finalising this page. But please don’t forget to add an introduction which clearly lists the outcomes that the page will hope to address

I really believe that this page would greatly benefit by re-structuring the entire layout by the headings suggested to us- ie. Development timeline, recent findings, current research and abnormalities. Seems a bit disjointed and is hard to follow.

Due to the manner in which you guys have subdivided the sections via organs, it is hard to comment and critique via the headings suggested. Some organs have been excellently covered (pancreas, thyroid, parathyroid), however, some organs do need a bit more development (eg. Pineal gland). Also, due to the way you guys have decided to approach this page, the writing styles and presentation of information does have notable differences amongst the oragans.

Overall, there is an excellent choice of headings and subheadings though. There is also excellent and correct citing in most of the sections. However, this page could be greatly benefited by re-structuring the entire page to follow the suggested headings. I really believe that the information and research included in this (hard) topic is excellent and demonstrates significant scientific research, however, the overall structure makes it hard to follow and understand! I believe re-structuring will address a lot of the issues mentioned. But again, excellent work so far in this very hard topic!

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In this review I intend to highlight the merits of your project and suggest some areas for improvement in light of the marking criterial provided.

I believe that an organ-by-organ approach to this section is great. This really helps organise the information. This layout also makes the page easy to navigate allowing students to directly refer to the section that they want to learn about. However by doing so I think you may have neglected some of the areas.

Each endocrine organ has a great introduction describing the structural features and nature of the organ. I suggest including an image or a hand-drawn diagram of each gland and location, as this would really aid understanding The time line is a great way to summaries the major stages in development, I feel that this section has been completed with sufficient research and detail.

The section on abnormalities needs to be completed, even if only one abnormality is addressed make sure you include information on the following areas. Epidemiology; Description; Cause and Treatment. Furthermore ensure that the section on current research and historical findings is researched and addressed addressed.

I feel that your project is incredibly cohesive and attempts to provide a through summary of all the main endocrine organs. However a number of sections are yet to be completed. You have a great template right now. If all these areas are completed the project will be a success. In addition; I suggest placing all the references at the end of your project page, under one heading. Good Luck!

== Group Project Topic - Endocrine ==

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 11:17, 20 August 2014 (EST) We have chosen our group project to be on the endocrine system.

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 13:07, 20 August 2014 (EST) We have decided to allocate 2 topics (endocrine organs) to each group member. We will go and research each and look for research articles and then figure out the best way to structure the content.

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 12:19, 26 August 2014 (EST) This is a draft allocation for research topics for our project.
Janaki - Pineal, Hypothalamus.
Ali (z3414648)- Pituitary, thyroid.
Samrah (z3418837) - parathyroid, thymus, pancreas.
Ruth - Adrenal, gonad, placenta.
Samrah and Ruth if there is heaps to do on those three parts that i've allocated just let Janaki and I know and we can also help out. If anyones topics are sparse on info also let us know and we can reshuffle the allocations

--[[User:Z3418698|Z3418698]] ([[User talk:Z3418698|talk]]) 22:02, 26 August 2014 (EST) Hey guys, I was thinking we should maybe have a heading 'Recent findings' for maybe a few of the topics and have a short, brief summary of any new developments. I think it would be really interesting!

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 00:00, 27 August 2014 (EST) That's a good idea, should we put a separate section on recent findings, or just some information on recent findings under each section? Also we need historical findings

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 00:44, 27 August 2014 (EST)Hey guys, it's better to post student numbers to the parts allocated to each group member so it's easier for the tutor to mark. I would do this but i'm not sure about who is who :P Also I like the idea of recent findings. I think it's also better to post articles related to the recent findings and abnormalities as we go along as this will make it easier instead of leaving it to the end. For now, I think we should just post up as many articles related to each topic as possible and then figure out how to structure the content.

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 21:22, 2 September 2014 (EST) Hey guys, I've done some research on the prenatal development of the thyroid gland so I'll add that to my section. We can always change it up later.

I also found this review article that goes into a lot of detail about the pituitary gland. It explains the cellular differentiation involved to create the cells responsible for manufacturing hormones like ACTH. There is a lot of complex gene involvement but I was thinking we could condense a lot of the information into a table. I suggest you guys do that for your organs too rather than having a lot of jargon on our page that only an advanced biochemist will understand.

<pubmed>22872762</pubmed>

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 10:09, 9 September 2014 (EST) Hey i found a great article on normal and abnormal thyroid development and it's given me a lot of great information for the timeline part.
<pubmed>10.1016/j.beem.2013.08.005</pubmed>

--[[User:Z3418698|Z3418698]] ([[User talk:Z3418698|talk]]) 12:44, 10 September 2014 (EST)We are going to incorporate the Timeline and Abnormalities under each individual sub heading rather than at the end of the page. We are also going to find image links and post them in the discussion page before uploading them. We are also going to tabulate the hormones released by the glands under the subheadings. This will summarise the function of the glands in the embryo and how they contribute to fetal development.

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 00:46, 17 September 2014 (EST) Hi guys, I've added some info about adrenal development through gestation, at this stage some simple dot points which will probably be expanded upon later. There is a lot of content about the cell morphology at different weeks but I'm not sure as yet whether it's necessary to include that level of detail?

--[[User:Z3414648|Z3414648]] ([[User talk:Z3414648|talk]]) 12:59, 17 September 2014 (EST) Hey guys, i found this link for an image that i'm thinking of using on the project. It's from PLOSone which is good because it's free to use those images. This is the link for it: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0016752

--[[User:Z3418698|Z3418698]] ([[User talk:Z3418698|talk]]) 13:06, 17 September 2014 (EST) Hey guys, I found this image I wanted to use for hypothalamus development in a rodent, it basically illustrates the different nuclei in the hypothalamus once it it fully developed but I will be focusing on those that are present during development and the role of hormones each of them releases.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2082685/figure/fig1/

--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 23:50, 23 September 2014 (EST)--[[User:Z3418702|Z3418702]] ([[User talk:Z3418702|talk]]) 23:50, 23 September 2014 (EST) Hi guys, I think I might use this image (figure 3), it's from the PLoS too so totally fine to re-use and shows the fetal adrenal gland using 3 different techniques, like MRI, gross imaging and histological stain. I like it because it shows the gland from different perspectives. I'll upload it soon but here's the link:
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0075511

--[[User:Z3418837|Z3418837]] ([[User talk:Z3418837|talk]]) 03:29, 24 September 2014 (EST) I might use this image for the pancreas section http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007739 . It basicallys shows the development of the islet of langerhans and the ratio of alpha & beta cells at different phases of fetal development. Also Z3418698, I don't think that image can be used as it has copyright restrictions. Try looking in Plos One =]

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*Firstly, props on choosing the endocrine system. It seems like one of the harder ones to take on
*I don't understand why you chose to divide tasks based on endocrine organs as that has seemed to cause your research to become really disjointed. I guess now work harder to collaborate your separate findings particularly for things like having 1 united timeline overview
*Ensure uniformity throughout the page with little things like is it "fetal" or "foetal"? Choose one then go with it
*Maybe have labels for tables more distinguished as being separate to the main text
*Include the references throughout discussion, rather than a collection at the end of each section. Then have the entire reference list at the bottom like all the other pages have. You can look at the "edit" of other pages to copy and paste the codes
*Your timeline isn't really a timeline if there are no times mentioned in the "pineal gland" section. Try using a week-by-week format and separating information that way for all of your findings altogether. Then format that into a table
*Proofread for typos "Abnormalities" in "pineal gland" section
*Need more images for earlier sections
*Great formatting of images and tables for the adrenal gland, parathyroid and pancreas sections

Talk:2014 Group Project 5

2014-10-14T13:01:57Z

Z3416697: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==

Group Project 5 – Integumentary Development

This page looks very neat and well organised, with an introduction that explains exactly what is going to appear and be discussed on the page. The Development Overview section is very well done, with the appropriate use of subheadings and content. The use of dot points is very effective, making the page look neater. Perhaps it would be good to draw a histological diagram of the skin layers, and uploading it to the skin development section. Specialised cells or important names throughout the page could be highlighted in bold or underlined as well, to highlight important terms and make it easier to learn and remember from. The title ‘Some Recent Findings’ accurately portrays what we as students can only do, which is identify SOME of the recent findings. This section could have more than 2 recent findings however and could be further subdivided by subheadings into the different components of the integumentary system – perhaps have 2-3 research articles for each component of the system. Historic findings are well researched but some more information would be good. The ‘Abnormalities’ section is so far the best looking section as it seems it is almost completed. Perhaps a few more abnormalities would be even better.

The table of the timeline in the ‘Development Overview’ section is superbly done and the use of histological images is fantastic as it provides the anatomical information visually. When I clicked on an image however, there was no proper referencing of the image and the copyright information and student image information was not present. The images are described very well.
One image has a problem and is present in red writing, so might need to remove this as something is wrong with the file and it could not be uploaded. There are no student-drawn images and I think if this group did this, it would really benefit their project and emphasise their understanding.

The ‘Some Recent Findings’ section has a purple background, which makes the page look more aesthetically pleasing and less monochrome. I like the ‘More recent papers’ box that can be expanded to reveal any more research papers related to the integumentary fetal development, in case anyone wants to have a further read- very clever.

Journal articles are correctly referenced but website references need to be improved upon- to find how to do this go to the ‘How to reference’ page. References are all over the place and need to be compiled under each heading or one main heading titled ‘References’ at the bottom of the page.

Overall, this page is looking fantastic at this point in time so keep up the great work!

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Introduction is short though luckily few words can go a long way, with all sections of the wiki page being properly addressed. Development overview content is good; the use of table integrated with pictures allows viewers to visually grasp the progression in skin and teeth development. The changing between dot-points and paragraph format should be standardized or use paragraphs with dot-point only for list based information. References need to be properly integrated into the page, instead of at the bottom of each section.

In the recent findings section 2 out of the 4 studies presented have any content. To improve cutting some of excess information for the 2 studies already addressed and creating summaries for the other 2 will create better scope of recent findings. The formatting of recent findings is unusual, proper placement of the “Hematoxylin/eosin” image”, removal of dot-point and removal of purple highlighting, will make the section easier for viewers to understand. Historical findings okay, more detail could be added to “skin”, “glands”, “nails”. Use of capital letters like “DEVELOPMENT” show be replaced with subheadings, the image “File:Screen Shot 2014-10-08 at 10.38.04 am.png” has not appeared properly, should be easy to fix.

Straight up the abnormalities section is amazing, no improvement needed. All 4 diseases have in-depth relevant information, sufficient referencing and images to allow viewers to visualise clinical manifestation. To improve use of dot-points or paragraphs should be standard throughout the project, referencing in beginning sections needs to compiled at ending of each Main heading or bottom of page, recent findings need 1-2 more studies, and recent findings need significant reformatting.

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Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once. I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

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This page seems to be done extremely well. It looks very visually appealing as multiple images are used, information is presented in tables, bullet points and very few slabs of text. The introduction is short and to the point. You could possibly add to this area a tiny bit of info concerning the embryonic development of this system, where it first started, then mention how you will expand on the fetal development. Otherwise it just seems way too short.

Explanation of the organs in this system is well done and concise. In the glands section, I would suggest not using dot points for the function of the vernix caseosa as it looks as though the dot points continue from those of the glands, therefore can be confusing when first looked at. Other than that, I would suggest that you make sure your referencing is correct and is used within the text.

The recent findings area is nicely done, but I still can’t help but feel the amount of text is just too much, even though the section is made better looking by making it purple (keep the colour, it looks awesome). The slab of text is just too much, so you should try and simplify it a bit. Historic findings are few but there is at least one for every organ which is good (more would be better). The abnormalities covered are done well, going into detail and providing a good image to describe what it looks like. I would suggest having at least 5 abnormalities, one for each organ discussed.

Overall, this page is very well done, with lots of images and colour used. The main thing I would suggest would be to make sure correct referencing is used. There were some paragraphs were no references were used at all. Also, all references should be at the bottom of the page, not within individual sections.

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This page has great overall structure and presentation. The introduction gives good insight of the overall contents of the page, however it is very brief and should be expanded upon.

The table included in the developmental overview serving, as a timeline is excellent, really well done. It’s easy to follow and looks very neat. I like how there is an image for each of the weeks mentioned, just don’t forget to add in-text citations for its contents. The glands sub-section is very brief and would benefit if there were more contents added. Great job on the images though. The nail section is the same, more contents needs to be added and image would look really good.

The developmental overview and historic findings sections also seems to lack in-text citations. There is also has an image with a broken link. The subsection hair seems to be well researched, however I would also suggest either bolding or underlining the words you want to emphasize such as “structure” for a neater look.

The recent findings section looks superb I love the purple background colour. Its very well researched and the link to more research papers are very helpful for readers. I would suggest you put the image at the bottom of the mentioned content though, just to avoid the big gap on the page, or even if you can manage to wrap the text around the image, it would look much better in terms of presentation.

Although disturbing, the abnormalities section I could not fault. Very well done. It is evident that it has been research well and the images allow for great visualization of the diseases mentioned.

Overall, excellent page just needs a very formatting edits and some expanded contents mentioned above. Good luck!

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This is a really well done project. You have made sure that that you have ticked all the boxes as well that Mark has asked for. The abnormalities section is really good. You have done well with most of your images as when you click on them there is a good description and they are well referenced. The development overview table is exceptional and makes the project easy to understand. For the week 22 maybe include the study in which you got your information from.

Apart from the abnormalities section it appears as though the referencing is a bit all over the place. Need to follow the abnormalities section and put references into the specific parts of the information you are using it for. Because otherwise it becomes difficult to know exactly where you got your information from. The historic findings are really good and well done however there is probably a space for more information to be included as I feel as though some of the findings are a bit hard to follow at times. It may have just been my computer I couldn’t see the picture of ‘fetal hair development’.

I think it would give a nice touch to the project if you were to add some student images because it would give the page a more ‘student’ and also make it easier to understand. Don’t mind the purple background on the ‘some recent findings’ part but it just looks a bit out of the blue. It’s certainly unique and attracts the eye but it puts a lot of emphasis on this section which I’m not entirely sure you want.

Overall though a really good project with excellent information. There needs to be a bit more focus on referencing technique, some minor edits which I have mentioned and maybe introduce some student pictures to make the project more student-like. Great work though and good luck in finishing it off.

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

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

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

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

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Overall this is an impressive and well researched wiki page incorporating lots of pictures and tables to keep the reader engaged and interested. However there are a few areas that have the potential to be tweaked. Firstly there are references scattered throughout the page. A more attractive way of presenting the references is as a long list at the end of the page. The introduction is clear, concise and short. All the organ development section is well presented and has the right amount of information. It is well structured in the sense that the student introduces the organ, it’s embryonic origin, the fetal growth stage and then goes into slightly more depth in a bullet point form. Along with complementary pictures, this is a very effective way of presenting their topic. This page could be improved by adding student-drawn schematic diagrams to summarise the layers of the skin in particular since histological images can be confusing and unclear to a non-expert embryology student.

The skin development section appears to dwell on the content that was covered in lectures. Considering there appears to be only three references associated with the entire integumentary organ development section, the depth of the information is limited. By doing some more research you might be able to find interesting additional information that can be added. The recent findings section is interesting and the images are great. However the dense block of information and slightly odd formatting make it hard to follow. Perhaps using diagrams to explain the differing gene expression and breaking down the information into bullet points would make it more readable.

The historic findings and abnormalities section is particularly well done. The images complement the minimal yet important points made. I was left wanting to read more into it so that suggests there’s room for further development and a deeper explanation of skin abnormalities.

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*Great overview given in the introduction. Maybe look to replacing the words "this page" to something else to avoid repetition
*I'm really liking how everything has been simplified into dot points and tables where relevant. Don't forget to include relevant references all throughout though, to justify all that you've included in each section
*I can't express how much I love your first table. Great work!
*Proofread so that you don't repeat the same things in your table though. You mention "in a study" numerous times but there's no indication to which studies they are
*I'm sure Mark would be thinking this same thing, but look to getting different references outside of this Embryology website, maybe from textbooks or otherwise for preliminary information on development
*The "recent findings" section looks nicely formatted but just a bit wordy. Maybe think of dividing the text up with bullet points or images
*Really liking your "historic findings" section! Great research
*Maybe think of re-creating some of the simpler pictures by drawing them yourselves. That way you're not using too many pictures from this Embryology website, Mark warned our group about this point
*Great choices for the "abnormalities" section. Traumatising at first, but very well-researched and presented

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==Week 5==
Hey guys!! I found some research material that we can use to construct our time line!

Historic information is hard to find! I might go look at some text books in the library
--[[User:Z3418340|Z3418340]] ([[User talk:Z3418340|talk]]) 12:50, 27 August 2014 (EST)
How is everyone else going?

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 12:52, 27 August 2014 (EST) Hey!! That's great! I also found some material for abnormalities. There seem to be a lot about septal defects. I'm gonna try to look up for more defects.

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 22:53, 30 August 2014 (EST)Woo!! Nice to see more links in the page! Rehmina and I also thought that it would be easier for marking if one of the two people in current research do timeline instead because that would make marking easier and less confusing. But that's not final, it's only a suggestion. Also, Dr. Hill gave us some tips on what to focus/include in our research such as:
*Remodelling during the fetal period
*Changes during ossification - haematopoietic elocution from liver to bone marrow
*Early development of WBCs — hot topic right now!!

Hey everyone, yeah that sounds good with me.. :) so rather each person focuses on 1 of the 4 topics right? --[[User:Z3417796|Z3417796]] ([[User talk:Z3417796|talk]]) 12:35, 31 August 2014 (EST)

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 18:36, 1 September 2014 (EST)Yep, exactly! I'm really glad that's alright with you but we can still talk about more in the lab.

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 12:14, 2 September 2014 (EST)Hey everyone! I just asked Dr. Hill about using review articles. He said it's alright to use review articles as long as you say that the information came from a review article when citing. We can also use images from review articles and there is no need to say that it came from a review article.

==Week 6==
--[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 20:19, 3 September 2014 (EST)Hey guys, I had a good talk with Mark today after the lab. Since we're doing the Cardiovascular system, it incorporates the (i) development of the heart, (ii) development of the blood vessels and (iii) the formation of red blood cells/white blood cells. But Mark said that as a group, we would be able to create and produce this web-site in a manner that we thought was appropriate. We could focus on one of the specific areas or more broadly on each area, if we chose to. But, MOST IMPORTANTLY, our project should be cohesive. What we talk about should be introduced well at the start and should be cohesive through out all of the subsections that we're working on. He really stressed the importance of us having a single, unified vision of our end product and that it should be succinct throughout it all. Im proposing that we actually decide what to focus on very soon.

: --[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 20:19, 3 September 2014 (EST) I'd particularly like to just focus on the development of the heart? Maybe incorporate the formation of blood cells if the research in the other areas is interesting and notable?

--[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 20:24, 3 September 2014 (EST)In regards to the use of the textbook, we are allowed to use the information from it if we cite it properly, but he really want us to be using articles (and even Review articles) to discuss our information.

I agree, the heart should remain our focus, but of course other aspects such as blood vessel formation/ blood cells would naturally fall into it as well- maybe just a brief mention wherever appropriate? --[[User:Z3417796|Z3417796]] ([[User talk:Z3417796|talk]]) 21:22, 3 September 2014 (EST)

==Week 7==
--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 21:05, 8 September 2014 (EST) Hmm. I agree. Let's try and focus on the heart for now and see how we go? And if time permits, maybe we will be able to include the development of blood vessels and blood cells. Sorry I didn't reply so soon, kinda busy week for me haha!
: --[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 00:24, 10 September 2014 (EST)Ok that sounds really good and reasonable! I'd be happy to follow that plan. And yeah, same! Very busy week for me as well! But yeah, I think lets just focus and refine our research to just the development of the heart at the moment

--[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 00:40, 10 September 2014 (EST)Hey guys, Im having difficulty knowing whether the use of an article is fine or not?! If it says "Full-free-text" does that mean we're allowed to incoporate it? Because a lot of the copyright information, is very brief. Thanks heaps, if you guys know an answer haha
: --[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 00:55, 10 September 2014 (EST)Ok, never mind.. I find out the answer haha. If it says "Open-Access" or "Full-free-text" it is only free to read online and may/may not be allowed for re-use. You'; have to read carefully or apply for permission lol. I guess i'll just be sticking to mainly the Public Library of Science (PLoS), Biomed central (BMC) and Springer Open... which we are pretty much able to use, with the right referencing and acknowledgement. I read this on the 'Copy rights' page on this wiki. http://php.med.unsw.edu.au/embryology/index.php?title=Help:Copyright_Tutorial. Can someone verify or correct me if i'm wrong haha?

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 11:56, 10 September 2014 (EST) I thought copyright only applied on images and not on content. It would be really difficult to write a report when the most papers have copyright. We can ask Dr. Hill in the lab just to confirm.

==Week 8==
--[[User:Z3417796|Z3417796]] ([[User talk:Z3417796|talk]]) 12:56, 17 September 2014 (EST) Hey guys, so Carl and I had a talk with Dr. Hill and he has agreed to allow us to change topics from Cardio to Integumentary. To finalise the change all members have to personally email him saying we all agree to the topic change. Carl and I have started thinking about our approach to the topic and we think we should have a main focus on skin and smaller sub-topics on hair, nails, glands and teeth. Each members role just remains the same and any problems we will all still help eachother :)

==Week 9==
--[[User:Z3417796|Z3417796]] ([[User talk:Z3417796|talk]]) 12:46, 22 September 2014 (EST)Hey guys, I've added some headings for our new page just to get a start, we've got alot to catch up on, I guess we still have to talk about it as a group for the overall layout, we should all start adding some content soon.

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 12:41, 23 September 2014 (EST) Thank you for fixing it! Yeah, we have a lot to do but that's okay. Midsem break is next week and hopefully we can get most of the bulk done before week 10.

==Midsem Break==
--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 23:24, 29 September 2014 (EST) Just wanted to let you guys know that Dr. Hill gave us some tips on what to look at a few weeks back. He mentioned "vernix caseosa and fetal hair." Here's a wikipedia link to vernix caseosa (http://en.wikipedia.org/wiki/Vernix_caseosa) just to give you guys an idea on what it is. I'm aiming to finish before the end of the week so that I could help anyone with their parts. Anyway, I hope everyone's having a good break!

Talk:2014 Group Project 5

2014-10-14T13:01:16Z

Z3416697: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==

Group Project 5 – Integumentary Development

This page looks very neat and well organised, with an introduction that explains exactly what is going to appear and be discussed on the page. The Development Overview section is very well done, with the appropriate use of subheadings and content. The use of dot points is very effective, making the page look neater. Perhaps it would be good to draw a histological diagram of the skin layers, and uploading it to the skin development section. Specialised cells or important names throughout the page could be highlighted in bold or underlined as well, to highlight important terms and make it easier to learn and remember from. The title ‘Some Recent Findings’ accurately portrays what we as students can only do, which is identify SOME of the recent findings. This section could have more than 2 recent findings however and could be further subdivided by subheadings into the different components of the integumentary system – perhaps have 2-3 research articles for each component of the system. Historic findings are well researched but some more information would be good. The ‘Abnormalities’ section is so far the best looking section as it seems it is almost completed. Perhaps a few more abnormalities would be even better.

The table of the timeline in the ‘Development Overview’ section is superbly done and the use of histological images is fantastic as it provides the anatomical information visually. When I clicked on an image however, there was no proper referencing of the image and the copyright information and student image information was not present. The images are described very well.
One image has a problem and is present in red writing, so might need to remove this as something is wrong with the file and it could not be uploaded. There are no student-drawn images and I think if this group did this, it would really benefit their project and emphasise their understanding.

The ‘Some Recent Findings’ section has a purple background, which makes the page look more aesthetically pleasing and less monochrome. I like the ‘More recent papers’ box that can be expanded to reveal any more research papers related to the integumentary fetal development, in case anyone wants to have a further read- very clever.

Journal articles are correctly referenced but website references need to be improved upon- to find how to do this go to the ‘How to reference’ page. References are all over the place and need to be compiled under each heading or one main heading titled ‘References’ at the bottom of the page.

Overall, this page is looking fantastic at this point in time so keep up the great work!

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Introduction is short though luckily few words can go a long way, with all sections of the wiki page being properly addressed. Development overview content is good; the use of table integrated with pictures allows viewers to visually grasp the progression in skin and teeth development. The changing between dot-points and paragraph format should be standardized or use paragraphs with dot-point only for list based information. References need to be properly integrated into the page, instead of at the bottom of each section.

In the recent findings section 2 out of the 4 studies presented have any content. To improve cutting some of excess information for the 2 studies already addressed and creating summaries for the other 2 will create better scope of recent findings. The formatting of recent findings is unusual, proper placement of the “Hematoxylin/eosin” image”, removal of dot-point and removal of purple highlighting, will make the section easier for viewers to understand. Historical findings okay, more detail could be added to “skin”, “glands”, “nails”. Use of capital letters like “DEVELOPMENT” show be replaced with subheadings, the image “File:Screen Shot 2014-10-08 at 10.38.04 am.png” has not appeared properly, should be easy to fix.

Straight up the abnormalities section is amazing, no improvement needed. All 4 diseases have in-depth relevant information, sufficient referencing and images to allow viewers to visualise clinical manifestation. To improve use of dot-points or paragraphs should be standard throughout the project, referencing in beginning sections needs to compiled at ending of each Main heading or bottom of page, recent findings need 1-2 more studies, and recent findings need significant reformatting.

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Overall I was very impressed with this project page. I loved your use of pictures and diagrams as it provided a great understanding of what was happening- and also, a lot of the images were quite interesting- which is a great thing for a project! I also enjoyed the use of bullet points- it was very to the point and it retained my attention throughout the piece. I did find, however, that the introduction was a bit short. Whilst it did cover most of what was required, I don’t think it hurts to be a bit more exhaustive in what you’re saying, because the introduction sets the mindset of the reader for the rest of the project- and if they have a clear understanding from the start, it makes it much easier when you are explaining more complex things such as the abnormalities later on.

Overall, I thought that the developmental timeline was extremely well done, and a highlight of your project. The rest of the developmental overview was quite well done, however I think in areas it was a bit sloppy, and it would be of great benefit to clear this up so as to improve the clarity of your work. Further, I enjoyed the succinctness of your paragraphs, it made it easy to read and wasn’t too much to take in at once.

I think that currently, your use of colour is a bit random in the recent findings. I think that this could really boost your project if you applied it to more areas of the page. As far as the content goes, I think that the recent findings is just too wordy and I began to lose my concentration a bit. I think maybe by forming more succinct dot points- you will be able to convey your message more clearly.

I think the historic findings could do with a bit more beefing up, but what you have so far is well done. The abnormalities is also very well done, and I think that your use of images really grab the readers attention.

I think that overall this project is shaping up to be a great one. I think you need to be careful and consistent with your referencing though as I noticed some sections lacked in-text citations.

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This page seems to be done extremely well. It looks very visually appealing as multiple images are used, information is presented in tables, bullet points and very few slabs of text. The introduction is short and to the point. You could possibly add to this area a tiny bit of info concerning the embryonic development of this system, where it first started, then mention how you will expand on the fetal development. Otherwise it just seems way too short.

Explanation of the organs in this system is well done and concise. In the glands section, I would suggest not using dot points for the function of the vernix caseosa as it looks as though the dot points continue from those of the glands, therefore can be confusing when first looked at. Other than that, I would suggest that you make sure your referencing is correct and is used within the text.

The recent findings area is nicely done, but I still can’t help but feel the amount of text is just too much, even though the section is made better looking by making it purple (keep the colour, it looks awesome). The slab of text is just too much, so you should try and simplify it a bit. Historic findings are few but there is at least one for every organ which is good (more would be better). The abnormalities covered are done well, going into detail and providing a good image to describe what it looks like. I would suggest having at least 5 abnormalities, one for each organ discussed.

Overall, this page is very well done, with lots of images and colour used. The main thing I would suggest would be to make sure correct referencing is used. There were some paragraphs were no references were used at all. Also, all references should be at the bottom of the page, not within individual sections.

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This page has great overall structure and presentation. The introduction gives good insight of the overall contents of the page, however it is very brief and should be expanded upon.

The table included in the developmental overview serving, as a timeline is excellent, really well done. It’s easy to follow and looks very neat. I like how there is an image for each of the weeks mentioned, just don’t forget to add in-text citations for its contents. The glands sub-section is very brief and would benefit if there were more contents added. Great job on the images though. The nail section is the same, more contents needs to be added and image would look really good.

The developmental overview and historic findings sections also seems to lack in-text citations. There is also has an image with a broken link. The subsection hair seems to be well researched, however I would also suggest either bolding or underlining the words you want to emphasize such as “structure” for a neater look.

The recent findings section looks superb I love the purple background colour. Its very well researched and the link to more research papers are very helpful for readers. I would suggest you put the image at the bottom of the mentioned content though, just to avoid the big gap on the page, or even if you can manage to wrap the text around the image, it would look much better in terms of presentation.

Although disturbing, the abnormalities section I could not fault. Very well done. It is evident that it has been research well and the images allow for great visualization of the diseases mentioned.

Overall, excellent page just needs a very formatting edits and some expanded contents mentioned above. Good luck!

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This is a really well done project. You have made sure that that you have ticked all the boxes as well that Mark has asked for. The abnormalities section is really good. You have done well with most of your images as when you click on them there is a good description and they are well referenced. The development overview table is exceptional and makes the project easy to understand. For the week 22 maybe include the study in which you got your information from.

Apart from the abnormalities section it appears as though the referencing is a bit all over the place. Need to follow the abnormalities section and put references into the specific parts of the information you are using it for. Because otherwise it becomes difficult to know exactly where you got your information from. The historic findings are really good and well done however there is probably a space for more information to be included as I feel as though some of the findings are a bit hard to follow at times. It may have just been my computer I couldn’t see the picture of ‘fetal hair development’.

I think it would give a nice touch to the project if you were to add some student images because it would give the page a more ‘student’ and also make it easier to understand. Don’t mind the purple background on the ‘some recent findings’ part but it just looks a bit out of the blue. It’s certainly unique and attracts the eye but it puts a lot of emphasis on this section which I’m not entirely sure you want.

Overall though a really good project with excellent information. There needs to be a bit more focus on referencing technique, some minor edits which I have mentioned and maybe introduce some student pictures to make the project more student-like. Great work though and good luck in finishing it off.

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

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

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

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

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Overall this is an impressive and well researched wiki page incorporating lots of pictures and tables to keep the reader engaged and interested. However there are a few areas that have the potential to be tweaked. Firstly there are references scattered throughout the page. A more attractive way of presenting the references is as a long list at the end of the page. The introduction is clear, concise and short. All the organ development section is well presented and has the right amount of information. It is well structured in the sense that the student introduces the organ, it’s embryonic origin, the fetal growth stage and then goes into slightly more depth in a bullet point form. Along with complementary pictures, this is a very effective way of presenting their topic. This page could be improved by adding student-drawn schematic diagrams to summarise the layers of the skin in particular since histological images can be confusing and unclear to a non-expert embryology student.

The skin development section appears to dwell on the content that was covered in lectures. Considering there appears to be only three references associated with the entire integumentary organ development section, the depth of the information is limited. By doing some more research you might be able to find interesting additional information that can be added. The recent findings section is interesting and the images are great. However the dense block of information and slightly odd formatting make it hard to follow. Perhaps using diagrams to explain the differing gene expression and breaking down the information into bullet points would make it more readable.

The historic findings and abnormalities section is particularly well done. The images complement the minimal yet important points made. I was left wanting to read more into it so that suggests there’s room for further development and a deeper explanation of skin abnormalities.

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*Great overview given in the introduction. Maybe look to replacing the words "this page" to something else to avoid repetition
*I'm really liking how everything has been simplified into dot points and tables where relevant. Don't forget to include relevant references all throughout though, to justify all that you've included in each section
*I can't express how much I love your first table. Great work!
*Proofread so that you don't repeat the same things in your table though. You mention "in a study" numerous times but there's no indication to which studies they are
*I'm sure Mark would be thinking this same thing, but look to getting different references outside of this Embryology website, maybe from textbooks or otherwise for preliminary information on development
*The "recent findings" section looks nicely formatted but just a bit wordy. Maybe think of dividing the text up with bullet points or images
*Really liking your "historic findings" section! Great research
*Maybe think of re-creating some of the simpler pictures by drawing them yourselves. That way you're not using too many pictures from this Embryology website, Mark warned our group about this point
*Great choices for the "abnormalities" section. Traumatising at first, but very well-researched and presented

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==Week 5==
Hey guys!! I found some research material that we can use to construct our time line!

Historic information is hard to find! I might go look at some text books in the library
--[[User:Z3418340|Z3418340]] ([[User talk:Z3418340|talk]]) 12:50, 27 August 2014 (EST)
How is everyone else going?

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 12:52, 27 August 2014 (EST) Hey!! That's great! I also found some material for abnormalities. There seem to be a lot about septal defects. I'm gonna try to look up for more defects.

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 22:53, 30 August 2014 (EST)Woo!! Nice to see more links in the page! Rehmina and I also thought that it would be easier for marking if one of the two people in current research do timeline instead because that would make marking easier and less confusing. But that's not final, it's only a suggestion. Also, Dr. Hill gave us some tips on what to focus/include in our research such as:
*Remodelling during the fetal period
*Changes during ossification - haematopoietic elocution from liver to bone marrow
*Early development of WBCs — hot topic right now!!

Hey everyone, yeah that sounds good with me.. :) so rather each person focuses on 1 of the 4 topics right? --[[User:Z3417796|Z3417796]] ([[User talk:Z3417796|talk]]) 12:35, 31 August 2014 (EST)

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 18:36, 1 September 2014 (EST)Yep, exactly! I'm really glad that's alright with you but we can still talk about more in the lab.

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 12:14, 2 September 2014 (EST)Hey everyone! I just asked Dr. Hill about using review articles. He said it's alright to use review articles as long as you say that the information came from a review article when citing. We can also use images from review articles and there is no need to say that it came from a review article.

==Week 6==
--[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 20:19, 3 September 2014 (EST)Hey guys, I had a good talk with Mark today after the lab. Since we're doing the Cardiovascular system, it incorporates the (i) development of the heart, (ii) development of the blood vessels and (iii) the formation of red blood cells/white blood cells. But Mark said that as a group, we would be able to create and produce this web-site in a manner that we thought was appropriate. We could focus on one of the specific areas or more broadly on each area, if we chose to. But, MOST IMPORTANTLY, our project should be cohesive. What we talk about should be introduced well at the start and should be cohesive through out all of the subsections that we're working on. He really stressed the importance of us having a single, unified vision of our end product and that it should be succinct throughout it all. Im proposing that we actually decide what to focus on very soon.

: --[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 20:19, 3 September 2014 (EST) I'd particularly like to just focus on the development of the heart? Maybe incorporate the formation of blood cells if the research in the other areas is interesting and notable?

--[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 20:24, 3 September 2014 (EST)In regards to the use of the textbook, we are allowed to use the information from it if we cite it properly, but he really want us to be using articles (and even Review articles) to discuss our information.

I agree, the heart should remain our focus, but of course other aspects such as blood vessel formation/ blood cells would naturally fall into it as well- maybe just a brief mention wherever appropriate? --[[User:Z3417796|Z3417796]] ([[User talk:Z3417796|talk]]) 21:22, 3 September 2014 (EST)

==Week 7==
--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 21:05, 8 September 2014 (EST) Hmm. I agree. Let's try and focus on the heart for now and see how we go? And if time permits, maybe we will be able to include the development of blood vessels and blood cells. Sorry I didn't reply so soon, kinda busy week for me haha!
: --[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 00:24, 10 September 2014 (EST)Ok that sounds really good and reasonable! I'd be happy to follow that plan. And yeah, same! Very busy week for me as well! But yeah, I think lets just focus and refine our research to just the development of the heart at the moment

--[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 00:40, 10 September 2014 (EST)Hey guys, Im having difficulty knowing whether the use of an article is fine or not?! If it says "Full-free-text" does that mean we're allowed to incoporate it? Because a lot of the copyright information, is very brief. Thanks heaps, if you guys know an answer haha
: --[[User:Z3418488|Z3418488]] ([[User talk:Z3418488|talk]]) 00:55, 10 September 2014 (EST)Ok, never mind.. I find out the answer haha. If it says "Open-Access" or "Full-free-text" it is only free to read online and may/may not be allowed for re-use. You'; have to read carefully or apply for permission lol. I guess i'll just be sticking to mainly the Public Library of Science (PLoS), Biomed central (BMC) and Springer Open... which we are pretty much able to use, with the right referencing and acknowledgement. I read this on the 'Copy rights' page on this wiki. http://php.med.unsw.edu.au/embryology/index.php?title=Help:Copyright_Tutorial. Can someone verify or correct me if i'm wrong haha?

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 11:56, 10 September 2014 (EST) I thought copyright only applied on images and not on content. It would be really difficult to write a report when the most papers have copyright. We can ask Dr. Hill in the lab just to confirm.

==Week 8==
--[[User:Z3417796|Z3417796]] ([[User talk:Z3417796|talk]]) 12:56, 17 September 2014 (EST) Hey guys, so Carl and I had a talk with Dr. Hill and he has agreed to allow us to change topics from Cardio to Integumentary. To finalise the change all members have to personally email him saying we all agree to the topic change. Carl and I have started thinking about our approach to the topic and we think we should have a main focus on skin and smaller sub-topics on hair, nails, glands and teeth. Each members role just remains the same and any problems we will all still help eachother :)

==Week 9==
--[[User:Z3417796|Z3417796]] ([[User talk:Z3417796|talk]]) 12:46, 22 September 2014 (EST)Hey guys, I've added some headings for our new page just to get a start, we've got alot to catch up on, I guess we still have to talk about it as a group for the overall layout, we should all start adding some content soon.

--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 12:41, 23 September 2014 (EST) Thank you for fixing it! Yeah, we have a lot to do but that's okay. Midsem break is next week and hopefully we can get most of the bulk done before week 10.

==Midsem Break==
--[[User:Z3417843|Z3417843]] ([[User talk:Z3417843|talk]]) 23:24, 29 September 2014 (EST) Just wanted to let you guys know that Dr. Hill gave us some tips on what to look at a few weeks back. He mentioned "vernix caseosa and fetal hair." Here's a wikipedia link to vernix caseosa (http://en.wikipedia.org/wiki/Vernix_caseosa) just to give you guys an idea on what it is. I'm aiming to finish before the end of the week so that I could help anyone with their parts. Anyway, I hope everyone's having a good break!

Talk:2014 Group Project 2

2014-10-14T12:44:16Z

Z3416697: /* Peer Reviews */

{{Template:ANAT2341Project2014discussionheader}}
==Peer Reviews==

The introduction provides a very informative description of the functions of the kidney and bladder. Perhaps it would be good to give some more details of the embryonic development just to quickly summarise what has been happening with the fetus up until this point. Also, maybe the introduction should introduce what the page’s content is going to cover. The order of historic findings and then developmental timeline is appropriate as historic findings can be used to compile the timeline. It would also be useful to have the timeline in a table format to make the page look neater and more simplified. Also, there is no research done on ‘historic findings’ so need to address that before final submission.

‘Current research models’ section is good but brief and requires more extensive research as only two articles are cited. There should be information on current models used to study renal development as well as current research and findings. The image in this section is well presented, with appropriate titling, referencing, image descriptions and copyright information with the student image template.
Sections 1.5-1.8 should be smaller sub headings under the larger heading ‘System Development’ and perhaps should go at the top of the page, beneath the introduction seeing as in order to understand research and historic findings, it is necessary to understand renal development first.

It is very good that there is a small section on early development, however maybe it would be better to have it more briefly explained, perhaps in the form of a student drawn diagram or presented as a table. There also is a problem with the image uploaded in the early development section, so should fix that before final submission. The ‘abnormalities’ section is also done well however more conditions should be listed and described with pictures for each one. There are also only abnormalities of the kidneys listed, so maybe it would be better to have more of the other components of the renal system as well (bladder, ureter, urethra).

Also, maybe more information regarding the anatomy of the kidneys and renal system should be added, as this is an anatomy course. Some images are also missing the student image template.
Most images are uploaded correctly with the right information, maybe more would make the page look more aesthetically pleasing as well as assist learning.

Referencing is done correctly with a numbering system and in-text citations are also correct. The in-text referencing in the ‘anatomical position’ sub section of ‘fetal development’ of the ‘Kidney’ section is not referenced appropriately so just fix that minor problem.

Overall, this is great work and should just include more information in certain sections and upload more images, preferably some student drawn images as well. Well done!

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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 footnotes 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.

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I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

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Really good introduction! It clearly outlines what is in the page. Most key points were done really well except for historic findings. There is a section on the Wikipage that has old books on embryology. It’s under the “Explore” tab and you’ll see “Historic embryo”. The developmental timeline would’ve been better if it was in a table, has an image showing the major steps in development, and is within the development section of the page. Regarding the development section, very detailed and informative. It clearly outlines the development of the renal system in the fetal stage. Dividing this section into the different organs is a very smart decision. It makes it a lot less confusing to the reader. Maybe try to breakdown some of the information and use dot points. There are lots of images to give the readers a visual of the developmental process. Also, the images have captions, which is great.

Great job on the current research section. The articles chosen for current research is highly relevant to the topic and to the project. This section is written concisely and very detailed. The image really helps to understand the findings of the research. The same can be said to the abnormalities section. Each disease was written concisely and is very informative. The images really help in terms of understanding the clinical manifestation/s of each disease. Try to find information on current treatments and/or management techniques for each disease.

Looking at the images included, all of them seems to be properly uploaded except for the “Kidney ascent.jpg”. It is missing its copyright information. From what I know, images from textbooks normally can’t be used because of copyright. Other than that, all the images are relevant and function as an aid to understanding what each section is about. In regards of citation and references, everything looks good. Each section was well-researched and properly cited. Great job on organising most of your references at the bottom of the page. The page looks very clean. In summary, focus on getting the historic findings section done and just minor fixes on images. Well done!

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In this review I will attempt to highlight the strengths of your project and identify some areas for improvement, in light of the criteria provided.

I believe the developmental timeline is a great way to summarise the major events at each stage in fetal development and serves as a simple introduction to the project. However I think it would be best if you presented this information in a tabulated format, and include a little more detail. For instance “Week 8 – Mature kidney is formed” could also mention some structures features seen at this stage, hallmarks that allows us to recognise a mature kidney.

I think the current research section delves into a number in interesting areas, mentioning studies on the treatment of congenital renal abnormalities. However, I think that there needs to be additional discussion on the molecular signalling that drives the underlying process of renal development in the fetus.

The abnormalities associated with renal development in the feral period have been well researched and the information provided is well structured. However this section seems incomplete. I see a number of additional links to interesting scholarly articles. I think you should discuss some more abnormalities at the stages of early and late fetal development. I also suggest including images to supper the text.

There is has been little information added on the historic findings. I suggest looking at text books in the library or searching the UNSW database to find information for this vital section.

I really like how you have selected labeled diagrams to compliment and break up the text. Each image is relevant to the topic being discussed and the small description attached really help the reader orient them selves. Overall this project is coming along nicely. Just ensure that you are making progress on all the sections. Also only include relevant references. Finally proof read and review your work before the final submission.

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This is an excellent introduction and gives a great expectation for the information to come later in the project. The current research models section needs to be checked for spelling and grammar. The information here is good but is also very dense and hard to follow. It would be great if you could break it up a bit with bullet points or more images or tables. This style of writing is very professional and would be perfect for a report or essay, however as a wiki page it is too hard to follow. Breaking up the information into bullet point and tables would allow you to guide the reader through a journey of renal system development.

There has clearly been a lot of research and work put into this project and that is very commendable. However on a whole, there is too much information. It’s difficult to read and grasp a wholesome understanding of the renal system when it delves too deep too quickly. One suggestion is giving a more brief explanation of the timeline of nephrogenesis, urethra, ureter and bladder development and then go into more detail in a subheading called “current research findings”. The references under the abnormalities heading should be incorporated at the very end.

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The introduction delivers a conventional scope of the renal system, allowing the audience to understand the structure and function to the parts of this system. Maybe consider uploading a picture that would illustrate the overall information in the introduction.

The developmental timeline is a great idea that outlines the significant events and in turn helps put major events into perspective, making it more effective for students to study and understand. However maybe consider presenting this information in the table format or see if you can get a vertical/horizontal line to represent the timeline. I feel that there is not enough information in the 'Historic findings' and perhaps you could do some more research.

The "Current research" section is very detailed and shows a great amount of research of recent articles that are relevant. The images included in the current research and the abnormalities section is great as it makes reference to the topic spoken about, giving the student a further understanding of the topic. The images are referenced properly except for “Kidney ascent.jpg”, it's missing a reference.

Overall this page is coming along nicely however you need to work on your development timeline formatting it in order to present a systematic presentation as a means to make it more friendly.

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This so far is a really good. You have all obviously done your research as well as you have got a lot of references throughout your page which again is great. The introduction is well done, clear and concise which is good. Maybe think about adding an image to make it a bit more appealing. You will obviously need to add some historic findings, but I’m sure your aware of that. The developmental timeline I think could be improved if you were to tabulate it as other projects have done that and it looks really good and more professional. The referencing is well done as it looks good having all the references down the bottom of the page. There are some references over the page which have just been listed so it may be a good idea to change this so that they are all down the bottom.

You have made a good start on the current research models. Note the buy in the line ‘One recent research paper buy Al-Odat et al.’ should be by. I don’t think you should actually reference the paper in your writing either. You should reference it but do so by using a footnote rather than actually saying the names of the people. The development of the kidney image has not worked so look at the formatting of that image.

On the bigger picture of this project something that I have noticed is that the balance of writing to images is heavily towards the information writing side. So I think it would be good if you were able to tip this balance with a few more pictures as it would make the page more appealing. I think in doing so you could add some student images as this will make the page more interesting, Also spacing your information out as at times when you look at a whole chink of writing you don’t feel like reading it, so I think spacing it out more will help.

Overall though it is a well done project. A few things such as the references that have been just listed on the page that need to go down the bottom, inclusion of some more student images, and tipping the balance of your page more in favor of images would go a long way in making your project even better. But you have done a good job so far and best of luck with the rest of it.

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At the first scroll of this page it already seemed completely sufficiently. The structural layout is done really well and it’s good to see that it’s done according to the advised sub headings. The introduction is really well done, provides a great explanation into renal development, an abundant overview of the whole page and topics that will be addressed. The info for ‘historic findings’ seems to be lacking content, might be useful to search under the “Explore” tab on the left had side of the embryo page, clicking on the sub heading ‘historic embryo’. Also a useful source is the unsw library as it spans a longer period of time and following the unsw search then research the article in the pubmed site. Might be nice to format a proper timeline or use a table. The ‘current research models’ section is done really well with an abundant amount of detail in each study presented and good use of images. The use of a descriptive caption under each image is done proficiently, it is nice to see that each section has incorporated some form of visual whether histological or from research studies. The ‘kidney’ section is structured really well, the use of the content under early development is unnecessarily but is useful in introducing the stage prior to fetal development. Under the’ anatomical position’ sub heading the in text citations need to be adjusted. For references that are not pubmed use this format; <ref> insert source </ref>. Also the image provided will most likely need to be deleted and then drawn, as we are not allowed to use images directly from textbooks. Just re draw the image if you can and then upload it as you would with any other image. Another suggestion for each of the corresponding organs in renal development, try to format some of the content into dot points or tables so not all lengthy paragraphs. Also noticed one of the images doesn’t have a caption this being under the urethra section. Very well detailed info on the abnormalities, would suggest to add a few more to be completely sufficient.

Lastly, the page has been completed to a high standard in the completion of all the info provided and subsequent images among each section. A few things have been noted, and there are only a few minor modifications that will need to be made these includes; referencing and some formatting as mentioned previously. The use of in text citations throughout the whole page is done efficiently, try to just try keep your references under one main heading. There is great effort noted in the research accumulated so far through the long list of references used to gather the info. Fantastic work everyone, keep up the great work !

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

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

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

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

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

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

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The introduction is good and describes the project well. It is good to mention the function of renal system. It would be better if it states that the website will be focused on fetal development, current research and abnormalities to give a better understanding of the content.

Information under historic findings is missing, it would be a good way to start it by looking at textbooks. Images, bullet points and table can be used for an easy understanding of this section.

Using timeline to summarise the development of kidney is a good idea, however it would be clearer if a table is used, more descriptions under each stages and some images are include. Also, some references should be included in this section.

There are a lot of details under development, current research and abnormalities. It would be easier to read if they are written in point form. It is a good idea to divide renal system into several parts (kidney, urethra…) for the explanation of development. For the abnormalities, it is well-researched but some of the details are missing. It would be better if the each type of abnormalities is discussed equally.

Regarding the images, it is good and clear to explain each of them. The only problem is that there is no copyright information under the file “kidney ascent.jpg”.

The project is informative but lacking some information under historic findings and the developmental timeline.

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The introduction of Group 2 is very succinct and straight to the point. I believe it could be improved with clear subheadings- such as ‘Bladder’ or ‘Nephrons’ (only a suggestion though!). I believe the group could add what they’re page hopes to achieve (outcomes).

The timeline/develop section of this project could be improved with a better. Add the table before or after the findings of the research paper. I believe with the table, that it could be better described and more information added to it. There is a good choice of headings though, as it has been clearly classified into distinct time points. The scientific research that accompanies this section also has a very good choice of headings/sub-headings. I do believe that this section could, however, be summarised and added to the table format above. There is excellent referencing and strong evidence of significant scientific research.
I believe more recent and varying studies in the “recent research and findings’ section could be included. I also believe this section could be improved with a better layout- with clear, concise headings identifying what these studies found and when.
The historic findings section needs to be addressed/included!

The Abnormalities section is excellent. It is informative, with a good choice of abnormalities and appropriate headings/sub-headings. It has a good choice of images and is correctly referenced.

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[[RENAL SYSTEM]]

Introduction
Background
Timeline of development - everyone will research first to get general idea of when,what and how long it will develop. Divide this area up from there.
Development of Actual system - all organs and parts that contribute to it (will be divided up later)
Abnormalities

ACTUAL RESEARCH FIRST, THEN DIVIDE. SEE HOW MUCH INFO AND PARTS THERE IS FIRST

==ANNOUNCEMENTS==
http://www.ehd.org/science_main.php?level=a&submit3.x=73&submit3.y=21&s18=on&ops=&re=on&L1=1&L2=0 have a look at this web site, good time line --[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 10:50, 26 August 2014 (EST)

Looks good. There wont be much we can say for all the individual events that occur since all of it is up to the 8th week, but it'll give us a good starting point. We can say 'such and such has been formed during the embryo period' and we can move on from there. I also found the following site which gives a nice intro into the components of the renal system and some general info on each part. Thought we might be able to incorporate a bit of it, talk about what the system/organ does, then follow on how it develops. Use it as a bit of a guide to how we could do our own. http://www.myvmc.com/anatomy/urinary-system-renal-system/ --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 13:48, 24 August 2014 (EST)

https://docs.google.com/viewer?url=http%3A%2F%2Fpediatrics.med.unc.edu%2Feducation%2Fcurrent-residents%2Frotation-information%2Fnephrology%2Ffiles-1%2FNephrogenesis.ppt this web site goes into quite a lot of detail regarding how the renal system develops.

I think in terms of dividing the work:
*1- urine formation (week 11~12) & amniotic sac
*2- kidneys descending from where they developed to adult anatomical positions (week 9)
*3- development of trigone of the bladder and allantois
*4- structures that arise from the Metanephric mesoderm
*5- structures that arise from the Ureteric bud
*6- abnormalities (developmental and genetic)
*7- introduction
*8- timeline of events in development

I've thought of 8 topics we can divide the work into, so lets choose 2 each?
I preferably want to do abnormalities and urine formation (number 1 and 6), is that ok? we need this sorted out for our lab homework thing for this week. please reply asap. --[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 10:50, 26 August 2014 (EST)

On the actual project page when you expand the bit at the top there are 5 bullet point but the first one is just to come up with our title, shall we divide our project into those 4 different headings?:
Review that system development during the fetal period.
Identify current research models and finding.
Identify historic findings.
Identify abnormalities that can occur in this system during the fetal period

Hey guys, i have now gone and updated the page and added sub-headings as suggested by above, please feel free to add or delete anything you seem unfit for the page. As for the online assessment due tomorrow, i agree that 2 each is appropriate although the timeline will be very long and would be unfair if one person to do the whole thing... We should probably divide the timetable based on weeks and then assign who wants to do what. Although i thought we agreed that i would do the abnormalities as discussed in the last lab...? i have already started to do some research on the topic....

Here is a basic summary of some of the development structures in the renal system, as well as their abnormalities
https://web.duke.edu/anatomy/embryology/urogenital/urogenital.html

--[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 16:52, 26 August 2014 (EST)

Ill look at 4 and 5 if that is alright with everyone (structures that arise from the Metanephric mesoderm
and the Ureteric bud), I think we need to also write a bit about Historic findings and current research models
--[[User:Z5030311|Z5030311]] ([[User talk:Z5030311|talk]]) 17:24, 26 August 2014 (EST)

I can do the descending of the kidneys and the development of the bladder (2 and 3) if everyone is fine with that --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 18:39, 26 August 2014 (EST)

Uh I guess that leaves 1 & 8 then, since no one wants to do the timeline xD
It doesnt look too hard so i dont mind doing timeline :)
so whoever only took 1 topic, can you please do the intro as well please?
Also im not 100% on the topics, but it'll have to do for now. add as we go i guess.
--[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 20:26, 26 August 2014 (EST)

yeah no worries, there will most likely be changes to the topics, or at least the headings. It's only set out the way it is now just so we can have a general layout, have some idea what to research. I also dont think we'll end up sticking to the subheading we chose, as there is a lot of stuff that will cross over to other topics.
I think we said that the timeline would be one of the last things we would do yeah? cause after we research all the organs and stuff as it develops, it would be easier to determine when it all develops as well, so we could just stick all that info together at the end. --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 21:04, 26 August 2014 (EST)

--[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 12:53, 27 August 2014 (EST)
*kidney(nephrogenesis0 - Sam
*ureter - Bahar
*urethra & fetal urination - Emily
*bladder - Rachel

*intro - Emily
*historic findings - Emily
*abnormalities - Bahar
*current models - Rachel

*developmental timeline (everyone)

HOW IS EVERYONE GOING WITH THEIR PART????
www.lab.anhb.uwa.edu.au/hsd212/.../KidneyDevelopmentPrint.ppt
--> this powerpoint gives a good general intro to renal development btw if anyone wants to see?

GIRLS
are we going to keep the whole assignment as apa referencing or as harvard? --[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 01:36, 22 September 2014 (EST)

umm i guess APA since thats the actual formal type of referencing. or you can just try and structure it the way its auto generated when you type in pubmed links haha. im gonna try and put some more content up about the kidneys in a couple days and a drawing or two. ill get some historic findings done as well.--[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 21:16, 23 September 2014 (EST)

hey guys, sorry i havent been putting anything up recently. i moved in to my new place over the weekend but the internet isnt up yet so i havent been able to upload anything. i dont know how much longer until its up, so ill be coming to uni just to use the internet (its where i am now lol). so when did the majority of our content have to be up by? was it friday or sunday? i cant remember. --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 12:48, 1 October 2014 (EST)

i found this really good article. it mainly focuses on the kidneys but there are a couple of lines here and there where it mentions some facts about the rest of the renal system. thought u guys might wanna take a look. i dont know whether full access to the article is normal or whether i only managed it because im using the uni library internet, but if u cant access it just let me know and ill send u the article (i downloaded it haha). --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 14:15, 1 October 2014 (EST)
oh i also just found this book, it has A LOT of info about the embryology of the renal system, though half the chapters seem to be focused towards abnormalities and defects of the organs http://books.google.com.au/books?id=IKexq6xCRmIC&pg=PA542&lpg=PA542&dq=rotation+of+fetal+kidney&source=bl&ots=0O-4VfybHS&sig=3VeDlTrB9HnJsdYQLP66IKNGPDU&hl=en&sa=X&ei=1ocrVPuiIoKUoQSyroEQ&ved=0CCoQ6AEwBA#v=onepage&q=rotation%20of%20fetal%20kidney&f=false --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 15:10, 1 October 2014 (EST)

Hey Girls hows the "break" going? :) i was wondering how many abnormalities we should have? 3/4? Also, is it just me or can we not access some of the journals that are free on Pubmed for e.g.
http://www.ncbi.nlm.nih.gov/pubmed/11458035 ?? --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 19:20, 1 October 2014 (EST)

Sorry this is way too late but I think 3/4 abnormalities sound good and for references I have just been doing the automated way of the references --[[User:Z5030311|Z5030311]] ([[User talk:Z5030311|talk]]) 23:07, 7 October 2014 (EST)

Also at the moment I have done 2 research models, do you think that is enough or shall I do another one? --[[User:Z5030311|Z5030311]] ([[User talk:Z5030311|talk]]) 00:01, 8 October 2014 (EST)

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*Great introduction! Your entire page's contents was introduced well and simple. I'm just wondering if you'd have to include more references to further justify some of the aspects you've mentioned in your explanation of the renal system development
*I noticed the historic findings have been left untouched. This section is in my opinion the trickiest because of the difficulty in finding information out there. My suggestions are to go onto pubmed and use key words like "Renal system development: a historical perspective" and then work from there. You can also adjust years to look at earlier papers from the 1920s and onwards. Also use Mark's historical textbooks on this website as a starting point, it's helpful too to see how ideas in fetal development have changed over the years
*I like how the timeline overview has been simplified. Maybe think of tabulating the findings? You can get the template for doing that off any other group project that has tables by copy and pasting, then just editing in what you need
*I wouldn't add that first like under "Current research models" but if you wanted to do that, maybe think of rewording it. An example could be: "Animal models are ideal to work with when researching renal system development due to their short gestation periods, making the identification of mutations much quicker." Although what you've said about ethics is technically true, the ethics of working with animal models are still lengthy considerations and the fact that our pages are accessed to the public, maybe something like ethics don't need to be mentioned
*Include the years of when the current research findings were discovered. Otherwise, good work on this section. Just proofread over it to fix minor errors
*Great images used throughout
*Maybe think of having some sections more concise rather than wordy by including dot points

Talk:2014 Group Project 1

2014-10-14T12:29:05Z

Z3416697: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==

The introduction is very informative and I particularly like how it describes the embryonic development of the respiratory system as well, since in order to understand what is happening in the fetal period, it is important to first understand what happened before that in the embryonic period. Perhaps the introduction could also introduce what information the page is going to contain.

The timeline is well presented in a table form, however maybe it would be better suited to be in the introduction section. The table could also incorporate the use of histological images to illustrate the differences between the time periods. Also, the sub sections titled ‘current models’ and ‘current research and findings’ could be part of a larger section and not fall under the ‘Lung Development Stages’ section.

There is no information as yet under ‘Current models’ however extensive research seems to be conducted on ‘current research findings’. Perhaps it would be better to include more journal articles in this section. The use of dot points and numbering systems is also very effective in allowing the information to be easily read and flow. More articles also need to be covered in the ‘Historic findings section’ as it is very brief at the moment with only a few sentences on each article.

The ‘abnormalities’ section is very well done with an abundance of conditions however more images should be uploaded for each abnormality in order to see what it visually presents as in the fetus and also to make the page look nicer.

The images uploaded onto the page contain adequate information explaining them, copyright information as well as the student image template, which is good. There is one student drawn image, which is also great, but maybe some more would further illustrate the group’s understanding of their topic.

The referencing is done correctly mostly throughout the page but is scattered throughout every section so perhaps it would be better to have them in one section at the bottom of the page under the heading entitled ‘References’ and numbered as they appear in the text. In-text citations are throughout and appear to be done correctly.

Overall, this is a very good effort and a bit of editing will make the page look much more neater and organized. Keep up the great work!

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This project is extremely well done. I found the overall layout of your work to be easy to read and succinct. It captured my attention throughout the entirety of the project and was engaging with the use of bullet points. I thought your use of diagrams was great in aiding the understanding of this topic, however I thought that more diagrams or pictures could be added in order to help the reader visualize exactly what’s going on. I thought that te developmental timeline was a great idea, however could benefit from some more images or diagrams to assist in understanding the developmental stages. I thought the historic findings sections was especially well done as it appears well researched and thoroughly informative. The abnormalities was also well done, however again could benefit from the addition of a few more diagrams.

I think that with the addition of more drawings needs to be some attention to detail when referencing and stating copyright. I’ve noticed that some pictures lack copyright and some don’t have a description, making it difficult to understand the context of the picture and to envisage how it relates to the content. Whilst this is mostly self explanatory- I think that because this is an informative piece it pays to spoon-feed us a bit. Also, your referencing could use a bit of a tidy, but that can easily be fixed before submission. I think that overall this has great potential to be a wonderful project and I look forward to seeing it at its completion!

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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 footnote 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 ‘</span> </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.

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This project was done really well. All key points, i.e. development, historic findings, etc., were clearly described. In terms of content, this group did a great job. It is very informative and all information they have included are relevant to the topic. There are a few mentions of embryonic stage but I do understand why, particularly for the development of the respiratory system. The developmental timeline is good but an image about the development would make it better. Remember to add in-text citations for this part. Historic findings section is very detailed and exceptional. Abnormalities is done well. A couple or more images would make this section really great. There are images that help with understanding the content. Try to find information on current treatments and/or management techniques for each disease.

However, some images have no captions and so some seem vague as to what they’re about. There are a few images missing copyright, specifically the 2nd photo on the project page and the historical image of lung development. From what I know, images from textbooks normally can’t be used because of copyright. The content is cited and referenced correctly. A bit messy with the references right now but I understand why. Just don’t forget to organise it before submission. Also, don’t forget to mention the other sections in the introduction. Overall, this project is done really well. It is very informative and easy to understand. In summary, just a few more images and correction of typos and this project would be remarkable. Well done!

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Firstly, great job on the layout and formatting of the project, everything is easy to find and overall, it reads well. The introduction provides great insight of what to expect on the page. However, it lacks in-text citations for the first three subheadings of the page, as well as the table of lung developmental stages. The first two images also don’t have a description when I click on it, I don’t know what I’m looking at. The “student template” is also missing for the images. I would suggest you look up the tutorial for uploading images on the pages as Mark has extensive information for the proper steps required for uploading images. Otherwise, the lung developmental stages table is informative and easy to read. I would also recommend adding an image for better visualization of the developmental process.

The historical findings and current research models have very detailed content, and look as though they have been referenced correctly using in-text citations, I’m impressed. Although, I would suggest you leave all the references to the end by simply putting </references> at the bottom of the page, as it looks neater to have them all in one place, rather than at the bottom of each sub-heading. The abnormalities section is done well and there are a wide number of abnormalities covered. The detail of the first two is more in depth than the rest, I’m unsure whether they was more information on those particular abnormalities or their still needs to be information added, but I suggest to have the same amount of information on each disease, if possible.
Overall, the project is very informative and presented well. It just need a few minor edits.

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The pages structure is well done, with appropriate use of heading. The introduction explains the general development of the respiratory system, differentiating embryonic, fetal and postnatal time-span. Like division of conducting and respiratory zones with strong general description of each zones components. The referencing of the first three heads content and images was not present though I presume this could be easily resolved. The Development stages table gives is simple yet informative, particularly liked how the stages during the fetal period had more in-depth feature description then the embryonic and postnatal stages.

The Current research and findings section was in-depth with strong explanations and in-text referencing; only part lacking referencing is the Functional unit section. Some sentences should be broken up to avoid excessive use of commas “However, a study conducted…”. There seems to be a picture missing or placed incorrectly for one of the 2013 studies. The Lung Model picture is relevant but with no caption, though the description and referencing when clicking on the image is solid. Little improvement is needed for the Historical findings and Abnormalities sections, great referencing and content. Particularly impressed with the sheer amount of abnormalities presented, with information being sourced from 2-3 references for each abnormality.

To improve further, referencing needs to be added particularly to the introduction, conduction and respiratory zone. The references need to be collected at the bottom of the page instead of after every couple of sections. The removal of the multiple reference subheadings would make the content and page in general easier to navigate. Many of the earlier images should be captioned properly and referenced properly, with missing info like ((Template: Student Image)), description, copyright info. The content of Respiratory and Lung Development Stages could be slightly more in-depth though not too significant of an issue. Overall content is written well, providing information on all the important objectives, only place improvement is properly required is referencing and some formatting.

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The introduction provided good background information about the lungs and its general development, however seemed to lack any further explanation as to what else would be covered on the page (current research, abnormalities). I found most of the sentences to be short and abrupt, and more in the form of statements rather than an explanation. This is the same for the following paragraphs regarding the two zones. I would combine several of the sentences together, and restructure them so that they do not start in the same manner e.g. of the first four sentence in your introduction, three of them begin with the words ‘The respiratory system’, and over half the sentences in the entire paragraph begin with ‘The’. There are a few grammatical errors within the text that should be corrected e.g. ‘till’ of ‘until’, ‘id’ instead of ‘is’. The images used fit well, but there is no caption to explain what they are images of and what they are trying to show. This is also not indicated on the summary of the image, one of which also doesn’t include any copyright information.

The lung development stages were done very well, simplified and tabulated making it very clear. My only concern for this part is that it should be the main part of the project, the area where the development of the lungs is fully explained, yet it is the smallest section of the page. Try to expand on it maybe? Or add a picture or two to enlarge the section?

The current research and findings section seems very thorough, lots of content, good explanations. Very minor problems however; a slight tendency to over use commas in some areas, while not in others. The current models area has not been added to; make sure to fill it in, or will it be scrapped? I have also noticed a picture has been deleted so make sure to get that issue fixed if you still want to use the same image. Is the second picture under this heading part of the section? As it is after the references so I'm not sure where it lies exactly. The image should be captioned as well.

I really like the historical findings section, the information seems more concise when it is presented in bullet points. The second picture within this section is well done and very neatly labeled (I thought it was an image from the internet). The first picture though, needs a caption added as well as copyright information. The abnormalities section is very extensive which can be bother good and bad. For some of the abnormalities there is a lot of detail presented, while for others there is very little. I think maybe that as long as you mention what it is, how you get it/how it forms, some statistics and maybe an image, that should be more than enough. Also, I would remove all the sub-headings under abnormalities and have them just written in bold. Otherwise, when looking at the contents at the top of the page, it looks as though half your page is solely focused on abnormalities.

Overall, I think this page is well done and only a focus on sentence structure, a bit on grammar, and captioning pictures with correct copyright info is needed. Other than these main focus areas, one other point to make would be all the references should be at the bottom of the page.

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In this review I intend to highlight the merits of your project as well as provide some constructive criticism in light of the marking criteria of this task.

The page is well structured and provides perfect balance between written text and images. However some of the included images do not compliment the text. I suggest adding labels or descriptive annotations to these images using paint. You could also include a simple written description of what each image showing. Alternatively you could refer to these images in your text e.g “ as seen in Figure 4a” and use them to make the content more engaging. I found the table on the stages of lung development really effective way of organising the content and I was able to understand much of it in a quick glimpse! I like how the text is summarised and highlights the main developmental changes that are occurring at each stage. Just to make it more engaging, perhaps you could include matching images in a another column.

Under the section of current findings, I believe that most of the information included is relevant and incredibly appropriate articles have been selected. I think its good that this section is delving into the area of molecular signalling underlying the morphological changes that we see. I believe your project would greatly benefit if there was more material discussing the biochemical signalling and recent findings in relation to this. However, I am not sure if the details on cell type should be in this section, this section might need some re-organising.

I understand that the history is a difficult topic to research. The information on our understanding of surfactant is appropriate, detailed and very informative. However I think you need to include more information on our understanding of stages in fetal lung development. Explore the transition in research focus investigating morphology to molecular changes. Perhaps use the library database to find relevant historic journal articles in the database. It was good to see the use of relevant historic images.

A number of abnormalities have been identified and described, I think its great that each section includes a description of the abnormality, and goes on to discuss the cause and implications of each disease. I would only recommend including matching images to make this section more engaging to readers. Great Work!

Overall the project is coming along really well ! Just ensure that you proof read and review before the final submission. Also include in-text references and compile all your references to one section at the end of the page. Good Luck!!

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Well explained introduction and the histological images provided are great.
In the first section the addition of in text citations would be useful. The content is explained really well and a good use of detail in the paragraphs is not too overwhelming. Good use of formatting with the inclusion of the table, helps to keep the content clear and concise. The current research, findings and models is present really well, good use of referencing and in text citations. Current findings, models and research is presented really well, good use of referencing and in text citations. Information is clear and with sufficient detail. There are a variety of formatting techniques used which is great to see. Good use of images, however seems to be missing info, suggest filling it out and maybe fixing some of the formatting errors shown but otherwise really well done. This section shows a good amount of research conducted. The historic findings are also well presented, the use of dot points to format the info is very useful and provides clarity. A timeline for the key historic dates might be helpful and another use of visuals. Great to see a variety of abnormalities, shows an extensive research really well presented. Would be great to see more images for this section and maybe drawings too.

This group overall has done really well, there are only a couple of suggestions for the page to be complete these include filling in the missing info under the sub heading ‘current models’. The in text citations and referencing in the first section should be added in to avoid losing marks. Also try adding captions to some of the images, a brief description of what the image is showing. Evidently the research conducted has been quite extensive and the group has worked well to ensure all parts are completed equally. Overall the page is structured really well and organized in an understandable manner. The use of a variety of images and formatting techniques is really great. Just a few minor adjustments and this page will be really great. Great work everyone !

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The intro is very good and the images are a good size but there needs to be some description to make it relevant to the project. Need to edit ‘Conducting Zone’ info since there are some grammatical and spelling errors. Also should have in-text referencing in this section of the project with a long list of all the references at the end. You can go onto other people’s reports to find the coding for this reference style.

The information on the lung development timeline is fantastic but it is a bit dense. Splitting it into bullet points might be a better way of organising it so peers get a more effective learning experience when they read it. In the conducting system under current findings it looks like there has been an attempt to upload an image called “400px” however the link leads nowhere. It has great information, very interesting and concise. However the references at the end of this section should be incorporated at the very end of the wiki page. This would make it flow better.

Excellent images of the diseased lung compared to normal lung, however it might make more sense for these to be under the lung abnormalities subheading. There is excellent information on the historical findings. It has been written in an easy to understand manner and all the information is relevant. There is also excellent referencing and good use of diagrams. However I still think that the references should all be together at the very end of the project page.

The abnormalities section is very in depth however there is a bit too much information. It would be easier to follow and more interesting if there were images associated with the information, or maybe if the information was tabulated that would make it easier to follow. Well done on this project! It is clear that a lot of research has been done outside.

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This is a really good project. First thing noticeable on the page is the amount of information you have which is great. The introduction is really well written and I like the fact that you have included images in this part as it makes it so much easier to understand. I also found it quite easy to grasp the difference in fetal and embryonic periods so well done as this is an important part of the project. This table of the lung development stages is great and really well done.

One thing you could maybe do here is add a few diagrams. I know you have more diagrams down below but I think it’s something that might make it even easier to follow. You obviously haven’t found any current models at the moment. Don’t know if this helps but it may for the models: PMID: 22876201. Current research and findings again is good. Something which seems to be reoccurring with your page is the fact that the references are spread all over the page. I think it would look much better if all the references were at the bottom of the page as this makes you page look more professional and aesthetically pleasing.

Maybe add some student drawings as I think this would more interesting for your page and be a bit more unique. Something else to note is the abnormalities part. It’s great that you have a lot of different abnormalities but I feel as though some of them such as cystic fibrosis and laryngeal atresia could have been given a bit more of information to supplement what you are saying. Also adding a diagram would be good to make it easier for the viewer to understand.

Overall it’s a well presented page with some quality information. Maybe look at your referencing technique, adding some more student images and a bit more detail to the abnormalities to take what at the moment is a good project to a great project. Best of luck!!

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

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

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

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

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

It is evident that a lot of work has been done on this page as each section is detailed and referenced well, with relevant information. Maybe just consider adding some student-drawn images too, but otherwise, the project is of very good quality so far.

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The product was done well overall with lots of information and a good structure. However, I am a bit confused about the sections “respiratory” and “lung development stages”. I guess “lung development stages” is also under “respiratory”, but it seems that they are separated into two big sections.

The introduction clearly explains the development of respiratory system. It is good to divide respiratory tract into 2 main parts and explain them separately. It would be better if it includes a sentence like ‘this website will focus on fetal development of respiratory system.

Using table to explain different stages of lung development is a good idea. It would be easier to read if they are typed in point forms with some images included.

More images could be added under current research, models and findings for easier understanding. Some information should be added under current models.

The historic findings and abnormalities are good and informative.

Some images do not have the information about copyright. It would be better if there is a title for each image included.

In terms of referencing, they are missing in the sections under introduction, conducting zone and respiratory zone. In-text references are also missing in the table about the stages and features of lung development. Also, the images used have not been referenced. Reference list at the end rather than under each section should be used instead.

It is overall a good project and well-researched. More images can be included to balance with the huge amount of text.

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 16:13, 17 August 2014 (EST)
Hey guys, it's Emanuel
I've had a look into the systems and respiratory caught my interest. I wanted to do cardio but another group has already chosen it so I think we should choose a system ASAP.

Respiratory looks like it has plenty of resources and there are some interesting abnormalities gat I found on this page:
[http://embryology.med.unsw.edu.au/embryology/index.php?title=Respiratory_System_-_Abnormalities Respiratory Abnormalities]

Do you guys have any other systems you would like to do or do you like respiratory?

--[[User:Z3372817|Z3372817]] ([[User talk:Z3372817|talk]]) 20:07, 17 August 2014 (EST)
Hey Emanuel, its Ish here.

As we said on the day, we're fine with anything. So if it's still free, let's lock it in before another group claims it?

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 20:59, 17 August 2014 (EST) Alright awesome, well I guess we're the Respiratory group. How do we let Dr Hill know?

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 22:30, 17 August 2014 (EST) Hi guys, it's Nadine. I'm happy to do the respiratory system :) I'm sure we have to email him, I'll do that now, since we all seem to be on the same page and in agreement with the respiratory system.

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 22:56, 17 August 2014 (EST) Just emailed Dr Mark and put a heading "respiratory" on our group page :)
Also we each need to pick one of the following;
# Review that system development during the fetal period.
# Identify current research models and finding.
# Identify historic findings.
# Identify abnormalities that can occur in this system during fetal period.
I'm happy to do number 1. Unless someone else wants to?

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 06:09, 18 August 2014 (EST)Thanks Nadine, I'll do number 4 if that's all good with you guys?

--[[User:Z3372817|Z3372817]] ([[User talk:Z3372817|talk]]) 19:54, 18 August 2014 (EST) Great work with allocating Nadine. I'd love to do the historic findings (number 3) that sounds interesting! Only if that's okay with you all though?

--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 15:17, 19 August 2014 (EST) Hey Guys! It's marina here :), I'm happy with number 2. If anyone comes across information for other parts of the project, let's let each other know :)

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 21:07, 26 August 2014 (EST)Hi guys its Nadine, just wanted to let you guys know that i added in subheadings to our page :) So feel free to add to your sections -pictures -articles -tables

--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 23:58, 26 August 2014 (EST)Marina: Thanks Nadine :) I'm just going to add our names next to each section that we are looking at so its easier to communicate with with one another and who's doing what :)

# Review that system development during the fetal period-Nadine
# Identify current research models and finding-Marina
# Identify historic findings-Ish
# Identify abnormalities that can occur in this system during fetal period-Emanuel

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 12:58, 27 August 2014 (EST)
'''Topics to cover'''
#Major stages of development - all fetal (only primordial embryonic development)
#Histological findings
#Separate into Functional elements (alveoli) and Tract (conducting system: upper and lower)
#Include diaphragm (musculoskeletal)
#Changes after birth

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 12:20, 2 September 2014 (EST) Emanuel: Hey guys just letting you know that I spoke to Dr Hill before the lecture with Carl from the cardio group about using review articles. He said we are allowed to use them as long as we refer to them appropriately (e.g as reviewed in..., according to review by..., etc).
He also said that any direct findings need to be referenced from the original article and not a review article.
We can reference to them as mentioned above and we can also add a subheading under references titled "review articles" if we want. When we start to formulate the page we can look at what previous projects have done when organising their review article references for ideas.
In regards to using images from review articles - there is no need to cite them as coming from review article.

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 15:41, 2 September 2014 (EST) Emanuel: Hey guys just looking through the lecture and I noticed the part about the development of the pharynx. It develops with the foregut (oesophagus) of the GIT. What do you think if Nadine mentions that groups page in an appendix for her section to link the two pages? There is also a relationship between the development of the liver in wk7 that stops the descent of the heart and lungs so it could make our project more interesting in that it links out page with others offering a wider scope of information along with our specific topic.

--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:37, 3 September 2014 (EST)Marina: Yeh I agree! I noticed that too Emanuel. The development of the oesophagus from the foregut and how it bifurcated from the common pharynx into the trachea is very much related to our topic. We can definitely include those relationships, and any others we come across

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 22:47, 9 September 2014 (EST) Emanuel: Hey Ish, just came across these articles regarding historical findings for pulmonary surfactant:

[http://www.ncbi.nlm.nih.gov/pubmed/18446178 Surfactants: past, preset and future.]

[http://www.ncbi.nlm.nih.gov/pubmed/14509914 The era of pulmonary surfactant from Laplace to nowadays]

Mary Ellen Avery and Jere Mead seem to be the godparents of surfactant discovery.
I also noticed that there is a little tool on the right hand side of the pubmed page when you search for articles called "Results by year". It's a little bar graph showing which years had the most articles and you can click on each year to bring up it's articles. This might be helpful if your looking for articles that sparked an increase in research by clicking on the years just before the spikes in articles.

--[[User:Z3372817|Z3372817]] ([[User talk:Z3372817|talk]]) 15:49, 16 September 2014 (EST) That is just amazing Emanuel, thanks! Just another thing I wanted to ask, I noticed you took notes when Mark came by to talk to our group at the last lab. When he was saying to focus on things like..
Yeah, do you mind just typing up what you had written. That would be so helpful!

--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 23:33, 16 September 2014 (EST)Marina: Hey guys, just uploaded an image onto our page. It's under current research because its something scientists are looking at the moment with tracking abnormalities. The picture compares the normal structure of a lung to a couple of diseased ones. I know this also links to other parts of our project so we can shift it around later if need be. Mark wanted a picture uploaded before tomorrow, so at least we have something up there for now :)

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 12:13, 17 September 2014 (EST) Nadine here, just wanted to inform you that we have a new group assessment that will be marked individually we need to pick 2-3 research papers on stem biology and we need to summarize the paper and present it in week 12 as a group. You will get an email in regards to this set assignment, just thought I'd give you a head up.

--[[User:Z3333429|Z3333429]] ([[User talk:Z3333429|talk]]) 12:44, 17 September 2014 (EST) Emanuel: This is for Ish, I found a link on the respiratory pages that should help you out. Just go to one of the pages (e.g Respiratory System - Abnormalities) and there is a 'Historic Embryology' link just after the introduction. It's small and in a blue box so click on it to expand. It has some really good links that will hopefully help you. Something else that was interesting was the disclaimer at the bottom of the links stressing that the content and scientific understanding are specific to the time of publication. You may want to ask Dr Hill if you need to include that at the bottom of the page to make sure that our audience does not get confused.

--[[User:Z3372817|Z3372817]] ([[User talk:Z3372817|talk]]) 13:27, 17 September 2014 (EST) Ish: Yup, I've seen that Emanuel. I sort of wrote a paragraph along those lines as an introduction to my section which serves as a type of disclaimer too, but I'll reconfirm with Mark whether it's necessary to have anything in addition to that. Nadine, thanks for the heads up.

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 16:21, 1 October 2014 (EST) Nadine: Hey guys, just wanted to remind you that by the end of this week all information should up for your section. Make sure that references are included, pictures if needed.

--[[User:Z3372817|Z3372817]] ([[User talk:Z3372817|talk]]) 20:34, 1 October 2014 (EST) Ish: Hey guys, anyone else having issues with the website lately? I'm trying to upload an image - can't. I completed my latest lab assessment a couple days ago and saved it - lost it. So just to be safe, once you've written everything you need down in your sections, copy and paste EVERYTHING into a separate word doc. Don't want you guys to lose hours of work like I did.

--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 19:02, 3 October 2014 (EST) Marina: Hey Ish yeh im also having trouble with it as well. Even the "uploading image" button is inactive for me, apparently others are having as few problems with this as well. Can you guys check if you yours is visible at the moment? I know this must be recent as you guys have uploaded images and i was able to before. Maybe it has to do with the website change Dr Mark was talking about.

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 21:10, 4 October 2014 (EST) Nadine: Thanks Ish! i had the same problem happened twice to me! But it worked out for me in the end. So i have been looking around -projects from years before us and i really like this layout. Have a look if you get the chance [https://embryology.med.unsw.edu.au/embryology/index.php/2012_Group_Project_3]

--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 22:50, 4 October 2014 (EST) Marina: Hey Nardine, i really like that layout, hopefully we can get something similar to that going for us as well :) I'm sorry I havent been able to upload any images as the tab for me is unavailable, i emailed Dr mark about it though so hopefully that gets fixed soon.

--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 22:51, 4 October 2014 (EST) Marina: I was thinking of adding a heading titled "Glossary" at the very end of our project for us to add any words we want to define.... what do you guys think of this?

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 20:33, 7 October 2014 (EST) Nadine: Hey Marina, i like that idea heaps and i was also thinking of drawing for my section i found a great paper with fantastic pictures but i cant find the copyright information its off Nature, or I'll just figure something out

--[[User:Z3330991|Z3330991]] ([[User talk:Z3330991|talk]]) 20:36, 7 October 2014 (EST) Nadine: Hey I was thinking we need to get on top of the week 12 project maybe we can talk about this further tomorrow? I just dont want all of the good papers to go fast and we get left with really hard ones.

Talk:2014 Group Project 3

2014-10-14T11:29:02Z

Z3416697: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==

Good introduction, initial description of fore/mid/hindgut with listing of respective structures gives the reader an anatomical starting point. Fetal development is presented in appropriate depth. There is no acknowledgement of embryonic origin, research or abnormalities. These sections should feature in the introduction to present all parts of the report in the intro. The three separate timelines defeat the purpose of a timeline. These should either be merged into a single large timeline and remain at their present location or moved to introduce the foregut/midget/hindgut sections later on. Recent findings has a single study which is covered in good detail though 2-3 more studies would allow the reader to further understand current GIT Research.

In foregut section the dot-points used should match your subheadings. For example duodenum development is covered in the stomach section but is not mentioned in the subheading resulting in its development being hard to find without trawling through the text or “Ctrl-f”. Additionally you seemed to have missed out on pancreas development entirely. Foregut could also use some more images 2-3 would be suffice. Midgut development has great information, strong table, 8/8 drawings(captions required though). Inclusion of histological features gives viewer a microscopic perspective on development. Hindgut cloaca partitioning content is well worded though references are lacking.

Anorectal deformities sections should be moved under the Deformities section. The type of dot-point style used should be standardized. Too few abnormalities in the deformities section, though after the hindgut deformities are mover there should be sufficient. There are no references supporting the possible causes of Gastroschisis. The referencing it very good unlike other pages there are no random reference subheadings. In overview format wise quite attractive, information is adequately in-depth in all sections, introduction fails to address whole page, referencing is great for a draft (exceptions being “introduction” “Liver, Gallbladder and Bile Duct”), some captions aren't present, abnormalities in development section should be moved into deformities/abnormalities section.

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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 footnotes 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.

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A good introduction to the page but only outlines the developmental part of the project. Don’t forget to include other sections as well like current findings, abnormalities, etc. Also, no need for the hyphen for foregut, midgut, and hindgut. The development timeline is really good. Its very concise and well-referenced. It could be improved by tabulating the whole thing and maybe try to fuse the three sections together. Also, add an image or drawing of the development of the system. It will definitely help in terms of understanding what is happening at each stage. On recent findings, it’s not as good as the other groups but it’s definitely a start. Most groups write about 2-4 research articles for their current findings sections. As for the development section, each section is very detailed and informative. Maybe add a few images for the foregut section because images are really helpful. As for midgut, great to see images and student drawings. Good job on that. The same can be said for the hindgut section. It’s written well but maybe put the deformities in this section with the “Deformities” section. Deformities (abnormalities) section is good. It is detailed and the image used clearly shows what the disease is like. Maybe writing about 1-2 more abnormalities would make this section better.

It terms of citation and referencing, midgut section did the best job. I recommend the other sections to look for a lot more related material. I understand that this topic was divided depending on the region of the GIT, particularly the development section, but make sure to reorganise each section to make the page coherent. As for the images, most of them are well referenced. It wouldn’t hurt to add a few more. It’s great to see a lot of student drawings. Overall, a good project page very detailed in most areas but very little in referencing. In summary, focus on adding more references, making the whole page coherent, and a few more on the abnormalities.

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The introduction provides a good basic outline of the overview of the GIT. Although, there are no in-text citations in the introduction and all sub-headings are not included into the overview. Be wary of spelling errors such as “GIT (Gastrointestinal Track) consist of the Fore-gut, Mid-gut and Hind-gut” that should read Gastrointestinal Tract consists of the foregut, midgut and hindgut. This section would be better it was expanded upon and images were added. The timeline provides good detail, though would benefit by better formatting and organisation of the information, maybe putting it all into a table, by week will tidy it up.

Adding images for the sections will definitely be beneficial. The images hand-drawn are great, although the colours used make it hard to read. If you plan to add anymore drawings, try and use dark colours that allow for easy readability. The images already uploaded are missing copyright, referencing and “student template” information for images such as “fetal week 10 sagittal plane”. I would suggest you look up the tutorial for uploading images on the pages as Mark has extensive information for the proper steps required for uploading images.

The deformities section should be re-titled abnormalities as per the assessment criteria and would ensure the group is following similar structure from the other projects. Again, adding an image per disease would be great. Try and do about 1-2 more abnormalities. Great job on putting all the references at the bottom of the page, it makes it very neat and accessible. Overall, a good project just needs a few edits.

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A good overview of the GIT, very descriptive. This section would need some referencing as most of this info isn’t exactly common knowledge. Some of the sentences seem too short for me e.g. I would reconfigure the third sentence and combine the fourth and fifth sentences into one: ‘The GIT (gastrointestinal tract) consists of three regions: the foregut, midgut and the hindgut. The majority of the organs are located in the foregut, including…..’. You also need to make sure not to use capital letters in the middle of sentences.

The timeline is sort of well organized; it’s good that you have it separated for each region so they’re not all muddled up together, but is the info in dot points under the week, or is it just written next to the week? It needs to be kept consistent. I feel like this section is a bit too spread out as well, a large portion of the left hand side has text, while the entire right side of the screen is empty. You could possible put in a picture showing these 3 regions of the gut to fill in the space? Or maybe format the info into a table, it would make it look more formal and structured. The proper referencing technique should also be used here, not added hyperlinks.

The recent findings area is a little sparse, so you should try to find a few more. The title does say findings (plural), so maybe add at least one more. The foregut section is very extensive on the information provided which is good, a lot of research has been made. Visually however, it looks a little bad as all that can be seen is a mass of text. This can be alleviated if the same thing is done as has been with the midgut and hindgut region: the use of bullet points, a small table and the use of images to offset the slabs of text. It makes it more visually appealing. Unlike the midgut portion of the page, if the images are hand drawn, make sure they are clear, legible, and with colours used that will not strain the eye. For the images drawn in that section are messy and the labels hard to read both due to the colour of the pen used and the handwriting. In both the foregut and hindgut, referencing needs to be done. There are slabs of text in both sections where no references are made.

The deformities section is good, kept simple with no extensive explanations. Are there only 2 possible deformaties? If so, might be good to write a sentence mentioning that. If not, would be good to have at least 2 more deformities listed. The image drawn in this section is very neat, I like it a lot. The only problem with it is that it’s too small, making it hard to read some of the labels.

Overall, I think this page is very well done in terms of content. You have a lot of text, but I think it could do with some more pictures especially to offset some of the large slabs of texts in some areas. Make sure the pictures you have a clear and neat, and make sure you are referencing and doing it correctly.

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Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

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

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

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

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This project overall is very good with a lot relevant information. There is some use of images and hand-drawn images that are excellent. It would be good to see more images, perhaps to complement the timeline section. It is clear the group have worked well together to create a wiki page that flows well and covers all the organs of the gastrointestinal system. All the citations formatted correctly and it is good that all the references appear in one long list at the end of the page. There is still room to add tables, maybe to summarise the timeline. Other groups who presented their timelines in a table achieved an element of wiki-sophistication. There are a few spelling errors in some of the sections (specified below) which need to be corrected so as to not interrupt the flow of information when the reader is reading it. Again, there are only minimal errors or problems with this page, overall it is excellent!

The section on the midgut is well presented and thoroughly researched, well done! It is easy to follow and the way it is described makes it easy to imagine visually. However just double check for typos, for example “to that of” is spelt “tot hat of”. Simple error that is easily fixed. These hand drawn images are excellent. The colour coding and minimal use of words is very effective in supporting the written material.

The hindgut section is also well written and there is a lot of extensive information. Also double check for spelling, mesenchyme is spelt “esenchyme” in one of the sentences. This area of the project is lacking images detracting from its readability and level of interest.

--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 20:38, 13 August 2014 (EST)

Alright so lets choose a topic quickly before it gets taken. I would like all of you to post 3 topics that you would like to do (here) in order of importance and the topic that gets chosen the most will win. This is the only way I could think of in order to decide, so sorry. By the way Cardiovascular is taken so we cannot do that any more. My three choices are: Gastrointestinal System, Immune System and Placenta. What are yours?

i choose renal, head and neck, GIT --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 22:22, 14 August 2014 (EST)

Im thinking GIT. Everyone so far has said GIT so I reckon that might be the best option as i think it will be relatively easy to understand and follow with the whole mid gut, hind gut formation ect.
--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 12:58, 15 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 10:16, 16 August 2014 (EST) I have just reformatted your project page heading as the major heading (single =) and capitalised the words). All page sub-heading (two ==).

z3415141: I am going to be looking up research of the midgut.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 13:08, 20 August 2014 (EST)

I choose to research on abnormalities of the GIT system--[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 13:14, 20 August 2014 (EST)

z3375627: I'm going to be doing Hind gut development research --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 13:10, 20 August 2014 (EST)

z3414515: I will be researching foregut. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 13:12, 20 August 2014 (EST)

Alright people lets get some work done on this project. I hope everyone could at least write up few paragraphs on their chosen section by Tuesday. Thanks :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 22:18, 30 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 22:47, 30 August 2014 (EST) I agree, times a wasting. While you have met the required addition of references, tarts all that is currently on your project page.

--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)The reference below might help you guys.
<pubmed>12943221</pubmed>
--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)

Is it only me or is everyone finding it hard to differentiate between embryo and fetal development?--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)

Yeh I agree there are so many times where they talk about it as one in the same thing. Just have to read really carefully as we don't want to cross over. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 14:46, 2 September 2014 (EST)

Also with what you have written so far about the oesophagus, it looks good but what are you doing about referencing. Are you just keeping a list that you will put down later or are you getting the information from the resources that you found last week?? --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 14:53, 2 September 2014 (EST)

I have my references saved on my laptop so when the time comes I can relate the information to specific reference. How are you coming along with your research so far?--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 00:08, 3 September 2014 (EST)

Just been reading heaps to make sure I get the information right. I'm trying to get a really good understanding of the midgut rotation as I believe it is a critical part in the development of the ftus. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 09:31, 3 September 2014 (EST)

I am still waiting for some information from z3375627 and z3415242. Common people get moving!!! Also I meant that in the nicest way possible :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 10:52, 3 September 2014 (EST)

I have found a picture to go with the adnormality that i am doing however i will not upload it until everyone is ok with it. I will work to add on the first abnormality i have started and done and continue to research on a second one. If i come across any useful articles for you guys i will post it on this. --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 19:02, 9 September 2014 (EST)

Show the group in class your image so we can discuss on it. Also I know everyone must be busy with mid semester exams or assessments so I appreciate the effort you guys are putting in so far. BUT do remember as soon as the mid semester exams are over we need to pick up the pace or pull up our socks for this embryology project. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 09:27, 10 September 2014 (EST)

Common people lets get a move on. I have put up some information on my section though it is on the embryo period, the fetal period is in progress and in detail. The embryo period is only there as a guideline to understand how the stomach actually attains its shape. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:47, 16 September 2014 (EST)

i have come across some research articles on omphalocele (abnormality occurs in week 10-12 YAY ) just reading through them as they are pretty long and abit difficult understanding so i'm trying to put some stuff into a paragraph or two will try and upload the stuff for it by this week sometime. cheers --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 21:50, 16 September 2014 (EST)

Alright this is the week to really get a good chunk of it done now that most of our mid sems are over. Not sure if anyone else has any good youtube videos, but because we only get one I'm gonna put this one out there relating to midgut rotation: https://www.youtube.com/watch?v=AscKR_cQExY --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 08:09, 17 September 2014 (EST)

Also we need to start our list of references so I reckon we just put them down under this heading. Leave the references at the bottom of the page ie. write above the heading references.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 08:18, 17 September 2014 (EST)

i found a simple sketch drawing of omphalocele just so we have some picture on our page but i don't want to put it on the page yet incase you guys don't like i and since we cant delete it once its up so after your approval i will put it up also i am trying to find good video on organ development since im sure alot are formed by week 10 as i have read in articlese. --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 00:42, 24 September 2014 (EST)

Apologies with my lack of input on this. I’ve added a bit of the Cloacal partitioning and deformities that I’ll expand upon. I’ve also found some great pictures on some of the other GIT deformities. If I’m unable to source permission for them, I’m happy to recreate them --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 07:55, 24 September 2014 (EST)

Definitely put that picture up about Omphalocele. That will work well because I'm talking about midgut herniation so if I talk about it in my stuff then I can just link it so that when you click on it goes down to the bottom of the page to where you talk about it in abnormalities. Not exactly sure how we do that but I'm sure we will work it out.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 13:02, 6 October 2014 (EST)

Hey all just wanted to note that when your referencing from now look at the editing page to see what mark does so that the references are footnotes down the bottom of the page. Obviously you will need to change the reference in the brackets but you get the point. This means that when you do this all the references will come up down the bottom of the page. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 23:34, 6 October 2014 (EST)

Not sure if we are supposed to get rid of the references that we used for our group assignment but I just did because they were taking up uneccesary space on our page. Just thought i would say this here just in case we were not meant to.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 09:17, 8 October 2014 (EST)

Everyone please take off your student signature from the group page as it looks unprofessional. Thanks guys and girls :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 10:07, 8 October 2014 (EST)

'''References'''

Won Kyu Kim, Hyun Kim, Dae Ho Ahn, Myoung Hee Kim, Hyoung Woo Park Timetable for intestinal rotation in staged human embryos and fetuses. Birth Defects Res. Part A Clin. Mol. Teratol.: 2003, 67(11);941-5 PMID:14745932. I used this in describing midgut rotation.
<gallery>

</gallery>

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*References are missing from the overview section. Although it serves as an introduction, you can still include references to support what you're saying. Also, maybe the language of this section should be edited to be a bit more formal, like the 2nd sentence in particular
*GIT = Gastrointestinal tract, not track
*The hyphens between "foregut" etc are not needed
*The timeline is a good idea! Everything was simplified. Maybe look to see if you can add some images to this section
*Week 6 of timeline: I don't think a liver can "obtain" a colour. Look to change the wording
*Maybe to simplify the timeline section better, tabulate the findings according to time (weeks), rather than dividing it by the midgut, foregut and hind gut section. It makes it hard to follow
*Need some more work on the recent findings section. Just some tips, when researching on pubmed, there's an option to look at recent articles by customising dates to say 2012-onwards
*Many potentials for adding images to the "foregut" section. If you find that copyright is too difficult to get around, then you can sketch or trace images from textbooks and upload them
*Great effort with the drawn images in the "midgut" section! Be wary of colour choice though, as the green highlighter and blue pen can be a bit difficult to see. Otherwise think of adjusting contrast on the images to make the diagram stand out more
*Maybe think of adding a video from YouTube to show some features of GIT fetal development, like the rotations. If you do that, be sure to include the 11-digit cache code as your reference point

Talk:2014 Group Project 3

2014-10-14T11:21:03Z

Z3416697: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==

Good introduction, initial description of fore/mid/hindgut with listing of respective structures gives the reader an anatomical starting point. Fetal development is presented in appropriate depth. There is no acknowledgement of embryonic origin, research or abnormalities. These sections should feature in the introduction to present all parts of the report in the intro. The three separate timelines defeat the purpose of a timeline. These should either be merged into a single large timeline and remain at their present location or moved to introduce the foregut/midget/hindgut sections later on. Recent findings has a single study which is covered in good detail though 2-3 more studies would allow the reader to further understand current GIT Research.

In foregut section the dot-points used should match your subheadings. For example duodenum development is covered in the stomach section but is not mentioned in the subheading resulting in its development being hard to find without trawling through the text or “Ctrl-f”. Additionally you seemed to have missed out on pancreas development entirely. Foregut could also use some more images 2-3 would be suffice. Midgut development has great information, strong table, 8/8 drawings(captions required though). Inclusion of histological features gives viewer a microscopic perspective on development. Hindgut cloaca partitioning content is well worded though references are lacking.

Anorectal deformities sections should be moved under the Deformities section. The type of dot-point style used should be standardized. Too few abnormalities in the deformities section, though after the hindgut deformities are mover there should be sufficient. There are no references supporting the possible causes of Gastroschisis. The referencing it very good unlike other pages there are no random reference subheadings. In overview format wise quite attractive, information is adequately in-depth in all sections, introduction fails to address whole page, referencing is great for a draft (exceptions being “introduction” “Liver, Gallbladder and Bile Duct”), some captions aren't present, abnormalities in development section should be moved into deformities/abnormalities section.

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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 footnotes 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.

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A good introduction to the page but only outlines the developmental part of the project. Don’t forget to include other sections as well like current findings, abnormalities, etc. Also, no need for the hyphen for foregut, midgut, and hindgut. The development timeline is really good. Its very concise and well-referenced. It could be improved by tabulating the whole thing and maybe try to fuse the three sections together. Also, add an image or drawing of the development of the system. It will definitely help in terms of understanding what is happening at each stage. On recent findings, it’s not as good as the other groups but it’s definitely a start. Most groups write about 2-4 research articles for their current findings sections. As for the development section, each section is very detailed and informative. Maybe add a few images for the foregut section because images are really helpful. As for midgut, great to see images and student drawings. Good job on that. The same can be said for the hindgut section. It’s written well but maybe put the deformities in this section with the “Deformities” section. Deformities (abnormalities) section is good. It is detailed and the image used clearly shows what the disease is like. Maybe writing about 1-2 more abnormalities would make this section better.

It terms of citation and referencing, midgut section did the best job. I recommend the other sections to look for a lot more related material. I understand that this topic was divided depending on the region of the GIT, particularly the development section, but make sure to reorganise each section to make the page coherent. As for the images, most of them are well referenced. It wouldn’t hurt to add a few more. It’s great to see a lot of student drawings. Overall, a good project page very detailed in most areas but very little in referencing. In summary, focus on adding more references, making the whole page coherent, and a few more on the abnormalities.

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The introduction provides a good basic outline of the overview of the GIT. Although, there are no in-text citations in the introduction and all sub-headings are not included into the overview. Be wary of spelling errors such as “GIT (Gastrointestinal Track) consist of the Fore-gut, Mid-gut and Hind-gut” that should read Gastrointestinal Tract consists of the foregut, midgut and hindgut. This section would be better it was expanded upon and images were added. The timeline provides good detail, though would benefit by better formatting and organisation of the information, maybe putting it all into a table, by week will tidy it up.

Adding images for the sections will definitely be beneficial. The images hand-drawn are great, although the colours used make it hard to read. If you plan to add anymore drawings, try and use dark colours that allow for easy readability. The images already uploaded are missing copyright, referencing and “student template” information for images such as “fetal week 10 sagittal plane”. I would suggest you look up the tutorial for uploading images on the pages as Mark has extensive information for the proper steps required for uploading images.

The deformities section should be re-titled abnormalities as per the assessment criteria and would ensure the group is following similar structure from the other projects. Again, adding an image per disease would be great. Try and do about 1-2 more abnormalities. Great job on putting all the references at the bottom of the page, it makes it very neat and accessible. Overall, a good project just needs a few edits.

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A good overview of the GIT, very descriptive. This section would need some referencing as most of this info isn’t exactly common knowledge. Some of the sentences seem too short for me e.g. I would reconfigure the third sentence and combine the fourth and fifth sentences into one: ‘The GIT (gastrointestinal tract) consists of three regions: the foregut, midgut and the hindgut. The majority of the organs are located in the foregut, including…..’. You also need to make sure not to use capital letters in the middle of sentences.

The timeline is sort of well organized; it’s good that you have it separated for each region so they’re not all muddled up together, but is the info in dot points under the week, or is it just written next to the week? It needs to be kept consistent. I feel like this section is a bit too spread out as well, a large portion of the left hand side has text, while the entire right side of the screen is empty. You could possible put in a picture showing these 3 regions of the gut to fill in the space? Or maybe format the info into a table, it would make it look more formal and structured. The proper referencing technique should also be used here, not added hyperlinks.

The recent findings area is a little sparse, so you should try to find a few more. The title does say findings (plural), so maybe add at least one more. The foregut section is very extensive on the information provided which is good, a lot of research has been made. Visually however, it looks a little bad as all that can be seen is a mass of text. This can be alleviated if the same thing is done as has been with the midgut and hindgut region: the use of bullet points, a small table and the use of images to offset the slabs of text. It makes it more visually appealing. Unlike the midgut portion of the page, if the images are hand drawn, make sure they are clear, legible, and with colours used that will not strain the eye. For the images drawn in that section are messy and the labels hard to read both due to the colour of the pen used and the handwriting. In both the foregut and hindgut, referencing needs to be done. There are slabs of text in both sections where no references are made.

The deformities section is good, kept simple with no extensive explanations. Are there only 2 possible deformaties? If so, might be good to write a sentence mentioning that. If not, would be good to have at least 2 more deformities listed. The image drawn in this section is very neat, I like it a lot. The only problem with it is that it’s too small, making it hard to read some of the labels.

Overall, I think this page is very well done in terms of content. You have a lot of text, but I think it could do with some more pictures especially to offset some of the large slabs of texts in some areas. Make sure the pictures you have a clear and neat, and make sure you are referencing and doing it correctly.

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Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section.

The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

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

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

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

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This project overall is very good with a lot relevant information. There is some use of images and hand-drawn images that are excellent. It would be good to see more images, perhaps to complement the timeline section. It is clear the group have worked well together to create a wiki page that flows well and covers all the organs of the gastrointestinal system. All the citations formatted correctly and it is good that all the references appear in one long list at the end of the page. There is still room to add tables, maybe to summarise the timeline. Other groups who presented their timelines in a table achieved an element of wiki-sophistication. There are a few spelling errors in some of the sections (specified below) which need to be corrected so as to not interrupt the flow of information when the reader is reading it. Again, there are only minimal errors or problems with this page, overall it is excellent!

The section on the midgut is well presented and thoroughly researched, well done! It is easy to follow and the way it is described makes it easy to imagine visually. However just double check for typos, for example “to that of” is spelt “tot hat of”. Simple error that is easily fixed. These hand drawn images are excellent. The colour coding and minimal use of words is very effective in supporting the written material.

The hindgut section is also well written and there is a lot of extensive information. Also double check for spelling, mesenchyme is spelt “esenchyme” in one of the sentences. This area of the project is lacking images detracting from its readability and level of interest.

--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 20:38, 13 August 2014 (EST)

Alright so lets choose a topic quickly before it gets taken. I would like all of you to post 3 topics that you would like to do (here) in order of importance and the topic that gets chosen the most will win. This is the only way I could think of in order to decide, so sorry. By the way Cardiovascular is taken so we cannot do that any more. My three choices are: Gastrointestinal System, Immune System and Placenta. What are yours?

i choose renal, head and neck, GIT --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 22:22, 14 August 2014 (EST)

Im thinking GIT. Everyone so far has said GIT so I reckon that might be the best option as i think it will be relatively easy to understand and follow with the whole mid gut, hind gut formation ect.
--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 12:58, 15 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 10:16, 16 August 2014 (EST) I have just reformatted your project page heading as the major heading (single =) and capitalised the words). All page sub-heading (two ==).

z3415141: I am going to be looking up research of the midgut.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 13:08, 20 August 2014 (EST)

I choose to research on abnormalities of the GIT system--[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 13:14, 20 August 2014 (EST)

z3375627: I'm going to be doing Hind gut development research --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 13:10, 20 August 2014 (EST)

z3414515: I will be researching foregut. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 13:12, 20 August 2014 (EST)

Alright people lets get some work done on this project. I hope everyone could at least write up few paragraphs on their chosen section by Tuesday. Thanks :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 22:18, 30 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 22:47, 30 August 2014 (EST) I agree, times a wasting. While you have met the required addition of references, tarts all that is currently on your project page.

--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)The reference below might help you guys.
<pubmed>12943221</pubmed>
--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)

Is it only me or is everyone finding it hard to differentiate between embryo and fetal development?--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)

Yeh I agree there are so many times where they talk about it as one in the same thing. Just have to read really carefully as we don't want to cross over. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 14:46, 2 September 2014 (EST)

Also with what you have written so far about the oesophagus, it looks good but what are you doing about referencing. Are you just keeping a list that you will put down later or are you getting the information from the resources that you found last week?? --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 14:53, 2 September 2014 (EST)

I have my references saved on my laptop so when the time comes I can relate the information to specific reference. How are you coming along with your research so far?--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 00:08, 3 September 2014 (EST)

Just been reading heaps to make sure I get the information right. I'm trying to get a really good understanding of the midgut rotation as I believe it is a critical part in the development of the ftus. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 09:31, 3 September 2014 (EST)

I am still waiting for some information from z3375627 and z3415242. Common people get moving!!! Also I meant that in the nicest way possible :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 10:52, 3 September 2014 (EST)

I have found a picture to go with the adnormality that i am doing however i will not upload it until everyone is ok with it. I will work to add on the first abnormality i have started and done and continue to research on a second one. If i come across any useful articles for you guys i will post it on this. --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 19:02, 9 September 2014 (EST)

Show the group in class your image so we can discuss on it. Also I know everyone must be busy with mid semester exams or assessments so I appreciate the effort you guys are putting in so far. BUT do remember as soon as the mid semester exams are over we need to pick up the pace or pull up our socks for this embryology project. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 09:27, 10 September 2014 (EST)

Common people lets get a move on. I have put up some information on my section though it is on the embryo period, the fetal period is in progress and in detail. The embryo period is only there as a guideline to understand how the stomach actually attains its shape. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:47, 16 September 2014 (EST)

i have come across some research articles on omphalocele (abnormality occurs in week 10-12 YAY ) just reading through them as they are pretty long and abit difficult understanding so i'm trying to put some stuff into a paragraph or two will try and upload the stuff for it by this week sometime. cheers --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 21:50, 16 September 2014 (EST)

Alright this is the week to really get a good chunk of it done now that most of our mid sems are over. Not sure if anyone else has any good youtube videos, but because we only get one I'm gonna put this one out there relating to midgut rotation: https://www.youtube.com/watch?v=AscKR_cQExY --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 08:09, 17 September 2014 (EST)

Also we need to start our list of references so I reckon we just put them down under this heading. Leave the references at the bottom of the page ie. write above the heading references.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 08:18, 17 September 2014 (EST)

i found a simple sketch drawing of omphalocele just so we have some picture on our page but i don't want to put it on the page yet incase you guys don't like i and since we cant delete it once its up so after your approval i will put it up also i am trying to find good video on organ development since im sure alot are formed by week 10 as i have read in articlese. --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 00:42, 24 September 2014 (EST)

Apologies with my lack of input on this. I’ve added a bit of the Cloacal partitioning and deformities that I’ll expand upon. I’ve also found some great pictures on some of the other GIT deformities. If I’m unable to source permission for them, I’m happy to recreate them --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 07:55, 24 September 2014 (EST)

Definitely put that picture up about Omphalocele. That will work well because I'm talking about midgut herniation so if I talk about it in my stuff then I can just link it so that when you click on it goes down to the bottom of the page to where you talk about it in abnormalities. Not exactly sure how we do that but I'm sure we will work it out.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 13:02, 6 October 2014 (EST)

Hey all just wanted to note that when your referencing from now look at the editing page to see what mark does so that the references are footnotes down the bottom of the page. Obviously you will need to change the reference in the brackets but you get the point. This means that when you do this all the references will come up down the bottom of the page. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 23:34, 6 October 2014 (EST)

Not sure if we are supposed to get rid of the references that we used for our group assignment but I just did because they were taking up uneccesary space on our page. Just thought i would say this here just in case we were not meant to.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 09:17, 8 October 2014 (EST)

Everyone please take off your student signature from the group page as it looks unprofessional. Thanks guys and girls :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 10:07, 8 October 2014 (EST)

'''References'''

Won Kyu Kim, Hyun Kim, Dae Ho Ahn, Myoung Hee Kim, Hyoung Woo Park Timetable for intestinal rotation in staged human embryos and fetuses. Birth Defects Res. Part A Clin. Mol. Teratol.: 2003, 67(11);941-5 PMID:14745932. I used this in describing midgut rotation.
<gallery>

</gallery>

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*References are missing from the overview section. Although it serves as an introduction, you can still include references to support what you're saying. Also, maybe the language of this section should be edited to be a bit more formal, like the 2nd sentence in particular
*GIT = Gastrointestinal tract, not track
*The hyphens between "foregut" etc are not needed
*The timeline is a good idea! Everything was simplified. Maybe look to see if you can add some images to this section
*Week 6 of timeline: I don't think a liver can "obtain" a colour. Look to change the wording
*Maybe to simplify the timeline section better, tabulate the findings according to time (weeks), rather than dividing it by the midgut, foregut and hind gut section. It makes it hard to follow
*Need some more work on the recent findings section. Just some tips, when researching on pubmed, there's an option to look at recent articles by customising dates to say 2012-onwards
*Many potentials for adding images to the "foregut" section. If you find that copyright is too difficult to get around, then you can sketch or trace images from textbooks and upload them
*Great effort with the drawn images in the "midgut" section! Be wary of colour choice though, as the green highlighter and blue pen can be a bit difficult to see. Otherwise think of adjusting contrast on the images to make the diagram stand out more
*Maybe think of adding a video from YouTube to show some features of GIT fetal development, like the rotations. If you do that, be sure to include the 11-digit cache code as your reference point

Talk:2014 Group Project 3

2014-10-14T11:19:52Z

Z3416697: /* Peer Reviews */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==

Good introduction, initial description of fore/mid/hindgut with listing of respective structures gives the reader an anatomical starting point. Fetal development is presented in appropriate depth. There is no acknowledgement of embryonic origin, research or abnormalities. These sections should feature in the introduction to present all parts of the report in the intro. The three separate timelines defeat the purpose of a timeline. These should either be merged into a single large timeline and remain at their present location or moved to introduce the foregut/midget/hindgut sections later on. Recent findings has a single study which is covered in good detail though 2-3 more studies would allow the reader to further understand current GIT Research.

In foregut section the dot-points used should match your subheadings. For example duodenum development is covered in the stomach section but is not mentioned in the subheading resulting in its development being hard to find without trawling through the text or “Ctrl-f”. Additionally you seemed to have missed out on pancreas development entirely. Foregut could also use some more images 2-3 would be suffice. Midgut development has great information, strong table, 8/8 drawings(captions required though). Inclusion of histological features gives viewer a microscopic perspective on development. Hindgut cloaca partitioning content is well worded though references are lacking.

Anorectal deformities sections should be moved under the Deformities section. The type of dot-point style used should be standardized. Too few abnormalities in the deformities section, though after the hindgut deformities are mover there should be sufficient. There are no references supporting the possible causes of Gastroschisis. The referencing it very good unlike other pages there are no random reference subheadings. In overview format wise quite attractive, information is adequately in-depth in all sections, introduction fails to address whole page, referencing is great for a draft (exceptions being “introduction” “Liver, Gallbladder and Bile Duct”), some captions aren't present, abnormalities in development section should be moved into deformities/abnormalities section.

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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 footnotes 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.

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A good introduction to the page but only outlines the developmental part of the project. Don’t forget to include other sections as well like current findings, abnormalities, etc. Also, no need for the hyphen for foregut, midgut, and hindgut. The development timeline is really good. Its very concise and well-referenced. It could be improved by tabulating the whole thing and maybe try to fuse the three sections together. Also, add an image or drawing of the development of the system. It will definitely help in terms of understanding what is happening at each stage. On recent findings, it’s not as good as the other groups but it’s definitely a start. Most groups write about 2-4 research articles for their current findings sections. As for the development section, each section is very detailed and informative. Maybe add a few images for the foregut section because images are really helpful. As for midgut, great to see images and student drawings. Good job on that. The same can be said for the hindgut section. It’s written well but maybe put the deformities in this section with the “Deformities” section. Deformities (abnormalities) section is good. It is detailed and the image used clearly shows what the disease is like. Maybe writing about 1-2 more abnormalities would make this section better.

It terms of citation and referencing, midgut section did the best job. I recommend the other sections to look for a lot more related material. I understand that this topic was divided depending on the region of the GIT, particularly the development section, but make sure to reorganise each section to make the page coherent. As for the images, most of them are well referenced. It wouldn’t hurt to add a few more. It’s great to see a lot of student drawings. Overall, a good project page very detailed in most areas but very little in referencing. In summary, focus on adding more references, making the whole page coherent, and a few more on the abnormalities.

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The introduction provides a good basic outline of the overview of the GIT. Although, there are no in-text citations in the introduction and all sub-headings are not included into the overview. Be wary of spelling errors such as “GIT (Gastrointestinal Track) consist of the Fore-gut, Mid-gut and Hind-gut” that should read Gastrointestinal Tract consists of the foregut, midgut and hindgut. This section would be better it was expanded upon and images were added. The timeline provides good detail, though would benefit by better formatting and organisation of the information, maybe putting it all into a table, by week will tidy it up.

Adding images for the sections will definitely be beneficial. The images hand-drawn are great, although the colours used make it hard to read. If you plan to add anymore drawings, try and use dark colours that allow for easy readability. The images already uploaded are missing copyright, referencing and “student template” information for images such as “fetal week 10 sagittal plane”. I would suggest you look up the tutorial for uploading images on the pages as Mark has extensive information for the proper steps required for uploading images.

The deformities section should be re-titled abnormalities as per the assessment criteria and would ensure the group is following similar structure from the other projects. Again, adding an image per disease would be great. Try and do about 1-2 more abnormalities. Great job on putting all the references at the bottom of the page, it makes it very neat and accessible. Overall, a good project just needs a few edits.

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A good overview of the GIT, very descriptive. This section would need some referencing as most of this info isn’t exactly common knowledge. Some of the sentences seem too short for me e.g. I would reconfigure the third sentence and combine the fourth and fifth sentences into one: ‘The GIT (gastrointestinal tract) consists of three regions: the foregut, midgut and the hindgut. The majority of the organs are located in the foregut, including…..’. You also need to make sure not to use capital letters in the middle of sentences.

The timeline is sort of well organized; it’s good that you have it separated for each region so they’re not all muddled up together, but is the info in dot points under the week, or is it just written next to the week? It needs to be kept consistent. I feel like this section is a bit too spread out as well, a large portion of the left hand side has text, while the entire right side of the screen is empty. You could possible put in a picture showing these 3 regions of the gut to fill in the space? Or maybe format the info into a table, it would make it look more formal and structured. The proper referencing technique should also be used here, not added hyperlinks.

The recent findings area is a little sparse, so you should try to find a few more. The title does say findings (plural), so maybe add at least one more. The foregut section is very extensive on the information provided which is good, a lot of research has been made. Visually however, it looks a little bad as all that can be seen is a mass of text. This can be alleviated if the same thing is done as has been with the midgut and hindgut region: the use of bullet points, a small table and the use of images to offset the slabs of text. It makes it more visually appealing. Unlike the midgut portion of the page, if the images are hand drawn, make sure they are clear, legible, and with colours used that will not strain the eye. For the images drawn in that section are messy and the labels hard to read both due to the colour of the pen used and the handwriting. In both the foregut and hindgut, referencing needs to be done. There are slabs of text in both sections where no references are made.

The deformities section is good, kept simple with no extensive explanations. Are there only 2 possible deformaties? If so, might be good to write a sentence mentioning that. If not, would be good to have at least 2 more deformities listed. The image drawn in this section is very neat, I like it a lot. The only problem with it is that it’s too small, making it hard to read some of the labels.

Overall, I think this page is very well done in terms of content. You have a lot of text, but I think it could do with some more pictures especially to offset some of the large slabs of texts in some areas. Make sure the pictures you have a clear and neat, and make sure you are referencing and doing it correctly.

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Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section.

The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

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

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

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

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This project overall is very good with a lot relevant information. There is some use of images and hand-drawn images that are excellent. It would be good to see more images, perhaps to complement the timeline section. It is clear the group have worked well together to create a wiki page that flows well and covers all the organs of the gastrointestinal system. All the citations formatted correctly and it is good that all the references appear in one long list at the end of the page. There is still room to add tables, maybe to summarise the timeline. Other groups who presented their timelines in a table achieved an element of wiki-sophistication. There are a few spelling errors in some of the sections (specified below) which need to be corrected so as to not interrupt the flow of information when the reader is reading it. Again, there are only minimal errors or problems with this page, overall it is excellent!

The section on the midgut is well presented and thoroughly researched, well done! It is easy to follow and the way it is described makes it easy to imagine visually. However just double check for typos, for example “to that of” is spelt “tot hat of”. Simple error that is easily fixed. These hand drawn images are excellent. The colour coding and minimal use of words is very effective in supporting the written material.

The hindgut section is also well written and there is a lot of extensive information. Also double check for spelling, mesenchyme is spelt “esenchyme” in one of the sentences. This area of the project is lacking images detracting from its readability and level of interest.

--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 20:38, 13 August 2014 (EST)

Alright so lets choose a topic quickly before it gets taken. I would like all of you to post 3 topics that you would like to do (here) in order of importance and the topic that gets chosen the most will win. This is the only way I could think of in order to decide, so sorry. By the way Cardiovascular is taken so we cannot do that any more. My three choices are: Gastrointestinal System, Immune System and Placenta. What are yours?

i choose renal, head and neck, GIT --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 22:22, 14 August 2014 (EST)

Im thinking GIT. Everyone so far has said GIT so I reckon that might be the best option as i think it will be relatively easy to understand and follow with the whole mid gut, hind gut formation ect.
--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 12:58, 15 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 10:16, 16 August 2014 (EST) I have just reformatted your project page heading as the major heading (single =) and capitalised the words). All page sub-heading (two ==).

z3415141: I am going to be looking up research of the midgut.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 13:08, 20 August 2014 (EST)

I choose to research on abnormalities of the GIT system--[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 13:14, 20 August 2014 (EST)

z3375627: I'm going to be doing Hind gut development research --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 13:10, 20 August 2014 (EST)

z3414515: I will be researching foregut. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 13:12, 20 August 2014 (EST)

Alright people lets get some work done on this project. I hope everyone could at least write up few paragraphs on their chosen section by Tuesday. Thanks :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 22:18, 30 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 22:47, 30 August 2014 (EST) I agree, times a wasting. While you have met the required addition of references, tarts all that is currently on your project page.

--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)The reference below might help you guys.
<pubmed>12943221</pubmed>
--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)

Is it only me or is everyone finding it hard to differentiate between embryo and fetal development?--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)

Yeh I agree there are so many times where they talk about it as one in the same thing. Just have to read really carefully as we don't want to cross over. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 14:46, 2 September 2014 (EST)

Also with what you have written so far about the oesophagus, it looks good but what are you doing about referencing. Are you just keeping a list that you will put down later or are you getting the information from the resources that you found last week?? --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 14:53, 2 September 2014 (EST)

I have my references saved on my laptop so when the time comes I can relate the information to specific reference. How are you coming along with your research so far?--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 00:08, 3 September 2014 (EST)

Just been reading heaps to make sure I get the information right. I'm trying to get a really good understanding of the midgut rotation as I believe it is a critical part in the development of the ftus. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 09:31, 3 September 2014 (EST)

I am still waiting for some information from z3375627 and z3415242. Common people get moving!!! Also I meant that in the nicest way possible :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 10:52, 3 September 2014 (EST)

I have found a picture to go with the adnormality that i am doing however i will not upload it until everyone is ok with it. I will work to add on the first abnormality i have started and done and continue to research on a second one. If i come across any useful articles for you guys i will post it on this. --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 19:02, 9 September 2014 (EST)

Show the group in class your image so we can discuss on it. Also I know everyone must be busy with mid semester exams or assessments so I appreciate the effort you guys are putting in so far. BUT do remember as soon as the mid semester exams are over we need to pick up the pace or pull up our socks for this embryology project. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 09:27, 10 September 2014 (EST)

Common people lets get a move on. I have put up some information on my section though it is on the embryo period, the fetal period is in progress and in detail. The embryo period is only there as a guideline to understand how the stomach actually attains its shape. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:47, 16 September 2014 (EST)

i have come across some research articles on omphalocele (abnormality occurs in week 10-12 YAY ) just reading through them as they are pretty long and abit difficult understanding so i'm trying to put some stuff into a paragraph or two will try and upload the stuff for it by this week sometime. cheers --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 21:50, 16 September 2014 (EST)

Alright this is the week to really get a good chunk of it done now that most of our mid sems are over. Not sure if anyone else has any good youtube videos, but because we only get one I'm gonna put this one out there relating to midgut rotation: https://www.youtube.com/watch?v=AscKR_cQExY --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 08:09, 17 September 2014 (EST)

Also we need to start our list of references so I reckon we just put them down under this heading. Leave the references at the bottom of the page ie. write above the heading references.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 08:18, 17 September 2014 (EST)

i found a simple sketch drawing of omphalocele just so we have some picture on our page but i don't want to put it on the page yet incase you guys don't like i and since we cant delete it once its up so after your approval i will put it up also i am trying to find good video on organ development since im sure alot are formed by week 10 as i have read in articlese. --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 00:42, 24 September 2014 (EST)

Apologies with my lack of input on this. I’ve added a bit of the Cloacal partitioning and deformities that I’ll expand upon. I’ve also found some great pictures on some of the other GIT deformities. If I’m unable to source permission for them, I’m happy to recreate them --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 07:55, 24 September 2014 (EST)

Definitely put that picture up about Omphalocele. That will work well because I'm talking about midgut herniation so if I talk about it in my stuff then I can just link it so that when you click on it goes down to the bottom of the page to where you talk about it in abnormalities. Not exactly sure how we do that but I'm sure we will work it out.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 13:02, 6 October 2014 (EST)

Hey all just wanted to note that when your referencing from now look at the editing page to see what mark does so that the references are footnotes down the bottom of the page. Obviously you will need to change the reference in the brackets but you get the point. This means that when you do this all the references will come up down the bottom of the page. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 23:34, 6 October 2014 (EST)

Not sure if we are supposed to get rid of the references that we used for our group assignment but I just did because they were taking up uneccesary space on our page. Just thought i would say this here just in case we were not meant to.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 09:17, 8 October 2014 (EST)

Everyone please take off your student signature from the group page as it looks unprofessional. Thanks guys and girls :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 10:07, 8 October 2014 (EST)

'''References'''

Won Kyu Kim, Hyun Kim, Dae Ho Ahn, Myoung Hee Kim, Hyoung Woo Park Timetable for intestinal rotation in staged human embryos and fetuses. Birth Defects Res. Part A Clin. Mol. Teratol.: 2003, 67(11);941-5 PMID:14745932. I used this in describing midgut rotation.
<gallery>

</gallery>

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*References are missing from the overview section. Although it serves as an introduction, you can still include references to support what you're saying. Also, maybe the language of this section should be edited to be a bit more formal, like the 2nd sentence in particular
*GIT = Gastrointestinal tract, not track
*The hyphens between "foregut" etc are not needed
*The timeline is a good idea! Everything was simplified. Maybe look to see if you can add some images to this section
*Week 6 of timeline: I don't think a liver can "obtain" a colour. Look to change the wording
*Maybe to simplify the timeline section better, tabulate the findings according to time (weeks), rather than dividing it by the midgut, foregut and hind gut section. It makes it hard to follow
*Need some more work on the recent findings section. Just some tips, when researching on pubmed, there's an option to look at recent articles by customising dates to say 2012-onwards
*Many potentials for adding images to the "foregut" section. If you find that copyright is too difficult to get around, then you can sketch or trace images from textbooks and upload them
*Great effort with the drawn images in the "midgut" section! Be wary of colour choice though, as the green highlighter and blue pen can be a bit difficult to see. Otherwise think of adjusting contrast on the images to make the diagram stand out more
*Maybe think of adding a video from YouTube to show some features of GIT fetal development, like the rotations. If you do that, be sure to include the 11-digit cache code as your reference point

User:Z3416697

2014-10-08T01:27:32Z

Z3416697: