https://embryology.med.unsw.edu.au/embryology/api.php?action=feedcontributions&user=Z3415716&feedformat=atomEmbryology - User contributions [en-gb]2024-03-29T13:03:19ZUser contributionsMediaWiki 1.39.6https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3415716&diff=161276User:Z34157162014-10-29T00:52:40Z<p>Z3415716: /* Lab Attendance */</p>
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<div>==Lab Attendance==<br />
Lab 1 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:52, 6 August 2014 (EST)<br />
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http://www.ncbi.nlm.nih.gov/pubmed<br />
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[http://www.ncbi.nlm.nih.gov/pubmed PubMed]<br />
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[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]<br />
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<pubmed>25084016</pubmed><br />
Lab 2 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 11:13, 13 August 2014 (EST)<br />
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Lab 3 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:54, 20 August 2014 (EST)<br />
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Lab 4--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:27, 27 August 2014 (EST)<br />
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Lab 5 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:56, 3 September 2014 (EST)<br />
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Lab 6 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:37, 10 September 2014 (EST)<br />
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Lab 8 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:57, 24 September 2014 (EST)<br />
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Lab 9 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:21, 8 October 2014 (EST)<br />
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Lab 10 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:57, 15 October 2014 (EST)<br />
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Lab 11 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:36, 22 October 2014 (EST)<br />
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Lab 12 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 11:52, 29 October 2014 (EST)<br />
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==Assessment Lab 1==<br />
===Article 1===<br />
'''Effect of Vitamin D status on clinical pregnancy rates following in vitro fertilisation'''<br />
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The study undertaken by Garbedian ''et al''. attempted to investigate whether vitamin D (25-hydroxy-vitamin D) serum level of in vitro patients could predict the successfulness of in vitro fertilisation (IVF). 173 patients participated, having met the criteria of age (18-41 years), follicle-stimulating hormone level (≤12IU/L at day 3 of the menstrual cycle), and consent.<br />
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Serum samples were collected from the participating women, prior to oocyte retrieval, and were analysed, dividing the patients into two groups, sufficient (≥75 nmol/L) or insufficient (<75 nmol/L), based on their serum vitamin D levels. Regardless of this division, the IVF procedures were undertaken as per standard protocol. <br />
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This article focused on two main outcomes, embryo implantation, and clinical pregnancy. Implantation was described as the establishment of a gestational sac upon ultrasonography screening. Whereas clinical pregnancy assessed via ultrasound, was determined by the visibility of an intrauterine sac. The results were collated, analysed, and compared between the groups in order to discover a relationship, if any, between serum vitamin D levels and both implantation and clinical pregnancy rates.<br />
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Garbedian and colleagues found significant differences between the groups’ rate of embryo transfer and clinical pregnancy, however this is not the case in implantation rate. In consistency with the IVF protocols, embryo transfer was to take place on day 5, if at least 5-6 acceptable embryos were developed by day 3 of fertilisation. It was discovered that women with a sufficient level of serum vitamin D were more likely to achieve this step by day 5 than women with low serum vitamin D. Moreover, a higher clinical pregnancy rate was observed within the same group of women. An increased value of embryo implantation rate was noted, however results were statistically insignificant. <br />
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With acknowledgement of the study’s limitations, Garbedian ''et al.'' concluded that women sufficient in vitamin D serum levels were more likely to achieve clinical pregnancy following IVF, with serum levels of the vitamin acting as an independent predictor. <br />
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[http://www.ncbi.nlm.nih.gov/pubmed/25077107 Effect of vitamin D status on clinical pregnancy rates following in vitro fertilization.]<br />
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<pubmed>25077107</pubmed><br />
===Article 2===<br />
'''The Role of SPRASA in Female Fertility'''<br />
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Sperm protein reactive with antisperm antibodies (SPRASA) also referred to as sperm lysosome-like protein 1 is a target protein of antisperm antibodies, and is the key protein explored within the article by Wagner ''et al.'' Numerous tests were preformed within this study investigating the role of this protein, particularly in fertilisation and embryonic development. <br />
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The Bovine IVF model was employed to determine the effect of SPRASA antiserum on fertilisation, cleavage, and embryo development. Both bovine zona pellucida-attached and zona pellucida-free oocyte-sperm binding was investigated with the presence of antiserum preparation. Wagner and colleagues were able to conclude that fertility rates significantly reduced when SPRASA antiserum was added to oocytes, and sperm and oocytes samples, but not to sperm samples alone. Further on this note, the study found that the antiserum preparation negatively influenced the zona pellucida-free oocyte (oolemma)-sperm binding process, whereas no significant effect was found in the zona pellucida-attached oocyte-sperm binding. In terms of development, it was discovered that the antiserum was able to inhibit morula stage growth but not the further development at the blastocyst stage. <br />
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Wagner and colleagues also assessed the influence on sperm motility by SPRASA and observed that sperm motility was not an affected area as there was no significant difference between motile sperm in antiserum perpetration and the control group. <br />
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As previously thought that SPRASA was only present in spermatozoa, this study examined whether the protein was also expressed in oocytes and ovaries. Bovine oocytes, and ovaries from cats and dogs, were obtained for this section of the research. Similarly, sperm and sperm precursor cells were collected from testis of cats and dogs in order to illustrate the presence of SPRASA proteins. Results indicated that oocytes express SPRASA and staining was able to localise the protein to the zona pellucida and oolemma of bovine oocytes. Similar preparation and staining was carried out on ovaries of cats and dogs, and returned with positive expression of SPRASA. <br />
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Fertilisation and embryo development was tested via immunisation and mating of female mice. Female mice were either continuously immunised with recombinant human SPRASA protein or irrelevant recombinant keyhole limpet hemocyanin (KLH) protein (control). The mice were then monitored, relocated for mating with male mice, and then compared in terms of pregnancy and fetal development. Wagner ''et al.'' found that all control mice became pregnant after 2 mating cycles, whereas the majority of SPRASA immunised mice failed to achieve pregnancy altogether. In regards to the number of embryo development and weight, no difference was recorded between the control and immunised mice. <br />
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The final test was comparing the antibody levels from blood samples of fertile and infertile couples. Upon analysis of results, Wagner ''et al.'' discovered no significant difference between both fertile and infertile men and women, however 3 of the infertile women presented with inflated levels of the antibodies. <br />
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Wagner ''et al.'' concluded that SPRASA, to a certain extent, plays a role in fertilisation and embryo development. They also rebutted the previous theory that the protein is solely expressed in male gametes with identifying SPRASA within the female reproductive structures.<br />
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[http://www.ncbi.nlm.nih.gov/pubmed/25038051 The Role of SPRASA in Female Fertility.]<br />
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<pubmed>25038051</pubmed><br />
==Assessment Lab 2==<br />
[[File:WNT4_screening_in_the_testis_of_the_tammar_wallaby.jpeg|300px|left|thumb|WNT4 screening in the testis of the tammar wallaby]]<br />
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<pubmed>17014734</pubmed>| [http://www.biomedcentral.com/1471-213X/6/44 Biomed Central]<br />
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--[[User:Z8600021|Mark Hill]] This is fine and description with the image is good. You should have also reproduced the figure description and the reference here on your page. (4/5)<br />
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==Assessment Lab 3==<br />
<pubmed>18462432</pubmed><br />
<pubmed>17232227</pubmed><br />
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]<br />
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--[[User:Z8600021|Mark Hill]] These are relevant articles. I wonder why the third reference is not listed in PubMed Database? This usually indicates the relevance of the journal in the peer review system (4/5).<br />
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==Assessment Lab 4==<br />
===Article 1===<br />
'''Conversion of human umbilical cord mesenchymal stem cells in Wharton's jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism'''<br />
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Parkinson’s disease is a neurodegenerative disorder associated with the degradation of the dopaminergic system in the striatum region of the brain. Current short-term treatment for Parkinson’s disease is antiparkinson medications, mainly enhancing dopamine levels, however such medications reduce in effectiveness with further degradation of the neurotransmitter’s pathway. The study led by Fu, however, proposes a potential long-term treatment for Parkinson’s disease, utilising induced human mesenchymal stem cells (HMSCs) originating in the Wharton’s jelly of the umbilical cord. <br />
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Fu ''et al.'' isolated HMSCs from the umbilical cord exposing the cells to subsequent chemical treatment resulting in the differentiation of these multipotent cells into dopaminergic neurones. These neurones were then injected into the subjects, adults rats with induced Parkinson’s post unilateral striatal lesioning. Subjects were compared with control untreated rats, concluding that the transplanted group exhibited a substantial improvement in rotational behaviour and Parkinson’s symptoms, however not enough to deem them cured from the disease. <br />
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The potential for HMSCs, isolated from the umbilical cord, to correct Parkinson’s disease is further emphasised in its easy isolation methods, the large amount of cells able to be isolated, and the simple duplication of these stem cells. Fu ''et al.'' were able to collect 1x10^6 HUMSCs from 20 cm of umbilical cord and duplicate the amount to 2x10^6 cells in a three day incubation period. Furthermore, the study found that the transplanted differentiated cells were still successful 4 months post procedure, suggesting that this method may be a long-term treatment for the disease. The investigation also comments on the prospect of HUMSCs as a source for transplantation, attributed to its non-immunological inducing characteristic.<br />
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<pubmed>16099997</pubmed><br />
===Vascular shunts===<br />
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There are three shunts within the foetal circulatory development that close postnatally:<br />
*Ductus arteriosus<br />
A canal that connects the foetal pulmonary artery to the aorta, distributing oxygenated blood to the foetus while bypassing the developing lungs. <br />
*Ductus venosus <br />
Connecting the left umbilical vein to the inferior vena cave, allowing placental oxygenated blood to bypass the liver.<br />
*Foramen ovale<br />
A foramen within the interatrial septum where blood from the right atrium enters the left atrium.<br />
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==Assessment Lab 5==<br />
===Oesophageal atresia===<br />
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Oesophageal atresia is a rare gastrointestinal developmental abnormality, however in terms of oesophageal anomaly it is the most common, with one newborn out of every 2500 to 4500 being diagnosed within the first 24 hours of life [1]. Oesophageal atresia is diagnosed with the discontinuity of the oesophagus from the oral cavity to the stomach, where the oesophagus ends abruptly not in contact with the cardia of the stomach.<br />
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Oesophageal atresia can be classified into five variants according to the location of the atresia and any associated tracheal fistulas (tracheoesophageal fistula) [1]. The five classifications include: oesophageal artesia without tracheoesophageal fistula, proximal tracheoesophageal fistula with distal oesophageal atresia, distal tracheoesophageal fistula with proximal oesophageal atresia, proximal and distal tracheoesophageal fistula, and tracheoesophageal fistula without oesophageal atresia [1]. <br />
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The cause for this gastrointestinal abnormality is unclear and research continues to take place. With that said, various theories of the embryological origin of this anomaly have been proposed [1]. Three forefront theories comment on the primitive digestive tube and its failure to form a successful diverticulum, resulting in the connection of the trachea and oesophagus (tracheoesophageal fistula). In terms of the formation of oesophageal atresia, two of the three theories reason that the cellular distal portion of the primitive digestive tube rearranges and results in an abnormal discontinuous growth; whereas the third theory emphasises that the atresia is a consequence from regression of that portion of the tube towards the main part of the embryo. Currently no genetic roles have been identified in this developmental abnormality [1].<br />
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Regardless of the lack of information gathered about the cause of oesophageal atresia, more advanced correctional surgeries have been introduced in the past decade [2]. Survival rates differ immensely between various nations, particularly when comparing developed to developing countries. In certain clinics, with state-of-the-art neonatal care, survival rates of up to 95% has been documented [1]. Surgical methods such as thoracoscopic repair has been improved within the past decade, resulting to a decrease in surgical complications and therefore an increase in survival rates [2].<br />
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[1] <pubmed>22851858</pubmed><br />
[2] <pubmed>22584690</pubmed><br />
==Assessment Lab 7==<br />
===Article 1===<br />
'''Fetal Adrenal Gland in the Second Half of Gestation: Morphometric Assessment with 3.0T Post-Mortem MRI'''<br />
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The adrenal gland, a bilateral organ located immediately superior the kidneys, are part of the endocrine system, playing an important role in releasing certain hormones such as cortisol and adrenaline in response to various situations including stressful situations. It is said that the adrenal gland is crucial in foetal development and that in comparison to other foetal organs, the foetal adrenal gland is relatively large. The study carried out by Zhonghe ''et al.'' quantitatively assessed the length, width, height, surface area and volume of normal foetal adrenal glands.<br />
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52 foetal specimens ranging from 23-40 gestation weeks old were the subjects of this experiment. 72 foetal specimen were collected based on parental consent and in accordance with the Ethical Committee at the School of Medicine, Shandong University. Out of the 72 only 52 were utilised as foetuses with known abnormal maternal pregnancy records did not meet the criteria. The 52 subjects were organised in terms of their gestational age, found by measuring their crown-rump length via MRI. A highly advanced MRI scanner, SIEMENNS 3.0T MR scanner, was then employed in this research, measuring the adrenal glands of the foetus in the transverse, coronal and sagittal axis. Post-scanning, four specimens (24, 26, 32 and 36 weeks gestation age) were selected for gross anatomy dissection and measurement. <br />
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Upon completing the measurements and gross dissections, Zhonghe ''et al.'' found that the bilateral organ was asymmetrical, with the right adrenal gland resembling an irregular triangle or pyramid, whereas the shape of the left adrenal gland was closer to a half-moon and larger than its right counterpart. No significant difference was found between the sexes, in contrast to previous research articles, however Zhonghe ''et al.'' attributed this discrepancy on it's relatively small group of specimens and uneven distribution of male and female foetuses. It was also discovered that as the gestational age increases the zona glomerulosa (outer zone of the cortex layer) became thicker.<br />
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Zhonghe ''et al.'' regard their research and results as valuable in clinical settings and useful reference for the foetal anatomy. <br />
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<pubmed>24116052</pubmed><br />
===Tooth Development===<br />
Odontogenesis begins in the sixth week of development. The embryonic cells/layers that differentiate to form the developing tooth include:<br />
* Odontoblasts — mesenchymal neural crest originating cells that secrete predentin, which calcifies to form dentin, the inner layer of the tooth. These cells are present throughout life and continuously produce dentin.<br />
* Ameloblasts — ectodermal cells of the oral epithelium that produce enamel, the outermost layer in the crown part of the tooth. Only present during odontogenesis. <br />
* Periodontal ligament — a specialised connective tissue that is in contact with the cementum layer (outer layer in the root of the tooth) and holds the tooth within the alveolar process.<br />
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==Assessment Lab 8==<br />
===Ovary Development===<br />
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Embryonic female differentiation and development was once perceived as a passive process, simply by the failure of developing male genital organs, however it is shown that this is not the case, with many molecular and genetic prerequisites required to develop the female genital system. <ref><pubmed>15664455</pubmed></ref><br />
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Identical to the testes, the ovaries originate from the mesothelium, the underlying mesenchyme, and primordial germ cells. Within the early embryo, the gonads consists of a mesonephric duct (Wolffian duct), paramesonephric ducts (Mullerian ducts), and the external cortex and internal medulla regions. <br />
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Gonadal development begins in the fifth week, medially to the mesonephros. The first structure of the developing gonad is the gonadal ridge. This ridge is formed by the proliferation of the mesenchyme tissue. The proliferating mesenchyme then grow epithelial cords, known as gonadal cords that extend to the developing ovary later on. <br />
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The primordial germ cells, undifferentiated sex cells, become visible by day 24 of the embryonic period. The germ cell is relocated to the gonadal ridges during the folding process of the embryo.<br />
In the late embryonic phase, the lack of anti-mullerian hormone and testosterone is what beings the differentiation between the male and female genital development. At this point of time the Wolffian duct degenerates but the Mullerian ducts remain, in contrast to the male gonadal development. It is the Mullerian ducts that develop into the internal genital organs, the upper part into the fallopian tubes, and the lower part into the uterus and the vagina. <ref><pubmed>13230915</pubmed></ref><br />
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During the 10th week, the ovaries become recognisable with the gonadal cords extending into the surface of the ovary. It is within this foetal developmental phase, beginning in the 16th week, that the gonadal cords commence degeneration forming primordial oocytes, referred to as oogonium. These oogonia, surrounded by a thin layer of epithelial cells, are the primordial follicles that a formed by mitosis.<br />
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[[File:Bailey329.jpg|600px]]<br />
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'''Transverse section of the ovary of a fox embryo'''<br />
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===References===<br />
<references/><br />
'''Textbook''' [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466393265-4#4-u1.0-B978-1-4377-2002-0..00012-6--f0150 Moore: The Developing Human Chapter 12]<br />
* ''Note: Access to UNSW database requires a valid UNSW username and zPass''<br />
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==Assessment Lab 9==<br />
===Peer review===<br />
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'''Group 1 — Respiratory'''<br />
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The introduction is shaping quite well. The information used are all relevant and provide an overall understanding of the respiratory system. It is great how you have divided the system into the two main parts, the conducting zone and respiratory zone, providing information and images for both. With that said, the images contain no caption or any description when clicked on and more work is needed in this area as explaining the images/slides will heighten the educational aim of the project. Furthermore, as Mark Hill has mentioned, you must cover all the components required in uploading and using an image, such as adding the copyright information. <br />
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Presenting the lung development stages in a table format is very clever and the table constructed contains valuable information simplifying the developmental stages of the respiratory system. You have gone one step further than the required by showing that development does not only occur embryonically but up to 8 years of age. Good work. In terms of the references in this section, they all seem to be fine, however I am unable to click on the “Lung Development” link, which returns with “object not found.” So please fix that issue as the reader/marker must be able to validate all the references if need be.<br />
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The current research section of this project page seems promising with a wide range of information. The foundations and structure are present however more information is required, which I know will be added before final submission. Identical to the introduction, it is good that you have divided the section into subsections based on the current research style and understanding that physiologically the lungs can be divided into the conduction system and functional unit. Numbering and dot points may be used, but I highly recommend that it is not used throughout the whole section. Moreover, your addition of an image highlighting Schematic lung disease and normal vs diseased lung models is appropriate for current research and models, however it should not be placed at the end under the references, you need to find a place between a paragraph that discusses or introduces this model. Lastly, there is a small formatting error in the middle of this section, I assume that is where an image should be located however check if you have written the command correctly. <br />
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It is obvious that the historical section is well researched and that a number of articles have been referenced. The use dot points and dates are great and simple to understand, however if you make a timeline and paragraphs, the page might look more professional. You have the information required to create a simple timeline and paragraphs that follow. Great historical images used however the first lacks any description and the second lacks a reference. <br />
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A vast range of abnormalities are addressed with references and thorough research into each. Some require more information, but overall all abnormalities are mentioned at a substantial extent with both full sentences and dot points. <br />
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Overall this group has provided a well researched project, certain formatting errors need to be addressed and some more information can be added, otherwise good work!<br />
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'''Group 2 — Renal'''<br />
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The introduction successfully touches on the project as a whole, including describing the system and its development, and the abnormalities that may arise. However it has failed to mention the importance of historical and current research. Also adding an image of the renal system or the renal units in particular will heighten the readers interest in this project.<br />
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There seems to be no information under the historical findings subheading, it might be hard to find research papers on this system, however a good start would be reading Mark Hill’s page on the renal development.<br />
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A very brief developmental timeline, however it does simply provide the information required to understanding the timeframe of renal development. More information about the structures mentioned in this timeline is required, this can be added within the timeline or following it.<br />
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The current research model section needs more information, if you are unable to find enough to make a substantial section then a possibility to work around that is to integrate the various research models with the organ sections. However, if more information can be obtained then this section should be left and continued as the image is correctly included and the information is written at a high standard.<br />
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The division of this page into the various organs in the renal system, the kidney, urethra, and ureter is clever as providing information on all in one section may be overwhelming. Each of these organs are well researched and written about. The layout looks fine with the paragraphs placed under subheadings and an abundant amount of images are located next to their corresponding information. Some images do not have a description, it is best to add a description, even a short one, to guide the reader and pinpoint the reason for uploading. An error has occurred for the first image under the Kidney section which has been removed by the administrator. Please take care with copyright. <br />
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I really like the abnormality section and the information added thus far. It is evident that you plan to continue as this section is not finished, however with what is there, great work. Both images used contain captions and clearly understood descriptions. One fault is the presence of references in this section. The group has one reference heading at the end of the project, however some of the references doubled up within the abnormalities section. One that note, please look carefully through the referencing list as you have the same articles more than once in the list, for example 23 and 24. There is a way of merging them together and having superscripts indicate that this article has been cited more than once, use article 28 and 30 as examples. <br />
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'''Group 3 — Gastrointestinal'''<br />
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The overview is quite short and lacks citations and images, however this is understandable seeing as it is a draft copy, but please make sure the overview informations are cited and images are included. The information uploaded so far is structured based on the division of the gut into fore-gut, mid-gut and hind-gut, and very easy to follow.<br />
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An extensive timeline, however the presentation can be improved as this timeline takes a lot of space and consists of a single word or a sentence. Maybe adding more information in the timeline or condensing the timeline in a table format.<br />
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I don’t understand the recent findings section as only one research paper has been considered. If more will be added then that is fine however when writing about these findings it’s good to incorporate it with other findings rather than simply summarising the results of one article. <br />
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Foregut, midgut and hindgut are well covered including innervations and structures of those areas. A range of format is used such as table, dot point and full paragraphs, which neatly tie all the information together and allows for a break in between paragraphs. Student redrawn images are a great source and you have referenced from where you have obtained the original image. No images are used for the foregut even though you have mentioned a few organs in detail. Furthermore, it is best to keep your formatting consistent as the dot points in the foregut section differs to those in midgut.<br />
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Detailed examples of deformities are present in the gastrointestinal system, however more deformities should be looked at and included. Deformities are also mentioned under the subheading of hindgut (Anorectal deformities, cloacal extrophy, and developmental problems), which might be best moved to the deformities block of the project page. This redrawn image is clear and labelled, however there is no reference. <br />
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Overall the project page is interesting, easy to comprehend and follow, however certain layout issues should be addressed and more information added. <br />
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'''Group 5 — Integumentary''' <br />
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The introduction covers all the topics of the project, however it does so briefly. Merging the development overview with the introduction will hide the fact that the introduction paragraph is short as this whole section will become one large detailed introduction about the integumentary system. The development overview is detailed and separated in terms of the structures found in the system. This is great, however less dot points should be used as it looks more like notes than presentable information. The creation of this timeline table is amazing and addition of the images according to the weeks is a well generated idea. Not all the images are described, so please do so for the final copy as it is essential that images of histological slides are describes as they can be confusion and difficult to understand. The information about hair and its adjacent image is the scaffold that should be followed throughout the whole section, as it has been written concisely and easily understandable. The hair development stages image is adequately describes and references with the copyright statement. Well done.<br />
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I appreciate the uniqueness in the layout of the recent findings, however I find it slightly overwhelming and out of place. Possibly adding a collapse and expand option to each article is beneficial. The summaries of the findings are in-depth and it is obvious that the author of this summary understands the topic.<br />
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A great start in historic findings with information present for a wide range of structures in this system. With that said, each section requires more research, however you are on the right path in finding articles greater than 50 years old. Only one image is attempted to be added, it is hard to find copyright granted images or historical drawings, but redrawing those original images is vital in providing solid historical information. In terms of the referencing, if you are unable to find a PMID for a certain article then manually add the reference and the URL link as you have but adhere to correct formatting.<br />
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Each abnormality is consistent with detailed information, statistics and a described image. The writing style is consistent and the image uploads with captions are correctly completed. Great work. The information is frequently cited emphasising efficient research ability. On that note, the references are correctly numbered and superscripts used instead of repeating the reference. <br />
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'''Group 6 — Endocrine'''<br />
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An introduction has not yet been added, however when doing so aim to mention the gist of the project and the manner in which is has been divided so that the reader/marker can effectively understand what is in this project. The wikipage is separated into the numerous endocrine organs, which is great as a future student can easily navigate to the organ of interest. <br />
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As it is only a draft copy it is assumed that improvement and adding of information will take place leading to the submission of the final as there are subheadings such as “Recent findings” that have been left blank. With what is currently present, each organ contains well researched information. In the beginning two organs, the pineal gland and hypothalamus, there is a subheading for abnormalities, however there is also a section towards the end of the wikipage solely for abnormalities, so refrain from doubling up on the information and either place all the abnormalities in one section or separate the malformations in terms of their respective structure. References are also seen at the end of each section or subsection and no in-text citation has been used yet, so it might be easier to cite the dot points or information as you go so you can remember where you got that from instead of trying to find that piece in the numerous research articles you have. Once that has been done, it will be best to relocate all the references at the end of the page, where you have already made the heading.<br />
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The structure is consistent throughout the page with each organ having a timeline and most containing an image and a table. This makes the project appealing and easy to read and understand. All the images uploaded contain comprehensive information and thus I am able to decipher the image and as a result enriches the learning aims of this assignment. The creation of a timeline for each organ is clever as each exhibits its own developmental process. The separation into many smaller timelines allows for specific events to be included that would otherwise overload a collective timeline. The setup of a table under the organisation of hormone, cells and function further simplifies an extremely complicated developmental system. As a student learning about the endocrine system I would be relieved to discover tables and content of this standard and structure. <br />
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'''Group 7 — Neural (CNS)'''<br />
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Solid introduction, it is well conveyed and divided into the two main organs of the CNS, the brain and the spinal cord. You have not just listed the two organs but also introduced both individually, describing their components and functions. Nice work.<br />
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The layout of this page is well thought through as you it begins with the overall neural development in the foetal period, then delves into the development of the two main organs, firstly the brain development, followed by the spinal cord development. This makes the project easy to understand as it is well organised. Within each subsection there has been images uploaded and tables added in addition to the information in both paragraph and dot point format. Majority of the images uploaded contain a description as well as the caption, however some descriptions require more to help clarify the image and for some no description is present, such as the image of the newborn with a giant occipital encephalocele. All have a caption, however I recommend you change the formatting of the image so that the caption is location just under the image and not within the text as you have done. <br />
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A timeline of neural development is added at the beginning in the form of a drawing and another timeline, more specific to sulcation and gyration, is added under brain development. These are great to use as it collaborates all the information into a clear and comprehensive piece. <br />
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The spinal cord development and meninges development lack information at this stage, so when filling up this section, it will be best to ensure you are consistent with the formatting and follow what has been used in the brain development section. Add as many tables, timelines and images as possible as this simplifies the information and enriches the page in terms of interest and completing the objectives of this assignment. The same goes for current research models and findings, I can see you have many references ready to be used and that this section has a lot of information. So that the project does not become overwhelming, it is not necessary to summarise or present all the findings, but only chose the most important and influential. You can also merge some research together if they focus on similar or identical concepts. <br />
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The abnormalities section is shaping up well. You have included many abnormalities that can occur in this system, so if you are able to write about each and include an image, then that will be great. Possibly refrain from writing it all in dot points, but that could only be the case because it is a draft copy. There is an error in an image uploaded about the facial characteristics associated with foetal alcohol syndrome. It returns with permission error so before uploading ensure that you are not breaching any copyright laws. You may even draw it or find another image similar that allows you to use it. <br />
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Listing all the references at the end of the page is a great idea. Some references are listed more than once because you have cited them in more than one place throughout the assignment. Such examples are 7 and 8, and 9 and 10. There is a command that allows you to use superscript where the one reference is listed with many superscripts, each corresponding to the different areas in which you have cited that article. <br />
----<br />
'''Group 8 — Musculoskeletal'''<br />
<br />
The Making Gains section is quite funny but as you said, this is not Broscience and I’m sure it will be removed for the final submission. Once that is removed, begin the project with an introduction and the developmental general timeline. The main idea of the timeline is present, however when constructing one, use specific weeks within the foetal period and what developmental changes occur in those weeks. The information found under Background Embryonic development may be used to form the introduction, but if you are going to do that do not make the introduction as detailed as this section is, particularly in terms of the transcription factors and signalling molecules, they can be moved and added into the other sections that look at the various musculoskeletal developments individually.<br />
<br />
It is evident that there is great understanding of this topic and that it is only a case of further research and addition of those information to complete the sections. Certain sections lack information all together, such as the Third Trimester Muscular development and Recent findings, whereas other sections only contain the research articles and no summaries of them such as Abnormalities. However I understand this is a draft and that all those areas will be addressed adequately, contributing to the final copy. <br />
<br />
Only the Background Embryonic development and Molecular and Cellular regulation of foetal myogenesis have in text citations, whereas the other sections that do contain information are not cited. It might become difficult to later find the correct article from which you obtained the information so it is advised to cite the text while adding it. In terms of the citations present, there is no need for a comma between the superscripts and you have also allocated two sections to references, one subsequent to Abnormalities and another at the bottom of the page, it is best to collate all the references in one list at the end of the page. This is also the case for Abnormalities as there are two subheadings for it, merge them into one. <br />
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No images, tables, or timelines are added. The information you have now is well written and divided into small paragraphs, which is a good way of presenting the information, however other forms such as images and tables should be used. A timeline should be added under the Muscle development General Timeline subheading, this may be done as a table or a drawing and uploaded as it simplifies the information and breaks the page from continuous writing. <br />
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Overall this group project page is great, containing all the headings and articles present. It is only a matter of summarising those articles and adding the information. All the information present thus far is appropriate and emphasises great research skills.<br />
<br />
==Assessment Lab 10==<br />
'''Neural crest contribution to lingual mesenchyme, epithelium and developing taste papillae and taste buds'''<br />
<br />
The study by Liu ''et al.'' aimed to discover if neural-crest derived cells contribute to the tongue mesenchyme and epithelium including taste papillae and taste buds. To test this, they utilised tissues from four different transgenic mice, separated by Cre recombinase enzyme, ''Wnt1-Cre'' and ''P0-Cre'', and further divided into two reporter lines, ''R26R lacZ'' and ''ZEG'' double reporter, producing four unique mouse lines (''Wnt1-Cre/R26R'', ''Wnt1-Cre/ZEG'', ''P0-Cre/R26R'' and ''P0-Cre/ZEG''). This then allowed Liu and his colleagues to quantitatively examine the expression of all the papillae, as previous research indicated that some of the papillae contain a distinct test array and require a different method of analysis. <br />
<br />
The mice population consisted of embryonic and postnatal mice, up to 10 days old, with their litter collected and genotyped via polymerase chain reaction (PCR). A control group was included with their litter also collected. Various experiments were carried out to test for the four types of lingual papillae; fungiform, filiform, foliate and circumvallate. <br />
<br />
X-Gal staining and labelling was used to test for fungiform papillae in the ''P0-Cre/R26R'' mouse tongue. The taste buds were then divided into three categories based on their expression rate under light microscopy. Immunohistochemistry was also employed in this study, with slides treated with primary and secondary antibodies to illicit an immunoreaction that could be quantitatively recorded. <br />
<br />
The embryonic mice sample and the newborn mice (P1) that were treated with ''Wnt1-Cre'' were examined for the location of the neural crest-derived cells. Upon completion, it was found that the neural crest-derived cells were primarily located in the lingual mesenchyme of both the embryonic and postnatal mice, however it was shown that as the tongue develops, the cells become more localised, immediately under the lingual epithelium. This was uniform with the findings on the tongues of the ''Wnt1-Cre/ZEG'' type mice, and thus Liu ''et al.'' concluded that these neural crest-derived cells are abundant within the papilla mesenchyme and in the core of the taste papillae. However, a different conclusion was reached for the tongue epithelium of the ''Wnt1-Cre'' type population, where these neural crest-derived cells were rarely found. <br />
<br />
The fungiform papillae were tested in the ''P0-Cre'' line mice. The distribution pattern of the neural crest-derived cells in the mesenchyme was similar to that in the ''Wnt1-Cre'' samples. A different result, however, was obtained for the epithelium, as the desired cells were found to be located in the epithelium and the taste buds of the tongue, indicating that neural crest-cells contributed greatly to the fungiform papillae.<br />
<br />
Antibodies were added into samples of developed tongues and no Cre immunoreactivity took place in those tissues, highlighting the validity of the study in tracing the cell lineage and removing doubts that ectopic ''Cre'' activity was in fact responsible for the results and not true ''P0''-expressing cells.<br />
<br />
Base on their findings, Liu et al. proposed that neural crest cell from the neural tube migrate to the developing tongue mesenchyme and epithelium. They further explained that subsequent to migration into the epithelium, these cells acquire different phenotypes and differentiate into taste papillae. The taste papillae interact with the neural crest-derived cells that remain in the mesenchyme, which have roles in the development and maintenance of the taste papillae.<br />
<br />
<pubmed>22659543</pubmed><br />
<br />
==Assessment Lab 11==<br />
'''Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration''' <br />
<br />
The research carried out by Masumoto et al. aimed to simultaneously induce cardiomyocytes and vascular cells, and generate human induced pluripotent stem cell (hiPSC)-engineered cardiovascular cell sheets. They hypothesised that a sheet of this sort can be therapeutically beneficial to patients with infarcted hearts. <br />
<br />
hiPSC was collected and established in a culture. Masumoto et al. used this type of stem cell because they were interested in its ability to continuously expand and efficiency in differentiate into most somatic cells lineages. These cells later underwent cardiovascular cell differentiation, forming cardiomyocytes, endothelial cells, and mural cells (vascular smooth muscle cells and pericytes), and further incubated. <br />
<br />
Male athymic nude rats, between the ages of 10-13 weeks were used in this study. Myocardial infarction was induced in all the rats. The subjects were then divided into two random groups, one group receiving the true cell sheets in transplant, the Tx group, and the other undergoing a sham-operation, the sham group. The translation took place 1 week after induced myocardial infarction, known as the “sub-acute phase”.<br />
<br />
The stem-cell graft was made by pilling 3 sheets together and then transplanted into the infarcted hearts of the Tx group rats. Upon concluding, Masumoto et al. found a significant improvement in the cardiac function of the rat population in the Tx group. Upon check-up at the 4th week post-surgery, they found presence of cardiomyocytes in more than 40% of the transplanted rats, therefore highlighting the importance of hiPSC-CTSs in cardiac regenerative therapy. <br />
<br />
<pubmed>25336194</pubmed></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3415716&diff=161174User:Z34157162014-10-28T23:09:17Z<p>Z3415716: /* Assessment Lab 11 */</p>
<hr />
<div>==Lab Attendance==<br />
Lab 1 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:52, 6 August 2014 (EST)<br />
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http://www.ncbi.nlm.nih.gov/pubmed<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed PubMed]<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]<br />
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<pubmed>25084016</pubmed><br />
Lab 2 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 11:13, 13 August 2014 (EST)<br />
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Lab 3 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:54, 20 August 2014 (EST)<br />
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Lab 4--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:27, 27 August 2014 (EST)<br />
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Lab 5 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:56, 3 September 2014 (EST)<br />
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Lab 6 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:37, 10 September 2014 (EST)<br />
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Lab 8 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:57, 24 September 2014 (EST)<br />
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Lab 9 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:21, 8 October 2014 (EST)<br />
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Lab 10 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:57, 15 October 2014 (EST)<br />
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Lab 11 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:36, 22 October 2014 (EST)<br />
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==Assessment Lab 1==<br />
===Article 1===<br />
'''Effect of Vitamin D status on clinical pregnancy rates following in vitro fertilisation'''<br />
<br />
The study undertaken by Garbedian ''et al''. attempted to investigate whether vitamin D (25-hydroxy-vitamin D) serum level of in vitro patients could predict the successfulness of in vitro fertilisation (IVF). 173 patients participated, having met the criteria of age (18-41 years), follicle-stimulating hormone level (≤12IU/L at day 3 of the menstrual cycle), and consent.<br />
<br />
Serum samples were collected from the participating women, prior to oocyte retrieval, and were analysed, dividing the patients into two groups, sufficient (≥75 nmol/L) or insufficient (<75 nmol/L), based on their serum vitamin D levels. Regardless of this division, the IVF procedures were undertaken as per standard protocol. <br />
<br />
This article focused on two main outcomes, embryo implantation, and clinical pregnancy. Implantation was described as the establishment of a gestational sac upon ultrasonography screening. Whereas clinical pregnancy assessed via ultrasound, was determined by the visibility of an intrauterine sac. The results were collated, analysed, and compared between the groups in order to discover a relationship, if any, between serum vitamin D levels and both implantation and clinical pregnancy rates.<br />
<br />
Garbedian and colleagues found significant differences between the groups’ rate of embryo transfer and clinical pregnancy, however this is not the case in implantation rate. In consistency with the IVF protocols, embryo transfer was to take place on day 5, if at least 5-6 acceptable embryos were developed by day 3 of fertilisation. It was discovered that women with a sufficient level of serum vitamin D were more likely to achieve this step by day 5 than women with low serum vitamin D. Moreover, a higher clinical pregnancy rate was observed within the same group of women. An increased value of embryo implantation rate was noted, however results were statistically insignificant. <br />
<br />
With acknowledgement of the study’s limitations, Garbedian ''et al.'' concluded that women sufficient in vitamin D serum levels were more likely to achieve clinical pregnancy following IVF, with serum levels of the vitamin acting as an independent predictor. <br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/25077107 Effect of vitamin D status on clinical pregnancy rates following in vitro fertilization.]<br />
<br />
<pubmed>25077107</pubmed><br />
===Article 2===<br />
'''The Role of SPRASA in Female Fertility'''<br />
<br />
Sperm protein reactive with antisperm antibodies (SPRASA) also referred to as sperm lysosome-like protein 1 is a target protein of antisperm antibodies, and is the key protein explored within the article by Wagner ''et al.'' Numerous tests were preformed within this study investigating the role of this protein, particularly in fertilisation and embryonic development. <br />
<br />
The Bovine IVF model was employed to determine the effect of SPRASA antiserum on fertilisation, cleavage, and embryo development. Both bovine zona pellucida-attached and zona pellucida-free oocyte-sperm binding was investigated with the presence of antiserum preparation. Wagner and colleagues were able to conclude that fertility rates significantly reduced when SPRASA antiserum was added to oocytes, and sperm and oocytes samples, but not to sperm samples alone. Further on this note, the study found that the antiserum preparation negatively influenced the zona pellucida-free oocyte (oolemma)-sperm binding process, whereas no significant effect was found in the zona pellucida-attached oocyte-sperm binding. In terms of development, it was discovered that the antiserum was able to inhibit morula stage growth but not the further development at the blastocyst stage. <br />
<br />
Wagner and colleagues also assessed the influence on sperm motility by SPRASA and observed that sperm motility was not an affected area as there was no significant difference between motile sperm in antiserum perpetration and the control group. <br />
<br />
As previously thought that SPRASA was only present in spermatozoa, this study examined whether the protein was also expressed in oocytes and ovaries. Bovine oocytes, and ovaries from cats and dogs, were obtained for this section of the research. Similarly, sperm and sperm precursor cells were collected from testis of cats and dogs in order to illustrate the presence of SPRASA proteins. Results indicated that oocytes express SPRASA and staining was able to localise the protein to the zona pellucida and oolemma of bovine oocytes. Similar preparation and staining was carried out on ovaries of cats and dogs, and returned with positive expression of SPRASA. <br />
<br />
Fertilisation and embryo development was tested via immunisation and mating of female mice. Female mice were either continuously immunised with recombinant human SPRASA protein or irrelevant recombinant keyhole limpet hemocyanin (KLH) protein (control). The mice were then monitored, relocated for mating with male mice, and then compared in terms of pregnancy and fetal development. Wagner ''et al.'' found that all control mice became pregnant after 2 mating cycles, whereas the majority of SPRASA immunised mice failed to achieve pregnancy altogether. In regards to the number of embryo development and weight, no difference was recorded between the control and immunised mice. <br />
<br />
The final test was comparing the antibody levels from blood samples of fertile and infertile couples. Upon analysis of results, Wagner ''et al.'' discovered no significant difference between both fertile and infertile men and women, however 3 of the infertile women presented with inflated levels of the antibodies. <br />
<br />
Wagner ''et al.'' concluded that SPRASA, to a certain extent, plays a role in fertilisation and embryo development. They also rebutted the previous theory that the protein is solely expressed in male gametes with identifying SPRASA within the female reproductive structures.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/25038051 The Role of SPRASA in Female Fertility.]<br />
<br />
<pubmed>25038051</pubmed><br />
==Assessment Lab 2==<br />
[[File:WNT4_screening_in_the_testis_of_the_tammar_wallaby.jpeg|300px|left|thumb|WNT4 screening in the testis of the tammar wallaby]]<br />
<br />
<br />
<pubmed>17014734</pubmed>| [http://www.biomedcentral.com/1471-213X/6/44 Biomed Central]<br />
<br />
--[[User:Z8600021|Mark Hill]] This is fine and description with the image is good. You should have also reproduced the figure description and the reference here on your page. (4/5)<br />
<br />
==Assessment Lab 3==<br />
<pubmed>18462432</pubmed><br />
<pubmed>17232227</pubmed><br />
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]<br />
<br />
--[[User:Z8600021|Mark Hill]] These are relevant articles. I wonder why the third reference is not listed in PubMed Database? This usually indicates the relevance of the journal in the peer review system (4/5).<br />
<br />
==Assessment Lab 4==<br />
===Article 1===<br />
'''Conversion of human umbilical cord mesenchymal stem cells in Wharton's jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism'''<br />
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Parkinson’s disease is a neurodegenerative disorder associated with the degradation of the dopaminergic system in the striatum region of the brain. Current short-term treatment for Parkinson’s disease is antiparkinson medications, mainly enhancing dopamine levels, however such medications reduce in effectiveness with further degradation of the neurotransmitter’s pathway. The study led by Fu, however, proposes a potential long-term treatment for Parkinson’s disease, utilising induced human mesenchymal stem cells (HMSCs) originating in the Wharton’s jelly of the umbilical cord. <br />
<br />
Fu ''et al.'' isolated HMSCs from the umbilical cord exposing the cells to subsequent chemical treatment resulting in the differentiation of these multipotent cells into dopaminergic neurones. These neurones were then injected into the subjects, adults rats with induced Parkinson’s post unilateral striatal lesioning. Subjects were compared with control untreated rats, concluding that the transplanted group exhibited a substantial improvement in rotational behaviour and Parkinson’s symptoms, however not enough to deem them cured from the disease. <br />
<br />
The potential for HMSCs, isolated from the umbilical cord, to correct Parkinson’s disease is further emphasised in its easy isolation methods, the large amount of cells able to be isolated, and the simple duplication of these stem cells. Fu ''et al.'' were able to collect 1x10^6 HUMSCs from 20 cm of umbilical cord and duplicate the amount to 2x10^6 cells in a three day incubation period. Furthermore, the study found that the transplanted differentiated cells were still successful 4 months post procedure, suggesting that this method may be a long-term treatment for the disease. The investigation also comments on the prospect of HUMSCs as a source for transplantation, attributed to its non-immunological inducing characteristic.<br />
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<pubmed>16099997</pubmed><br />
===Vascular shunts===<br />
<br />
There are three shunts within the foetal circulatory development that close postnatally:<br />
*Ductus arteriosus<br />
A canal that connects the foetal pulmonary artery to the aorta, distributing oxygenated blood to the foetus while bypassing the developing lungs. <br />
*Ductus venosus <br />
Connecting the left umbilical vein to the inferior vena cave, allowing placental oxygenated blood to bypass the liver.<br />
*Foramen ovale<br />
A foramen within the interatrial septum where blood from the right atrium enters the left atrium.<br />
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==Assessment Lab 5==<br />
===Oesophageal atresia===<br />
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Oesophageal atresia is a rare gastrointestinal developmental abnormality, however in terms of oesophageal anomaly it is the most common, with one newborn out of every 2500 to 4500 being diagnosed within the first 24 hours of life [1]. Oesophageal atresia is diagnosed with the discontinuity of the oesophagus from the oral cavity to the stomach, where the oesophagus ends abruptly not in contact with the cardia of the stomach.<br />
<br />
Oesophageal atresia can be classified into five variants according to the location of the atresia and any associated tracheal fistulas (tracheoesophageal fistula) [1]. The five classifications include: oesophageal artesia without tracheoesophageal fistula, proximal tracheoesophageal fistula with distal oesophageal atresia, distal tracheoesophageal fistula with proximal oesophageal atresia, proximal and distal tracheoesophageal fistula, and tracheoesophageal fistula without oesophageal atresia [1]. <br />
<br />
The cause for this gastrointestinal abnormality is unclear and research continues to take place. With that said, various theories of the embryological origin of this anomaly have been proposed [1]. Three forefront theories comment on the primitive digestive tube and its failure to form a successful diverticulum, resulting in the connection of the trachea and oesophagus (tracheoesophageal fistula). In terms of the formation of oesophageal atresia, two of the three theories reason that the cellular distal portion of the primitive digestive tube rearranges and results in an abnormal discontinuous growth; whereas the third theory emphasises that the atresia is a consequence from regression of that portion of the tube towards the main part of the embryo. Currently no genetic roles have been identified in this developmental abnormality [1].<br />
<br />
Regardless of the lack of information gathered about the cause of oesophageal atresia, more advanced correctional surgeries have been introduced in the past decade [2]. Survival rates differ immensely between various nations, particularly when comparing developed to developing countries. In certain clinics, with state-of-the-art neonatal care, survival rates of up to 95% has been documented [1]. Surgical methods such as thoracoscopic repair has been improved within the past decade, resulting to a decrease in surgical complications and therefore an increase in survival rates [2].<br />
<br />
[1] <pubmed>22851858</pubmed><br />
[2] <pubmed>22584690</pubmed><br />
==Assessment Lab 7==<br />
===Article 1===<br />
'''Fetal Adrenal Gland in the Second Half of Gestation: Morphometric Assessment with 3.0T Post-Mortem MRI'''<br />
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The adrenal gland, a bilateral organ located immediately superior the kidneys, are part of the endocrine system, playing an important role in releasing certain hormones such as cortisol and adrenaline in response to various situations including stressful situations. It is said that the adrenal gland is crucial in foetal development and that in comparison to other foetal organs, the foetal adrenal gland is relatively large. The study carried out by Zhonghe ''et al.'' quantitatively assessed the length, width, height, surface area and volume of normal foetal adrenal glands.<br />
<br />
52 foetal specimens ranging from 23-40 gestation weeks old were the subjects of this experiment. 72 foetal specimen were collected based on parental consent and in accordance with the Ethical Committee at the School of Medicine, Shandong University. Out of the 72 only 52 were utilised as foetuses with known abnormal maternal pregnancy records did not meet the criteria. The 52 subjects were organised in terms of their gestational age, found by measuring their crown-rump length via MRI. A highly advanced MRI scanner, SIEMENNS 3.0T MR scanner, was then employed in this research, measuring the adrenal glands of the foetus in the transverse, coronal and sagittal axis. Post-scanning, four specimens (24, 26, 32 and 36 weeks gestation age) were selected for gross anatomy dissection and measurement. <br />
<br />
Upon completing the measurements and gross dissections, Zhonghe ''et al.'' found that the bilateral organ was asymmetrical, with the right adrenal gland resembling an irregular triangle or pyramid, whereas the shape of the left adrenal gland was closer to a half-moon and larger than its right counterpart. No significant difference was found between the sexes, in contrast to previous research articles, however Zhonghe ''et al.'' attributed this discrepancy on it's relatively small group of specimens and uneven distribution of male and female foetuses. It was also discovered that as the gestational age increases the zona glomerulosa (outer zone of the cortex layer) became thicker.<br />
<br />
Zhonghe ''et al.'' regard their research and results as valuable in clinical settings and useful reference for the foetal anatomy. <br />
<br />
<pubmed>24116052</pubmed><br />
===Tooth Development===<br />
Odontogenesis begins in the sixth week of development. The embryonic cells/layers that differentiate to form the developing tooth include:<br />
* Odontoblasts — mesenchymal neural crest originating cells that secrete predentin, which calcifies to form dentin, the inner layer of the tooth. These cells are present throughout life and continuously produce dentin.<br />
* Ameloblasts — ectodermal cells of the oral epithelium that produce enamel, the outermost layer in the crown part of the tooth. Only present during odontogenesis. <br />
* Periodontal ligament — a specialised connective tissue that is in contact with the cementum layer (outer layer in the root of the tooth) and holds the tooth within the alveolar process.<br />
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==Assessment Lab 8==<br />
===Ovary Development===<br />
<br />
Embryonic female differentiation and development was once perceived as a passive process, simply by the failure of developing male genital organs, however it is shown that this is not the case, with many molecular and genetic prerequisites required to develop the female genital system. <ref><pubmed>15664455</pubmed></ref><br />
<br />
Identical to the testes, the ovaries originate from the mesothelium, the underlying mesenchyme, and primordial germ cells. Within the early embryo, the gonads consists of a mesonephric duct (Wolffian duct), paramesonephric ducts (Mullerian ducts), and the external cortex and internal medulla regions. <br />
<br />
Gonadal development begins in the fifth week, medially to the mesonephros. The first structure of the developing gonad is the gonadal ridge. This ridge is formed by the proliferation of the mesenchyme tissue. The proliferating mesenchyme then grow epithelial cords, known as gonadal cords that extend to the developing ovary later on. <br />
<br />
The primordial germ cells, undifferentiated sex cells, become visible by day 24 of the embryonic period. The germ cell is relocated to the gonadal ridges during the folding process of the embryo.<br />
In the late embryonic phase, the lack of anti-mullerian hormone and testosterone is what beings the differentiation between the male and female genital development. At this point of time the Wolffian duct degenerates but the Mullerian ducts remain, in contrast to the male gonadal development. It is the Mullerian ducts that develop into the internal genital organs, the upper part into the fallopian tubes, and the lower part into the uterus and the vagina. <ref><pubmed>13230915</pubmed></ref><br />
<br />
During the 10th week, the ovaries become recognisable with the gonadal cords extending into the surface of the ovary. It is within this foetal developmental phase, beginning in the 16th week, that the gonadal cords commence degeneration forming primordial oocytes, referred to as oogonium. These oogonia, surrounded by a thin layer of epithelial cells, are the primordial follicles that a formed by mitosis.<br />
<br />
[[File:Bailey329.jpg|600px]]<br />
<br />
'''Transverse section of the ovary of a fox embryo'''<br />
<br />
===References===<br />
<references/><br />
'''Textbook''' [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466393265-4#4-u1.0-B978-1-4377-2002-0..00012-6--f0150 Moore: The Developing Human Chapter 12]<br />
* ''Note: Access to UNSW database requires a valid UNSW username and zPass''<br />
<br />
==Assessment Lab 9==<br />
===Peer review===<br />
<br />
'''Group 1 — Respiratory'''<br />
<br />
The introduction is shaping quite well. The information used are all relevant and provide an overall understanding of the respiratory system. It is great how you have divided the system into the two main parts, the conducting zone and respiratory zone, providing information and images for both. With that said, the images contain no caption or any description when clicked on and more work is needed in this area as explaining the images/slides will heighten the educational aim of the project. Furthermore, as Mark Hill has mentioned, you must cover all the components required in uploading and using an image, such as adding the copyright information. <br />
<br />
Presenting the lung development stages in a table format is very clever and the table constructed contains valuable information simplifying the developmental stages of the respiratory system. You have gone one step further than the required by showing that development does not only occur embryonically but up to 8 years of age. Good work. In terms of the references in this section, they all seem to be fine, however I am unable to click on the “Lung Development” link, which returns with “object not found.” So please fix that issue as the reader/marker must be able to validate all the references if need be.<br />
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The current research section of this project page seems promising with a wide range of information. The foundations and structure are present however more information is required, which I know will be added before final submission. Identical to the introduction, it is good that you have divided the section into subsections based on the current research style and understanding that physiologically the lungs can be divided into the conduction system and functional unit. Numbering and dot points may be used, but I highly recommend that it is not used throughout the whole section. Moreover, your addition of an image highlighting Schematic lung disease and normal vs diseased lung models is appropriate for current research and models, however it should not be placed at the end under the references, you need to find a place between a paragraph that discusses or introduces this model. Lastly, there is a small formatting error in the middle of this section, I assume that is where an image should be located however check if you have written the command correctly. <br />
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It is obvious that the historical section is well researched and that a number of articles have been referenced. The use dot points and dates are great and simple to understand, however if you make a timeline and paragraphs, the page might look more professional. You have the information required to create a simple timeline and paragraphs that follow. Great historical images used however the first lacks any description and the second lacks a reference. <br />
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A vast range of abnormalities are addressed with references and thorough research into each. Some require more information, but overall all abnormalities are mentioned at a substantial extent with both full sentences and dot points. <br />
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Overall this group has provided a well researched project, certain formatting errors need to be addressed and some more information can be added, otherwise good work!<br />
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'''Group 2 — Renal'''<br />
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The introduction successfully touches on the project as a whole, including describing the system and its development, and the abnormalities that may arise. However it has failed to mention the importance of historical and current research. Also adding an image of the renal system or the renal units in particular will heighten the readers interest in this project.<br />
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There seems to be no information under the historical findings subheading, it might be hard to find research papers on this system, however a good start would be reading Mark Hill’s page on the renal development.<br />
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A very brief developmental timeline, however it does simply provide the information required to understanding the timeframe of renal development. More information about the structures mentioned in this timeline is required, this can be added within the timeline or following it.<br />
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The current research model section needs more information, if you are unable to find enough to make a substantial section then a possibility to work around that is to integrate the various research models with the organ sections. However, if more information can be obtained then this section should be left and continued as the image is correctly included and the information is written at a high standard.<br />
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The division of this page into the various organs in the renal system, the kidney, urethra, and ureter is clever as providing information on all in one section may be overwhelming. Each of these organs are well researched and written about. The layout looks fine with the paragraphs placed under subheadings and an abundant amount of images are located next to their corresponding information. Some images do not have a description, it is best to add a description, even a short one, to guide the reader and pinpoint the reason for uploading. An error has occurred for the first image under the Kidney section which has been removed by the administrator. Please take care with copyright. <br />
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I really like the abnormality section and the information added thus far. It is evident that you plan to continue as this section is not finished, however with what is there, great work. Both images used contain captions and clearly understood descriptions. One fault is the presence of references in this section. The group has one reference heading at the end of the project, however some of the references doubled up within the abnormalities section. One that note, please look carefully through the referencing list as you have the same articles more than once in the list, for example 23 and 24. There is a way of merging them together and having superscripts indicate that this article has been cited more than once, use article 28 and 30 as examples. <br />
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'''Group 3 — Gastrointestinal'''<br />
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The overview is quite short and lacks citations and images, however this is understandable seeing as it is a draft copy, but please make sure the overview informations are cited and images are included. The information uploaded so far is structured based on the division of the gut into fore-gut, mid-gut and hind-gut, and very easy to follow.<br />
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An extensive timeline, however the presentation can be improved as this timeline takes a lot of space and consists of a single word or a sentence. Maybe adding more information in the timeline or condensing the timeline in a table format.<br />
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I don’t understand the recent findings section as only one research paper has been considered. If more will be added then that is fine however when writing about these findings it’s good to incorporate it with other findings rather than simply summarising the results of one article. <br />
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Foregut, midgut and hindgut are well covered including innervations and structures of those areas. A range of format is used such as table, dot point and full paragraphs, which neatly tie all the information together and allows for a break in between paragraphs. Student redrawn images are a great source and you have referenced from where you have obtained the original image. No images are used for the foregut even though you have mentioned a few organs in detail. Furthermore, it is best to keep your formatting consistent as the dot points in the foregut section differs to those in midgut.<br />
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Detailed examples of deformities are present in the gastrointestinal system, however more deformities should be looked at and included. Deformities are also mentioned under the subheading of hindgut (Anorectal deformities, cloacal extrophy, and developmental problems), which might be best moved to the deformities block of the project page. This redrawn image is clear and labelled, however there is no reference. <br />
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Overall the project page is interesting, easy to comprehend and follow, however certain layout issues should be addressed and more information added. <br />
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'''Group 5 — Integumentary''' <br />
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The introduction covers all the topics of the project, however it does so briefly. Merging the development overview with the introduction will hide the fact that the introduction paragraph is short as this whole section will become one large detailed introduction about the integumentary system. The development overview is detailed and separated in terms of the structures found in the system. This is great, however less dot points should be used as it looks more like notes than presentable information. The creation of this timeline table is amazing and addition of the images according to the weeks is a well generated idea. Not all the images are described, so please do so for the final copy as it is essential that images of histological slides are describes as they can be confusion and difficult to understand. The information about hair and its adjacent image is the scaffold that should be followed throughout the whole section, as it has been written concisely and easily understandable. The hair development stages image is adequately describes and references with the copyright statement. Well done.<br />
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I appreciate the uniqueness in the layout of the recent findings, however I find it slightly overwhelming and out of place. Possibly adding a collapse and expand option to each article is beneficial. The summaries of the findings are in-depth and it is obvious that the author of this summary understands the topic.<br />
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A great start in historic findings with information present for a wide range of structures in this system. With that said, each section requires more research, however you are on the right path in finding articles greater than 50 years old. Only one image is attempted to be added, it is hard to find copyright granted images or historical drawings, but redrawing those original images is vital in providing solid historical information. In terms of the referencing, if you are unable to find a PMID for a certain article then manually add the reference and the URL link as you have but adhere to correct formatting.<br />
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Each abnormality is consistent with detailed information, statistics and a described image. The writing style is consistent and the image uploads with captions are correctly completed. Great work. The information is frequently cited emphasising efficient research ability. On that note, the references are correctly numbered and superscripts used instead of repeating the reference. <br />
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'''Group 6 — Endocrine'''<br />
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An introduction has not yet been added, however when doing so aim to mention the gist of the project and the manner in which is has been divided so that the reader/marker can effectively understand what is in this project. The wikipage is separated into the numerous endocrine organs, which is great as a future student can easily navigate to the organ of interest. <br />
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As it is only a draft copy it is assumed that improvement and adding of information will take place leading to the submission of the final as there are subheadings such as “Recent findings” that have been left blank. With what is currently present, each organ contains well researched information. In the beginning two organs, the pineal gland and hypothalamus, there is a subheading for abnormalities, however there is also a section towards the end of the wikipage solely for abnormalities, so refrain from doubling up on the information and either place all the abnormalities in one section or separate the malformations in terms of their respective structure. References are also seen at the end of each section or subsection and no in-text citation has been used yet, so it might be easier to cite the dot points or information as you go so you can remember where you got that from instead of trying to find that piece in the numerous research articles you have. Once that has been done, it will be best to relocate all the references at the end of the page, where you have already made the heading.<br />
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The structure is consistent throughout the page with each organ having a timeline and most containing an image and a table. This makes the project appealing and easy to read and understand. All the images uploaded contain comprehensive information and thus I am able to decipher the image and as a result enriches the learning aims of this assignment. The creation of a timeline for each organ is clever as each exhibits its own developmental process. The separation into many smaller timelines allows for specific events to be included that would otherwise overload a collective timeline. The setup of a table under the organisation of hormone, cells and function further simplifies an extremely complicated developmental system. As a student learning about the endocrine system I would be relieved to discover tables and content of this standard and structure. <br />
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'''Group 7 — Neural (CNS)'''<br />
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Solid introduction, it is well conveyed and divided into the two main organs of the CNS, the brain and the spinal cord. You have not just listed the two organs but also introduced both individually, describing their components and functions. Nice work.<br />
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The layout of this page is well thought through as you it begins with the overall neural development in the foetal period, then delves into the development of the two main organs, firstly the brain development, followed by the spinal cord development. This makes the project easy to understand as it is well organised. Within each subsection there has been images uploaded and tables added in addition to the information in both paragraph and dot point format. Majority of the images uploaded contain a description as well as the caption, however some descriptions require more to help clarify the image and for some no description is present, such as the image of the newborn with a giant occipital encephalocele. All have a caption, however I recommend you change the formatting of the image so that the caption is location just under the image and not within the text as you have done. <br />
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A timeline of neural development is added at the beginning in the form of a drawing and another timeline, more specific to sulcation and gyration, is added under brain development. These are great to use as it collaborates all the information into a clear and comprehensive piece. <br />
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The spinal cord development and meninges development lack information at this stage, so when filling up this section, it will be best to ensure you are consistent with the formatting and follow what has been used in the brain development section. Add as many tables, timelines and images as possible as this simplifies the information and enriches the page in terms of interest and completing the objectives of this assignment. The same goes for current research models and findings, I can see you have many references ready to be used and that this section has a lot of information. So that the project does not become overwhelming, it is not necessary to summarise or present all the findings, but only chose the most important and influential. You can also merge some research together if they focus on similar or identical concepts. <br />
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The abnormalities section is shaping up well. You have included many abnormalities that can occur in this system, so if you are able to write about each and include an image, then that will be great. Possibly refrain from writing it all in dot points, but that could only be the case because it is a draft copy. There is an error in an image uploaded about the facial characteristics associated with foetal alcohol syndrome. It returns with permission error so before uploading ensure that you are not breaching any copyright laws. You may even draw it or find another image similar that allows you to use it. <br />
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Listing all the references at the end of the page is a great idea. Some references are listed more than once because you have cited them in more than one place throughout the assignment. Such examples are 7 and 8, and 9 and 10. There is a command that allows you to use superscript where the one reference is listed with many superscripts, each corresponding to the different areas in which you have cited that article. <br />
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'''Group 8 — Musculoskeletal'''<br />
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The Making Gains section is quite funny but as you said, this is not Broscience and I’m sure it will be removed for the final submission. Once that is removed, begin the project with an introduction and the developmental general timeline. The main idea of the timeline is present, however when constructing one, use specific weeks within the foetal period and what developmental changes occur in those weeks. The information found under Background Embryonic development may be used to form the introduction, but if you are going to do that do not make the introduction as detailed as this section is, particularly in terms of the transcription factors and signalling molecules, they can be moved and added into the other sections that look at the various musculoskeletal developments individually.<br />
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It is evident that there is great understanding of this topic and that it is only a case of further research and addition of those information to complete the sections. Certain sections lack information all together, such as the Third Trimester Muscular development and Recent findings, whereas other sections only contain the research articles and no summaries of them such as Abnormalities. However I understand this is a draft and that all those areas will be addressed adequately, contributing to the final copy. <br />
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Only the Background Embryonic development and Molecular and Cellular regulation of foetal myogenesis have in text citations, whereas the other sections that do contain information are not cited. It might become difficult to later find the correct article from which you obtained the information so it is advised to cite the text while adding it. In terms of the citations present, there is no need for a comma between the superscripts and you have also allocated two sections to references, one subsequent to Abnormalities and another at the bottom of the page, it is best to collate all the references in one list at the end of the page. This is also the case for Abnormalities as there are two subheadings for it, merge them into one. <br />
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No images, tables, or timelines are added. The information you have now is well written and divided into small paragraphs, which is a good way of presenting the information, however other forms such as images and tables should be used. A timeline should be added under the Muscle development General Timeline subheading, this may be done as a table or a drawing and uploaded as it simplifies the information and breaks the page from continuous writing. <br />
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Overall this group project page is great, containing all the headings and articles present. It is only a matter of summarising those articles and adding the information. All the information present thus far is appropriate and emphasises great research skills.<br />
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==Assessment Lab 10==<br />
'''Neural crest contribution to lingual mesenchyme, epithelium and developing taste papillae and taste buds'''<br />
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The study by Liu ''et al.'' aimed to discover if neural-crest derived cells contribute to the tongue mesenchyme and epithelium including taste papillae and taste buds. To test this, they utilised tissues from four different transgenic mice, separated by Cre recombinase enzyme, ''Wnt1-Cre'' and ''P0-Cre'', and further divided into two reporter lines, ''R26R lacZ'' and ''ZEG'' double reporter, producing four unique mouse lines (''Wnt1-Cre/R26R'', ''Wnt1-Cre/ZEG'', ''P0-Cre/R26R'' and ''P0-Cre/ZEG''). This then allowed Liu and his colleagues to quantitatively examine the expression of all the papillae, as previous research indicated that some of the papillae contain a distinct test array and require a different method of analysis. <br />
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The mice population consisted of embryonic and postnatal mice, up to 10 days old, with their litter collected and genotyped via polymerase chain reaction (PCR). A control group was included with their litter also collected. Various experiments were carried out to test for the four types of lingual papillae; fungiform, filiform, foliate and circumvallate. <br />
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X-Gal staining and labelling was used to test for fungiform papillae in the ''P0-Cre/R26R'' mouse tongue. The taste buds were then divided into three categories based on their expression rate under light microscopy. Immunohistochemistry was also employed in this study, with slides treated with primary and secondary antibodies to illicit an immunoreaction that could be quantitatively recorded. <br />
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The embryonic mice sample and the newborn mice (P1) that were treated with ''Wnt1-Cre'' were examined for the location of the neural crest-derived cells. Upon completion, it was found that the neural crest-derived cells were primarily located in the lingual mesenchyme of both the embryonic and postnatal mice, however it was shown that as the tongue develops, the cells become more localised, immediately under the lingual epithelium. This was uniform with the findings on the tongues of the ''Wnt1-Cre/ZEG'' type mice, and thus Liu ''et al.'' concluded that these neural crest-derived cells are abundant within the papilla mesenchyme and in the core of the taste papillae. However, a different conclusion was reached for the tongue epithelium of the ''Wnt1-Cre'' type population, where these neural crest-derived cells were rarely found. <br />
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The fungiform papillae were tested in the ''P0-Cre'' line mice. The distribution pattern of the neural crest-derived cells in the mesenchyme was similar to that in the ''Wnt1-Cre'' samples. A different result, however, was obtained for the epithelium, as the desired cells were found to be located in the epithelium and the taste buds of the tongue, indicating that neural crest-cells contributed greatly to the fungiform papillae.<br />
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Antibodies were added into samples of developed tongues and no Cre immunoreactivity took place in those tissues, highlighting the validity of the study in tracing the cell lineage and removing doubts that ectopic ''Cre'' activity was in fact responsible for the results and not true ''P0''-expressing cells.<br />
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Base on their findings, Liu et al. proposed that neural crest cell from the neural tube migrate to the developing tongue mesenchyme and epithelium. They further explained that subsequent to migration into the epithelium, these cells acquire different phenotypes and differentiate into taste papillae. The taste papillae interact with the neural crest-derived cells that remain in the mesenchyme, which have roles in the development and maintenance of the taste papillae.<br />
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<pubmed>22659543</pubmed><br />
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==Assessment Lab 11==<br />
'''Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration''' <br />
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The research carried out by Masumoto et al. aimed to simultaneously induce cardiomyocytes and vascular cells, and generate human induced pluripotent stem cell (hiPSC)-engineered cardiovascular cell sheets. They hypothesised that a sheet of this sort can be therapeutically beneficial to patients with infarcted hearts. <br />
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hiPSC was collected and established in a culture. Masumoto et al. used this type of stem cell because they were interested in its ability to continuously expand and efficiency in differentiate into most somatic cells lineages. These cells later underwent cardiovascular cell differentiation, forming cardiomyocytes, endothelial cells, and mural cells (vascular smooth muscle cells and pericytes), and further incubated. <br />
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Male athymic nude rats, between the ages of 10-13 weeks were used in this study. Myocardial infarction was induced in all the rats. The subjects were then divided into two random groups, one group receiving the true cell sheets in transplant, the Tx group, and the other undergoing a sham-operation, the sham group. The translation took place 1 week after induced myocardial infarction, known as the “sub-acute phase”.<br />
<br />
The stem-cell graft was made by pilling 3 sheets together and then transplanted into the infarcted hearts of the Tx group rats. Upon concluding, Masumoto et al. found a significant improvement in the cardiac function of the rat population in the Tx group. Upon check-up at the 4th week post-surgery, they found presence of cardiomyocytes in more than 40% of the transplanted rats, therefore highlighting the importance of hiPSC-CTSs in cardiac regenerative therapy. <br />
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<pubmed>25336194</pubmed></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3415716&diff=161171User:Z34157162014-10-28T23:08:13Z<p>Z3415716: /* Assessment Lab 11 */</p>
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<div>==Lab Attendance==<br />
Lab 1 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:52, 6 August 2014 (EST)<br />
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http://www.ncbi.nlm.nih.gov/pubmed<br />
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[http://www.ncbi.nlm.nih.gov/pubmed PubMed]<br />
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[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]<br />
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<pubmed>25084016</pubmed><br />
Lab 2 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 11:13, 13 August 2014 (EST)<br />
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Lab 3 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:54, 20 August 2014 (EST)<br />
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Lab 4--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:27, 27 August 2014 (EST)<br />
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Lab 5 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:56, 3 September 2014 (EST)<br />
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Lab 6 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:37, 10 September 2014 (EST)<br />
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Lab 8 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:57, 24 September 2014 (EST)<br />
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Lab 9 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:21, 8 October 2014 (EST)<br />
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Lab 10 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:57, 15 October 2014 (EST)<br />
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Lab 11 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:36, 22 October 2014 (EST)<br />
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==Assessment Lab 1==<br />
===Article 1===<br />
'''Effect of Vitamin D status on clinical pregnancy rates following in vitro fertilisation'''<br />
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The study undertaken by Garbedian ''et al''. attempted to investigate whether vitamin D (25-hydroxy-vitamin D) serum level of in vitro patients could predict the successfulness of in vitro fertilisation (IVF). 173 patients participated, having met the criteria of age (18-41 years), follicle-stimulating hormone level (≤12IU/L at day 3 of the menstrual cycle), and consent.<br />
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Serum samples were collected from the participating women, prior to oocyte retrieval, and were analysed, dividing the patients into two groups, sufficient (≥75 nmol/L) or insufficient (<75 nmol/L), based on their serum vitamin D levels. Regardless of this division, the IVF procedures were undertaken as per standard protocol. <br />
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This article focused on two main outcomes, embryo implantation, and clinical pregnancy. Implantation was described as the establishment of a gestational sac upon ultrasonography screening. Whereas clinical pregnancy assessed via ultrasound, was determined by the visibility of an intrauterine sac. The results were collated, analysed, and compared between the groups in order to discover a relationship, if any, between serum vitamin D levels and both implantation and clinical pregnancy rates.<br />
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Garbedian and colleagues found significant differences between the groups’ rate of embryo transfer and clinical pregnancy, however this is not the case in implantation rate. In consistency with the IVF protocols, embryo transfer was to take place on day 5, if at least 5-6 acceptable embryos were developed by day 3 of fertilisation. It was discovered that women with a sufficient level of serum vitamin D were more likely to achieve this step by day 5 than women with low serum vitamin D. Moreover, a higher clinical pregnancy rate was observed within the same group of women. An increased value of embryo implantation rate was noted, however results were statistically insignificant. <br />
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With acknowledgement of the study’s limitations, Garbedian ''et al.'' concluded that women sufficient in vitamin D serum levels were more likely to achieve clinical pregnancy following IVF, with serum levels of the vitamin acting as an independent predictor. <br />
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[http://www.ncbi.nlm.nih.gov/pubmed/25077107 Effect of vitamin D status on clinical pregnancy rates following in vitro fertilization.]<br />
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<pubmed>25077107</pubmed><br />
===Article 2===<br />
'''The Role of SPRASA in Female Fertility'''<br />
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Sperm protein reactive with antisperm antibodies (SPRASA) also referred to as sperm lysosome-like protein 1 is a target protein of antisperm antibodies, and is the key protein explored within the article by Wagner ''et al.'' Numerous tests were preformed within this study investigating the role of this protein, particularly in fertilisation and embryonic development. <br />
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The Bovine IVF model was employed to determine the effect of SPRASA antiserum on fertilisation, cleavage, and embryo development. Both bovine zona pellucida-attached and zona pellucida-free oocyte-sperm binding was investigated with the presence of antiserum preparation. Wagner and colleagues were able to conclude that fertility rates significantly reduced when SPRASA antiserum was added to oocytes, and sperm and oocytes samples, but not to sperm samples alone. Further on this note, the study found that the antiserum preparation negatively influenced the zona pellucida-free oocyte (oolemma)-sperm binding process, whereas no significant effect was found in the zona pellucida-attached oocyte-sperm binding. In terms of development, it was discovered that the antiserum was able to inhibit morula stage growth but not the further development at the blastocyst stage. <br />
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Wagner and colleagues also assessed the influence on sperm motility by SPRASA and observed that sperm motility was not an affected area as there was no significant difference between motile sperm in antiserum perpetration and the control group. <br />
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As previously thought that SPRASA was only present in spermatozoa, this study examined whether the protein was also expressed in oocytes and ovaries. Bovine oocytes, and ovaries from cats and dogs, were obtained for this section of the research. Similarly, sperm and sperm precursor cells were collected from testis of cats and dogs in order to illustrate the presence of SPRASA proteins. Results indicated that oocytes express SPRASA and staining was able to localise the protein to the zona pellucida and oolemma of bovine oocytes. Similar preparation and staining was carried out on ovaries of cats and dogs, and returned with positive expression of SPRASA. <br />
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Fertilisation and embryo development was tested via immunisation and mating of female mice. Female mice were either continuously immunised with recombinant human SPRASA protein or irrelevant recombinant keyhole limpet hemocyanin (KLH) protein (control). The mice were then monitored, relocated for mating with male mice, and then compared in terms of pregnancy and fetal development. Wagner ''et al.'' found that all control mice became pregnant after 2 mating cycles, whereas the majority of SPRASA immunised mice failed to achieve pregnancy altogether. In regards to the number of embryo development and weight, no difference was recorded between the control and immunised mice. <br />
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The final test was comparing the antibody levels from blood samples of fertile and infertile couples. Upon analysis of results, Wagner ''et al.'' discovered no significant difference between both fertile and infertile men and women, however 3 of the infertile women presented with inflated levels of the antibodies. <br />
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Wagner ''et al.'' concluded that SPRASA, to a certain extent, plays a role in fertilisation and embryo development. They also rebutted the previous theory that the protein is solely expressed in male gametes with identifying SPRASA within the female reproductive structures.<br />
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[http://www.ncbi.nlm.nih.gov/pubmed/25038051 The Role of SPRASA in Female Fertility.]<br />
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<pubmed>25038051</pubmed><br />
==Assessment Lab 2==<br />
[[File:WNT4_screening_in_the_testis_of_the_tammar_wallaby.jpeg|300px|left|thumb|WNT4 screening in the testis of the tammar wallaby]]<br />
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<pubmed>17014734</pubmed>| [http://www.biomedcentral.com/1471-213X/6/44 Biomed Central]<br />
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--[[User:Z8600021|Mark Hill]] This is fine and description with the image is good. You should have also reproduced the figure description and the reference here on your page. (4/5)<br />
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==Assessment Lab 3==<br />
<pubmed>18462432</pubmed><br />
<pubmed>17232227</pubmed><br />
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]<br />
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--[[User:Z8600021|Mark Hill]] These are relevant articles. I wonder why the third reference is not listed in PubMed Database? This usually indicates the relevance of the journal in the peer review system (4/5).<br />
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==Assessment Lab 4==<br />
===Article 1===<br />
'''Conversion of human umbilical cord mesenchymal stem cells in Wharton's jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism'''<br />
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Parkinson’s disease is a neurodegenerative disorder associated with the degradation of the dopaminergic system in the striatum region of the brain. Current short-term treatment for Parkinson’s disease is antiparkinson medications, mainly enhancing dopamine levels, however such medications reduce in effectiveness with further degradation of the neurotransmitter’s pathway. The study led by Fu, however, proposes a potential long-term treatment for Parkinson’s disease, utilising induced human mesenchymal stem cells (HMSCs) originating in the Wharton’s jelly of the umbilical cord. <br />
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Fu ''et al.'' isolated HMSCs from the umbilical cord exposing the cells to subsequent chemical treatment resulting in the differentiation of these multipotent cells into dopaminergic neurones. These neurones were then injected into the subjects, adults rats with induced Parkinson’s post unilateral striatal lesioning. Subjects were compared with control untreated rats, concluding that the transplanted group exhibited a substantial improvement in rotational behaviour and Parkinson’s symptoms, however not enough to deem them cured from the disease. <br />
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The potential for HMSCs, isolated from the umbilical cord, to correct Parkinson’s disease is further emphasised in its easy isolation methods, the large amount of cells able to be isolated, and the simple duplication of these stem cells. Fu ''et al.'' were able to collect 1x10^6 HUMSCs from 20 cm of umbilical cord and duplicate the amount to 2x10^6 cells in a three day incubation period. Furthermore, the study found that the transplanted differentiated cells were still successful 4 months post procedure, suggesting that this method may be a long-term treatment for the disease. The investigation also comments on the prospect of HUMSCs as a source for transplantation, attributed to its non-immunological inducing characteristic.<br />
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<pubmed>16099997</pubmed><br />
===Vascular shunts===<br />
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There are three shunts within the foetal circulatory development that close postnatally:<br />
*Ductus arteriosus<br />
A canal that connects the foetal pulmonary artery to the aorta, distributing oxygenated blood to the foetus while bypassing the developing lungs. <br />
*Ductus venosus <br />
Connecting the left umbilical vein to the inferior vena cave, allowing placental oxygenated blood to bypass the liver.<br />
*Foramen ovale<br />
A foramen within the interatrial septum where blood from the right atrium enters the left atrium.<br />
<br />
==Assessment Lab 5==<br />
===Oesophageal atresia===<br />
<br />
Oesophageal atresia is a rare gastrointestinal developmental abnormality, however in terms of oesophageal anomaly it is the most common, with one newborn out of every 2500 to 4500 being diagnosed within the first 24 hours of life [1]. Oesophageal atresia is diagnosed with the discontinuity of the oesophagus from the oral cavity to the stomach, where the oesophagus ends abruptly not in contact with the cardia of the stomach.<br />
<br />
Oesophageal atresia can be classified into five variants according to the location of the atresia and any associated tracheal fistulas (tracheoesophageal fistula) [1]. The five classifications include: oesophageal artesia without tracheoesophageal fistula, proximal tracheoesophageal fistula with distal oesophageal atresia, distal tracheoesophageal fistula with proximal oesophageal atresia, proximal and distal tracheoesophageal fistula, and tracheoesophageal fistula without oesophageal atresia [1]. <br />
<br />
The cause for this gastrointestinal abnormality is unclear and research continues to take place. With that said, various theories of the embryological origin of this anomaly have been proposed [1]. Three forefront theories comment on the primitive digestive tube and its failure to form a successful diverticulum, resulting in the connection of the trachea and oesophagus (tracheoesophageal fistula). In terms of the formation of oesophageal atresia, two of the three theories reason that the cellular distal portion of the primitive digestive tube rearranges and results in an abnormal discontinuous growth; whereas the third theory emphasises that the atresia is a consequence from regression of that portion of the tube towards the main part of the embryo. Currently no genetic roles have been identified in this developmental abnormality [1].<br />
<br />
Regardless of the lack of information gathered about the cause of oesophageal atresia, more advanced correctional surgeries have been introduced in the past decade [2]. Survival rates differ immensely between various nations, particularly when comparing developed to developing countries. In certain clinics, with state-of-the-art neonatal care, survival rates of up to 95% has been documented [1]. Surgical methods such as thoracoscopic repair has been improved within the past decade, resulting to a decrease in surgical complications and therefore an increase in survival rates [2].<br />
<br />
[1] <pubmed>22851858</pubmed><br />
[2] <pubmed>22584690</pubmed><br />
==Assessment Lab 7==<br />
===Article 1===<br />
'''Fetal Adrenal Gland in the Second Half of Gestation: Morphometric Assessment with 3.0T Post-Mortem MRI'''<br />
<br />
The adrenal gland, a bilateral organ located immediately superior the kidneys, are part of the endocrine system, playing an important role in releasing certain hormones such as cortisol and adrenaline in response to various situations including stressful situations. It is said that the adrenal gland is crucial in foetal development and that in comparison to other foetal organs, the foetal adrenal gland is relatively large. The study carried out by Zhonghe ''et al.'' quantitatively assessed the length, width, height, surface area and volume of normal foetal adrenal glands.<br />
<br />
52 foetal specimens ranging from 23-40 gestation weeks old were the subjects of this experiment. 72 foetal specimen were collected based on parental consent and in accordance with the Ethical Committee at the School of Medicine, Shandong University. Out of the 72 only 52 were utilised as foetuses with known abnormal maternal pregnancy records did not meet the criteria. The 52 subjects were organised in terms of their gestational age, found by measuring their crown-rump length via MRI. A highly advanced MRI scanner, SIEMENNS 3.0T MR scanner, was then employed in this research, measuring the adrenal glands of the foetus in the transverse, coronal and sagittal axis. Post-scanning, four specimens (24, 26, 32 and 36 weeks gestation age) were selected for gross anatomy dissection and measurement. <br />
<br />
Upon completing the measurements and gross dissections, Zhonghe ''et al.'' found that the bilateral organ was asymmetrical, with the right adrenal gland resembling an irregular triangle or pyramid, whereas the shape of the left adrenal gland was closer to a half-moon and larger than its right counterpart. No significant difference was found between the sexes, in contrast to previous research articles, however Zhonghe ''et al.'' attributed this discrepancy on it's relatively small group of specimens and uneven distribution of male and female foetuses. It was also discovered that as the gestational age increases the zona glomerulosa (outer zone of the cortex layer) became thicker.<br />
<br />
Zhonghe ''et al.'' regard their research and results as valuable in clinical settings and useful reference for the foetal anatomy. <br />
<br />
<pubmed>24116052</pubmed><br />
===Tooth Development===<br />
Odontogenesis begins in the sixth week of development. The embryonic cells/layers that differentiate to form the developing tooth include:<br />
* Odontoblasts — mesenchymal neural crest originating cells that secrete predentin, which calcifies to form dentin, the inner layer of the tooth. These cells are present throughout life and continuously produce dentin.<br />
* Ameloblasts — ectodermal cells of the oral epithelium that produce enamel, the outermost layer in the crown part of the tooth. Only present during odontogenesis. <br />
* Periodontal ligament — a specialised connective tissue that is in contact with the cementum layer (outer layer in the root of the tooth) and holds the tooth within the alveolar process.<br />
<br />
==Assessment Lab 8==<br />
===Ovary Development===<br />
<br />
Embryonic female differentiation and development was once perceived as a passive process, simply by the failure of developing male genital organs, however it is shown that this is not the case, with many molecular and genetic prerequisites required to develop the female genital system. <ref><pubmed>15664455</pubmed></ref><br />
<br />
Identical to the testes, the ovaries originate from the mesothelium, the underlying mesenchyme, and primordial germ cells. Within the early embryo, the gonads consists of a mesonephric duct (Wolffian duct), paramesonephric ducts (Mullerian ducts), and the external cortex and internal medulla regions. <br />
<br />
Gonadal development begins in the fifth week, medially to the mesonephros. The first structure of the developing gonad is the gonadal ridge. This ridge is formed by the proliferation of the mesenchyme tissue. The proliferating mesenchyme then grow epithelial cords, known as gonadal cords that extend to the developing ovary later on. <br />
<br />
The primordial germ cells, undifferentiated sex cells, become visible by day 24 of the embryonic period. The germ cell is relocated to the gonadal ridges during the folding process of the embryo.<br />
In the late embryonic phase, the lack of anti-mullerian hormone and testosterone is what beings the differentiation between the male and female genital development. At this point of time the Wolffian duct degenerates but the Mullerian ducts remain, in contrast to the male gonadal development. It is the Mullerian ducts that develop into the internal genital organs, the upper part into the fallopian tubes, and the lower part into the uterus and the vagina. <ref><pubmed>13230915</pubmed></ref><br />
<br />
During the 10th week, the ovaries become recognisable with the gonadal cords extending into the surface of the ovary. It is within this foetal developmental phase, beginning in the 16th week, that the gonadal cords commence degeneration forming primordial oocytes, referred to as oogonium. These oogonia, surrounded by a thin layer of epithelial cells, are the primordial follicles that a formed by mitosis.<br />
<br />
[[File:Bailey329.jpg|600px]]<br />
<br />
'''Transverse section of the ovary of a fox embryo'''<br />
<br />
===References===<br />
<references/><br />
'''Textbook''' [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466393265-4#4-u1.0-B978-1-4377-2002-0..00012-6--f0150 Moore: The Developing Human Chapter 12]<br />
* ''Note: Access to UNSW database requires a valid UNSW username and zPass''<br />
<br />
==Assessment Lab 9==<br />
===Peer review===<br />
<br />
'''Group 1 — Respiratory'''<br />
<br />
The introduction is shaping quite well. The information used are all relevant and provide an overall understanding of the respiratory system. It is great how you have divided the system into the two main parts, the conducting zone and respiratory zone, providing information and images for both. With that said, the images contain no caption or any description when clicked on and more work is needed in this area as explaining the images/slides will heighten the educational aim of the project. Furthermore, as Mark Hill has mentioned, you must cover all the components required in uploading and using an image, such as adding the copyright information. <br />
<br />
Presenting the lung development stages in a table format is very clever and the table constructed contains valuable information simplifying the developmental stages of the respiratory system. You have gone one step further than the required by showing that development does not only occur embryonically but up to 8 years of age. Good work. In terms of the references in this section, they all seem to be fine, however I am unable to click on the “Lung Development” link, which returns with “object not found.” So please fix that issue as the reader/marker must be able to validate all the references if need be.<br />
<br />
The current research section of this project page seems promising with a wide range of information. The foundations and structure are present however more information is required, which I know will be added before final submission. Identical to the introduction, it is good that you have divided the section into subsections based on the current research style and understanding that physiologically the lungs can be divided into the conduction system and functional unit. Numbering and dot points may be used, but I highly recommend that it is not used throughout the whole section. Moreover, your addition of an image highlighting Schematic lung disease and normal vs diseased lung models is appropriate for current research and models, however it should not be placed at the end under the references, you need to find a place between a paragraph that discusses or introduces this model. Lastly, there is a small formatting error in the middle of this section, I assume that is where an image should be located however check if you have written the command correctly. <br />
<br />
It is obvious that the historical section is well researched and that a number of articles have been referenced. The use dot points and dates are great and simple to understand, however if you make a timeline and paragraphs, the page might look more professional. You have the information required to create a simple timeline and paragraphs that follow. Great historical images used however the first lacks any description and the second lacks a reference. <br />
<br />
A vast range of abnormalities are addressed with references and thorough research into each. Some require more information, but overall all abnormalities are mentioned at a substantial extent with both full sentences and dot points. <br />
<br />
Overall this group has provided a well researched project, certain formatting errors need to be addressed and some more information can be added, otherwise good work!<br />
----<br />
'''Group 2 — Renal'''<br />
<br />
The introduction successfully touches on the project as a whole, including describing the system and its development, and the abnormalities that may arise. However it has failed to mention the importance of historical and current research. Also adding an image of the renal system or the renal units in particular will heighten the readers interest in this project.<br />
<br />
There seems to be no information under the historical findings subheading, it might be hard to find research papers on this system, however a good start would be reading Mark Hill’s page on the renal development.<br />
<br />
A very brief developmental timeline, however it does simply provide the information required to understanding the timeframe of renal development. More information about the structures mentioned in this timeline is required, this can be added within the timeline or following it.<br />
<br />
The current research model section needs more information, if you are unable to find enough to make a substantial section then a possibility to work around that is to integrate the various research models with the organ sections. However, if more information can be obtained then this section should be left and continued as the image is correctly included and the information is written at a high standard.<br />
<br />
The division of this page into the various organs in the renal system, the kidney, urethra, and ureter is clever as providing information on all in one section may be overwhelming. Each of these organs are well researched and written about. The layout looks fine with the paragraphs placed under subheadings and an abundant amount of images are located next to their corresponding information. Some images do not have a description, it is best to add a description, even a short one, to guide the reader and pinpoint the reason for uploading. An error has occurred for the first image under the Kidney section which has been removed by the administrator. Please take care with copyright. <br />
<br />
I really like the abnormality section and the information added thus far. It is evident that you plan to continue as this section is not finished, however with what is there, great work. Both images used contain captions and clearly understood descriptions. One fault is the presence of references in this section. The group has one reference heading at the end of the project, however some of the references doubled up within the abnormalities section. One that note, please look carefully through the referencing list as you have the same articles more than once in the list, for example 23 and 24. There is a way of merging them together and having superscripts indicate that this article has been cited more than once, use article 28 and 30 as examples. <br />
----<br />
'''Group 3 — Gastrointestinal'''<br />
<br />
The overview is quite short and lacks citations and images, however this is understandable seeing as it is a draft copy, but please make sure the overview informations are cited and images are included. The information uploaded so far is structured based on the division of the gut into fore-gut, mid-gut and hind-gut, and very easy to follow.<br />
<br />
An extensive timeline, however the presentation can be improved as this timeline takes a lot of space and consists of a single word or a sentence. Maybe adding more information in the timeline or condensing the timeline in a table format.<br />
<br />
I don’t understand the recent findings section as only one research paper has been considered. If more will be added then that is fine however when writing about these findings it’s good to incorporate it with other findings rather than simply summarising the results of one article. <br />
<br />
Foregut, midgut and hindgut are well covered including innervations and structures of those areas. A range of format is used such as table, dot point and full paragraphs, which neatly tie all the information together and allows for a break in between paragraphs. Student redrawn images are a great source and you have referenced from where you have obtained the original image. No images are used for the foregut even though you have mentioned a few organs in detail. Furthermore, it is best to keep your formatting consistent as the dot points in the foregut section differs to those in midgut.<br />
<br />
Detailed examples of deformities are present in the gastrointestinal system, however more deformities should be looked at and included. Deformities are also mentioned under the subheading of hindgut (Anorectal deformities, cloacal extrophy, and developmental problems), which might be best moved to the deformities block of the project page. This redrawn image is clear and labelled, however there is no reference. <br />
<br />
Overall the project page is interesting, easy to comprehend and follow, however certain layout issues should be addressed and more information added. <br />
----<br />
'''Group 5 — Integumentary''' <br />
<br />
The introduction covers all the topics of the project, however it does so briefly. Merging the development overview with the introduction will hide the fact that the introduction paragraph is short as this whole section will become one large detailed introduction about the integumentary system. The development overview is detailed and separated in terms of the structures found in the system. This is great, however less dot points should be used as it looks more like notes than presentable information. The creation of this timeline table is amazing and addition of the images according to the weeks is a well generated idea. Not all the images are described, so please do so for the final copy as it is essential that images of histological slides are describes as they can be confusion and difficult to understand. The information about hair and its adjacent image is the scaffold that should be followed throughout the whole section, as it has been written concisely and easily understandable. The hair development stages image is adequately describes and references with the copyright statement. Well done.<br />
<br />
I appreciate the uniqueness in the layout of the recent findings, however I find it slightly overwhelming and out of place. Possibly adding a collapse and expand option to each article is beneficial. The summaries of the findings are in-depth and it is obvious that the author of this summary understands the topic.<br />
<br />
A great start in historic findings with information present for a wide range of structures in this system. With that said, each section requires more research, however you are on the right path in finding articles greater than 50 years old. Only one image is attempted to be added, it is hard to find copyright granted images or historical drawings, but redrawing those original images is vital in providing solid historical information. In terms of the referencing, if you are unable to find a PMID for a certain article then manually add the reference and the URL link as you have but adhere to correct formatting.<br />
<br />
Each abnormality is consistent with detailed information, statistics and a described image. The writing style is consistent and the image uploads with captions are correctly completed. Great work. The information is frequently cited emphasising efficient research ability. On that note, the references are correctly numbered and superscripts used instead of repeating the reference. <br />
----<br />
'''Group 6 — Endocrine'''<br />
<br />
An introduction has not yet been added, however when doing so aim to mention the gist of the project and the manner in which is has been divided so that the reader/marker can effectively understand what is in this project. The wikipage is separated into the numerous endocrine organs, which is great as a future student can easily navigate to the organ of interest. <br />
<br />
As it is only a draft copy it is assumed that improvement and adding of information will take place leading to the submission of the final as there are subheadings such as “Recent findings” that have been left blank. With what is currently present, each organ contains well researched information. In the beginning two organs, the pineal gland and hypothalamus, there is a subheading for abnormalities, however there is also a section towards the end of the wikipage solely for abnormalities, so refrain from doubling up on the information and either place all the abnormalities in one section or separate the malformations in terms of their respective structure. References are also seen at the end of each section or subsection and no in-text citation has been used yet, so it might be easier to cite the dot points or information as you go so you can remember where you got that from instead of trying to find that piece in the numerous research articles you have. Once that has been done, it will be best to relocate all the references at the end of the page, where you have already made the heading.<br />
<br />
The structure is consistent throughout the page with each organ having a timeline and most containing an image and a table. This makes the project appealing and easy to read and understand. All the images uploaded contain comprehensive information and thus I am able to decipher the image and as a result enriches the learning aims of this assignment. The creation of a timeline for each organ is clever as each exhibits its own developmental process. The separation into many smaller timelines allows for specific events to be included that would otherwise overload a collective timeline. The setup of a table under the organisation of hormone, cells and function further simplifies an extremely complicated developmental system. As a student learning about the endocrine system I would be relieved to discover tables and content of this standard and structure. <br />
----<br />
'''Group 7 — Neural (CNS)'''<br />
<br />
Solid introduction, it is well conveyed and divided into the two main organs of the CNS, the brain and the spinal cord. You have not just listed the two organs but also introduced both individually, describing their components and functions. Nice work.<br />
<br />
The layout of this page is well thought through as you it begins with the overall neural development in the foetal period, then delves into the development of the two main organs, firstly the brain development, followed by the spinal cord development. This makes the project easy to understand as it is well organised. Within each subsection there has been images uploaded and tables added in addition to the information in both paragraph and dot point format. Majority of the images uploaded contain a description as well as the caption, however some descriptions require more to help clarify the image and for some no description is present, such as the image of the newborn with a giant occipital encephalocele. All have a caption, however I recommend you change the formatting of the image so that the caption is location just under the image and not within the text as you have done. <br />
<br />
A timeline of neural development is added at the beginning in the form of a drawing and another timeline, more specific to sulcation and gyration, is added under brain development. These are great to use as it collaborates all the information into a clear and comprehensive piece. <br />
<br />
The spinal cord development and meninges development lack information at this stage, so when filling up this section, it will be best to ensure you are consistent with the formatting and follow what has been used in the brain development section. Add as many tables, timelines and images as possible as this simplifies the information and enriches the page in terms of interest and completing the objectives of this assignment. The same goes for current research models and findings, I can see you have many references ready to be used and that this section has a lot of information. So that the project does not become overwhelming, it is not necessary to summarise or present all the findings, but only chose the most important and influential. You can also merge some research together if they focus on similar or identical concepts. <br />
<br />
The abnormalities section is shaping up well. You have included many abnormalities that can occur in this system, so if you are able to write about each and include an image, then that will be great. Possibly refrain from writing it all in dot points, but that could only be the case because it is a draft copy. There is an error in an image uploaded about the facial characteristics associated with foetal alcohol syndrome. It returns with permission error so before uploading ensure that you are not breaching any copyright laws. You may even draw it or find another image similar that allows you to use it. <br />
<br />
Listing all the references at the end of the page is a great idea. Some references are listed more than once because you have cited them in more than one place throughout the assignment. Such examples are 7 and 8, and 9 and 10. There is a command that allows you to use superscript where the one reference is listed with many superscripts, each corresponding to the different areas in which you have cited that article. <br />
----<br />
'''Group 8 — Musculoskeletal'''<br />
<br />
The Making Gains section is quite funny but as you said, this is not Broscience and I’m sure it will be removed for the final submission. Once that is removed, begin the project with an introduction and the developmental general timeline. The main idea of the timeline is present, however when constructing one, use specific weeks within the foetal period and what developmental changes occur in those weeks. The information found under Background Embryonic development may be used to form the introduction, but if you are going to do that do not make the introduction as detailed as this section is, particularly in terms of the transcription factors and signalling molecules, they can be moved and added into the other sections that look at the various musculoskeletal developments individually.<br />
<br />
It is evident that there is great understanding of this topic and that it is only a case of further research and addition of those information to complete the sections. Certain sections lack information all together, such as the Third Trimester Muscular development and Recent findings, whereas other sections only contain the research articles and no summaries of them such as Abnormalities. However I understand this is a draft and that all those areas will be addressed adequately, contributing to the final copy. <br />
<br />
Only the Background Embryonic development and Molecular and Cellular regulation of foetal myogenesis have in text citations, whereas the other sections that do contain information are not cited. It might become difficult to later find the correct article from which you obtained the information so it is advised to cite the text while adding it. In terms of the citations present, there is no need for a comma between the superscripts and you have also allocated two sections to references, one subsequent to Abnormalities and another at the bottom of the page, it is best to collate all the references in one list at the end of the page. This is also the case for Abnormalities as there are two subheadings for it, merge them into one. <br />
<br />
No images, tables, or timelines are added. The information you have now is well written and divided into small paragraphs, which is a good way of presenting the information, however other forms such as images and tables should be used. A timeline should be added under the Muscle development General Timeline subheading, this may be done as a table or a drawing and uploaded as it simplifies the information and breaks the page from continuous writing. <br />
<br />
Overall this group project page is great, containing all the headings and articles present. It is only a matter of summarising those articles and adding the information. All the information present thus far is appropriate and emphasises great research skills.<br />
<br />
==Assessment Lab 10==<br />
'''Neural crest contribution to lingual mesenchyme, epithelium and developing taste papillae and taste buds'''<br />
<br />
The study by Liu ''et al.'' aimed to discover if neural-crest derived cells contribute to the tongue mesenchyme and epithelium including taste papillae and taste buds. To test this, they utilised tissues from four different transgenic mice, separated by Cre recombinase enzyme, ''Wnt1-Cre'' and ''P0-Cre'', and further divided into two reporter lines, ''R26R lacZ'' and ''ZEG'' double reporter, producing four unique mouse lines (''Wnt1-Cre/R26R'', ''Wnt1-Cre/ZEG'', ''P0-Cre/R26R'' and ''P0-Cre/ZEG''). This then allowed Liu and his colleagues to quantitatively examine the expression of all the papillae, as previous research indicated that some of the papillae contain a distinct test array and require a different method of analysis. <br />
<br />
The mice population consisted of embryonic and postnatal mice, up to 10 days old, with their litter collected and genotyped via polymerase chain reaction (PCR). A control group was included with their litter also collected. Various experiments were carried out to test for the four types of lingual papillae; fungiform, filiform, foliate and circumvallate. <br />
<br />
X-Gal staining and labelling was used to test for fungiform papillae in the ''P0-Cre/R26R'' mouse tongue. The taste buds were then divided into three categories based on their expression rate under light microscopy. Immunohistochemistry was also employed in this study, with slides treated with primary and secondary antibodies to illicit an immunoreaction that could be quantitatively recorded. <br />
<br />
The embryonic mice sample and the newborn mice (P1) that were treated with ''Wnt1-Cre'' were examined for the location of the neural crest-derived cells. Upon completion, it was found that the neural crest-derived cells were primarily located in the lingual mesenchyme of both the embryonic and postnatal mice, however it was shown that as the tongue develops, the cells become more localised, immediately under the lingual epithelium. This was uniform with the findings on the tongues of the ''Wnt1-Cre/ZEG'' type mice, and thus Liu ''et al.'' concluded that these neural crest-derived cells are abundant within the papilla mesenchyme and in the core of the taste papillae. However, a different conclusion was reached for the tongue epithelium of the ''Wnt1-Cre'' type population, where these neural crest-derived cells were rarely found. <br />
<br />
The fungiform papillae were tested in the ''P0-Cre'' line mice. The distribution pattern of the neural crest-derived cells in the mesenchyme was similar to that in the ''Wnt1-Cre'' samples. A different result, however, was obtained for the epithelium, as the desired cells were found to be located in the epithelium and the taste buds of the tongue, indicating that neural crest-cells contributed greatly to the fungiform papillae.<br />
<br />
Antibodies were added into samples of developed tongues and no Cre immunoreactivity took place in those tissues, highlighting the validity of the study in tracing the cell lineage and removing doubts that ectopic ''Cre'' activity was in fact responsible for the results and not true ''P0''-expressing cells.<br />
<br />
Base on their findings, Liu et al. proposed that neural crest cell from the neural tube migrate to the developing tongue mesenchyme and epithelium. They further explained that subsequent to migration into the epithelium, these cells acquire different phenotypes and differentiate into taste papillae. The taste papillae interact with the neural crest-derived cells that remain in the mesenchyme, which have roles in the development and maintenance of the taste papillae.<br />
<br />
<pubmed>22659543</pubmed><br />
<br />
==Assessment Lab 11==<br />
'''Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration''' <br />
<br />
The research carried out by Masumoto et al. aimed to simultaneously induce cardiomyocytes and vascular cells, and generate human induced pluripotent stem cell (hiPSC)-engineered cardiovascular cell sheets. They hypothesised that a sheet of this sort can be therapeutically beneficial to patients with infarcted hearts. <br />
<br />
hiPSC was collected and established in a culture. Masumoto et al. used this type of stem cell because they were interested in its ability to continuously expand and efficiency in differentiate into most somatic cells lineages. These cells later underwent cardiovascular cell differentiation, forming cardiomyocytes, endothelial cells, and mural cells (vascular smooth muscle cells and pericytes), and further incubated. <br />
<br />
Male athymic nude rats, between the ages of 10-13 weeks were used in this study. Myocardial infarction was induced in all the rats. The subjects were then divided into two random groups, one group receiving the true cell sheets in transplant, the Tx group, and the other undergoing a sham-operation, the sham group. The translation took place 1 week after induced myocardial infarction, known as the “sub-acute phase”.<br />
<br />
The stem-cell graft was made by pilling 3 sheets together and then transplanted into the infarcted hearts of the Tx group rats. Upon concluding, Masumoto et al. found a significant improvement in the cardiac function of the rat population in the Tx group. Upon check-up at the 4th week post-surgery, they found presence of cardiomyocytes in more than 40% of the transplanted rats, therefore highlighting the importance of hiPSC-CTSs in cardiac regenerative therapy. <br />
<br />
<pubmed>25336194</pubmed></ref></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3415716&diff=161168User:Z34157162014-10-28T23:06:35Z<p>Z3415716: </p>
<hr />
<div>==Lab Attendance==<br />
Lab 1 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:52, 6 August 2014 (EST)<br />
<br />
http://www.ncbi.nlm.nih.gov/pubmed<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed PubMed]<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]<br />
<br />
<pubmed>25084016</pubmed><br />
Lab 2 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 11:13, 13 August 2014 (EST)<br />
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Lab 3 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:54, 20 August 2014 (EST)<br />
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Lab 4--[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:27, 27 August 2014 (EST)<br />
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Lab 5 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:56, 3 September 2014 (EST)<br />
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Lab 6 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:37, 10 September 2014 (EST)<br />
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Lab 8 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:57, 24 September 2014 (EST)<br />
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Lab 9 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:21, 8 October 2014 (EST)<br />
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Lab 10 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:57, 15 October 2014 (EST)<br />
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Lab 11 --[[User:Z3415716|Z3415716]] ([[User talk:Z3415716|talk]]) 12:36, 22 October 2014 (EST)<br />
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==Assessment Lab 1==<br />
===Article 1===<br />
'''Effect of Vitamin D status on clinical pregnancy rates following in vitro fertilisation'''<br />
<br />
The study undertaken by Garbedian ''et al''. attempted to investigate whether vitamin D (25-hydroxy-vitamin D) serum level of in vitro patients could predict the successfulness of in vitro fertilisation (IVF). 173 patients participated, having met the criteria of age (18-41 years), follicle-stimulating hormone level (≤12IU/L at day 3 of the menstrual cycle), and consent.<br />
<br />
Serum samples were collected from the participating women, prior to oocyte retrieval, and were analysed, dividing the patients into two groups, sufficient (≥75 nmol/L) or insufficient (<75 nmol/L), based on their serum vitamin D levels. Regardless of this division, the IVF procedures were undertaken as per standard protocol. <br />
<br />
This article focused on two main outcomes, embryo implantation, and clinical pregnancy. Implantation was described as the establishment of a gestational sac upon ultrasonography screening. Whereas clinical pregnancy assessed via ultrasound, was determined by the visibility of an intrauterine sac. The results were collated, analysed, and compared between the groups in order to discover a relationship, if any, between serum vitamin D levels and both implantation and clinical pregnancy rates.<br />
<br />
Garbedian and colleagues found significant differences between the groups’ rate of embryo transfer and clinical pregnancy, however this is not the case in implantation rate. In consistency with the IVF protocols, embryo transfer was to take place on day 5, if at least 5-6 acceptable embryos were developed by day 3 of fertilisation. It was discovered that women with a sufficient level of serum vitamin D were more likely to achieve this step by day 5 than women with low serum vitamin D. Moreover, a higher clinical pregnancy rate was observed within the same group of women. An increased value of embryo implantation rate was noted, however results were statistically insignificant. <br />
<br />
With acknowledgement of the study’s limitations, Garbedian ''et al.'' concluded that women sufficient in vitamin D serum levels were more likely to achieve clinical pregnancy following IVF, with serum levels of the vitamin acting as an independent predictor. <br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/25077107 Effect of vitamin D status on clinical pregnancy rates following in vitro fertilization.]<br />
<br />
<pubmed>25077107</pubmed><br />
===Article 2===<br />
'''The Role of SPRASA in Female Fertility'''<br />
<br />
Sperm protein reactive with antisperm antibodies (SPRASA) also referred to as sperm lysosome-like protein 1 is a target protein of antisperm antibodies, and is the key protein explored within the article by Wagner ''et al.'' Numerous tests were preformed within this study investigating the role of this protein, particularly in fertilisation and embryonic development. <br />
<br />
The Bovine IVF model was employed to determine the effect of SPRASA antiserum on fertilisation, cleavage, and embryo development. Both bovine zona pellucida-attached and zona pellucida-free oocyte-sperm binding was investigated with the presence of antiserum preparation. Wagner and colleagues were able to conclude that fertility rates significantly reduced when SPRASA antiserum was added to oocytes, and sperm and oocytes samples, but not to sperm samples alone. Further on this note, the study found that the antiserum preparation negatively influenced the zona pellucida-free oocyte (oolemma)-sperm binding process, whereas no significant effect was found in the zona pellucida-attached oocyte-sperm binding. In terms of development, it was discovered that the antiserum was able to inhibit morula stage growth but not the further development at the blastocyst stage. <br />
<br />
Wagner and colleagues also assessed the influence on sperm motility by SPRASA and observed that sperm motility was not an affected area as there was no significant difference between motile sperm in antiserum perpetration and the control group. <br />
<br />
As previously thought that SPRASA was only present in spermatozoa, this study examined whether the protein was also expressed in oocytes and ovaries. Bovine oocytes, and ovaries from cats and dogs, were obtained for this section of the research. Similarly, sperm and sperm precursor cells were collected from testis of cats and dogs in order to illustrate the presence of SPRASA proteins. Results indicated that oocytes express SPRASA and staining was able to localise the protein to the zona pellucida and oolemma of bovine oocytes. Similar preparation and staining was carried out on ovaries of cats and dogs, and returned with positive expression of SPRASA. <br />
<br />
Fertilisation and embryo development was tested via immunisation and mating of female mice. Female mice were either continuously immunised with recombinant human SPRASA protein or irrelevant recombinant keyhole limpet hemocyanin (KLH) protein (control). The mice were then monitored, relocated for mating with male mice, and then compared in terms of pregnancy and fetal development. Wagner ''et al.'' found that all control mice became pregnant after 2 mating cycles, whereas the majority of SPRASA immunised mice failed to achieve pregnancy altogether. In regards to the number of embryo development and weight, no difference was recorded between the control and immunised mice. <br />
<br />
The final test was comparing the antibody levels from blood samples of fertile and infertile couples. Upon analysis of results, Wagner ''et al.'' discovered no significant difference between both fertile and infertile men and women, however 3 of the infertile women presented with inflated levels of the antibodies. <br />
<br />
Wagner ''et al.'' concluded that SPRASA, to a certain extent, plays a role in fertilisation and embryo development. They also rebutted the previous theory that the protein is solely expressed in male gametes with identifying SPRASA within the female reproductive structures.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/25038051 The Role of SPRASA in Female Fertility.]<br />
<br />
<pubmed>25038051</pubmed><br />
==Assessment Lab 2==<br />
[[File:WNT4_screening_in_the_testis_of_the_tammar_wallaby.jpeg|300px|left|thumb|WNT4 screening in the testis of the tammar wallaby]]<br />
<br />
<br />
<pubmed>17014734</pubmed>| [http://www.biomedcentral.com/1471-213X/6/44 Biomed Central]<br />
<br />
--[[User:Z8600021|Mark Hill]] This is fine and description with the image is good. You should have also reproduced the figure description and the reference here on your page. (4/5)<br />
<br />
==Assessment Lab 3==<br />
<pubmed>18462432</pubmed><br />
<pubmed>17232227</pubmed><br />
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]<br />
<br />
--[[User:Z8600021|Mark Hill]] These are relevant articles. I wonder why the third reference is not listed in PubMed Database? This usually indicates the relevance of the journal in the peer review system (4/5).<br />
<br />
==Assessment Lab 4==<br />
===Article 1===<br />
'''Conversion of human umbilical cord mesenchymal stem cells in Wharton's jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism'''<br />
<br />
Parkinson’s disease is a neurodegenerative disorder associated with the degradation of the dopaminergic system in the striatum region of the brain. Current short-term treatment for Parkinson’s disease is antiparkinson medications, mainly enhancing dopamine levels, however such medications reduce in effectiveness with further degradation of the neurotransmitter’s pathway. The study led by Fu, however, proposes a potential long-term treatment for Parkinson’s disease, utilising induced human mesenchymal stem cells (HMSCs) originating in the Wharton’s jelly of the umbilical cord. <br />
<br />
Fu ''et al.'' isolated HMSCs from the umbilical cord exposing the cells to subsequent chemical treatment resulting in the differentiation of these multipotent cells into dopaminergic neurones. These neurones were then injected into the subjects, adults rats with induced Parkinson’s post unilateral striatal lesioning. Subjects were compared with control untreated rats, concluding that the transplanted group exhibited a substantial improvement in rotational behaviour and Parkinson’s symptoms, however not enough to deem them cured from the disease. <br />
<br />
The potential for HMSCs, isolated from the umbilical cord, to correct Parkinson’s disease is further emphasised in its easy isolation methods, the large amount of cells able to be isolated, and the simple duplication of these stem cells. Fu ''et al.'' were able to collect 1x10^6 HUMSCs from 20 cm of umbilical cord and duplicate the amount to 2x10^6 cells in a three day incubation period. Furthermore, the study found that the transplanted differentiated cells were still successful 4 months post procedure, suggesting that this method may be a long-term treatment for the disease. The investigation also comments on the prospect of HUMSCs as a source for transplantation, attributed to its non-immunological inducing characteristic.<br />
<br />
<pubmed>16099997</pubmed><br />
===Vascular shunts===<br />
<br />
There are three shunts within the foetal circulatory development that close postnatally:<br />
*Ductus arteriosus<br />
A canal that connects the foetal pulmonary artery to the aorta, distributing oxygenated blood to the foetus while bypassing the developing lungs. <br />
*Ductus venosus <br />
Connecting the left umbilical vein to the inferior vena cave, allowing placental oxygenated blood to bypass the liver.<br />
*Foramen ovale<br />
A foramen within the interatrial septum where blood from the right atrium enters the left atrium.<br />
<br />
==Assessment Lab 5==<br />
===Oesophageal atresia===<br />
<br />
Oesophageal atresia is a rare gastrointestinal developmental abnormality, however in terms of oesophageal anomaly it is the most common, with one newborn out of every 2500 to 4500 being diagnosed within the first 24 hours of life [1]. Oesophageal atresia is diagnosed with the discontinuity of the oesophagus from the oral cavity to the stomach, where the oesophagus ends abruptly not in contact with the cardia of the stomach.<br />
<br />
Oesophageal atresia can be classified into five variants according to the location of the atresia and any associated tracheal fistulas (tracheoesophageal fistula) [1]. The five classifications include: oesophageal artesia without tracheoesophageal fistula, proximal tracheoesophageal fistula with distal oesophageal atresia, distal tracheoesophageal fistula with proximal oesophageal atresia, proximal and distal tracheoesophageal fistula, and tracheoesophageal fistula without oesophageal atresia [1]. <br />
<br />
The cause for this gastrointestinal abnormality is unclear and research continues to take place. With that said, various theories of the embryological origin of this anomaly have been proposed [1]. Three forefront theories comment on the primitive digestive tube and its failure to form a successful diverticulum, resulting in the connection of the trachea and oesophagus (tracheoesophageal fistula). In terms of the formation of oesophageal atresia, two of the three theories reason that the cellular distal portion of the primitive digestive tube rearranges and results in an abnormal discontinuous growth; whereas the third theory emphasises that the atresia is a consequence from regression of that portion of the tube towards the main part of the embryo. Currently no genetic roles have been identified in this developmental abnormality [1].<br />
<br />
Regardless of the lack of information gathered about the cause of oesophageal atresia, more advanced correctional surgeries have been introduced in the past decade [2]. Survival rates differ immensely between various nations, particularly when comparing developed to developing countries. In certain clinics, with state-of-the-art neonatal care, survival rates of up to 95% has been documented [1]. Surgical methods such as thoracoscopic repair has been improved within the past decade, resulting to a decrease in surgical complications and therefore an increase in survival rates [2].<br />
<br />
[1] <pubmed>22851858</pubmed><br />
[2] <pubmed>22584690</pubmed><br />
==Assessment Lab 7==<br />
===Article 1===<br />
'''Fetal Adrenal Gland in the Second Half of Gestation: Morphometric Assessment with 3.0T Post-Mortem MRI'''<br />
<br />
The adrenal gland, a bilateral organ located immediately superior the kidneys, are part of the endocrine system, playing an important role in releasing certain hormones such as cortisol and adrenaline in response to various situations including stressful situations. It is said that the adrenal gland is crucial in foetal development and that in comparison to other foetal organs, the foetal adrenal gland is relatively large. The study carried out by Zhonghe ''et al.'' quantitatively assessed the length, width, height, surface area and volume of normal foetal adrenal glands.<br />
<br />
52 foetal specimens ranging from 23-40 gestation weeks old were the subjects of this experiment. 72 foetal specimen were collected based on parental consent and in accordance with the Ethical Committee at the School of Medicine, Shandong University. Out of the 72 only 52 were utilised as foetuses with known abnormal maternal pregnancy records did not meet the criteria. The 52 subjects were organised in terms of their gestational age, found by measuring their crown-rump length via MRI. A highly advanced MRI scanner, SIEMENNS 3.0T MR scanner, was then employed in this research, measuring the adrenal glands of the foetus in the transverse, coronal and sagittal axis. Post-scanning, four specimens (24, 26, 32 and 36 weeks gestation age) were selected for gross anatomy dissection and measurement. <br />
<br />
Upon completing the measurements and gross dissections, Zhonghe ''et al.'' found that the bilateral organ was asymmetrical, with the right adrenal gland resembling an irregular triangle or pyramid, whereas the shape of the left adrenal gland was closer to a half-moon and larger than its right counterpart. No significant difference was found between the sexes, in contrast to previous research articles, however Zhonghe ''et al.'' attributed this discrepancy on it's relatively small group of specimens and uneven distribution of male and female foetuses. It was also discovered that as the gestational age increases the zona glomerulosa (outer zone of the cortex layer) became thicker.<br />
<br />
Zhonghe ''et al.'' regard their research and results as valuable in clinical settings and useful reference for the foetal anatomy. <br />
<br />
<pubmed>24116052</pubmed><br />
===Tooth Development===<br />
Odontogenesis begins in the sixth week of development. The embryonic cells/layers that differentiate to form the developing tooth include:<br />
* Odontoblasts — mesenchymal neural crest originating cells that secrete predentin, which calcifies to form dentin, the inner layer of the tooth. These cells are present throughout life and continuously produce dentin.<br />
* Ameloblasts — ectodermal cells of the oral epithelium that produce enamel, the outermost layer in the crown part of the tooth. Only present during odontogenesis. <br />
* Periodontal ligament — a specialised connective tissue that is in contact with the cementum layer (outer layer in the root of the tooth) and holds the tooth within the alveolar process.<br />
<br />
==Assessment Lab 8==<br />
===Ovary Development===<br />
<br />
Embryonic female differentiation and development was once perceived as a passive process, simply by the failure of developing male genital organs, however it is shown that this is not the case, with many molecular and genetic prerequisites required to develop the female genital system. <ref><pubmed>15664455</pubmed></ref><br />
<br />
Identical to the testes, the ovaries originate from the mesothelium, the underlying mesenchyme, and primordial germ cells. Within the early embryo, the gonads consists of a mesonephric duct (Wolffian duct), paramesonephric ducts (Mullerian ducts), and the external cortex and internal medulla regions. <br />
<br />
Gonadal development begins in the fifth week, medially to the mesonephros. The first structure of the developing gonad is the gonadal ridge. This ridge is formed by the proliferation of the mesenchyme tissue. The proliferating mesenchyme then grow epithelial cords, known as gonadal cords that extend to the developing ovary later on. <br />
<br />
The primordial germ cells, undifferentiated sex cells, become visible by day 24 of the embryonic period. The germ cell is relocated to the gonadal ridges during the folding process of the embryo.<br />
In the late embryonic phase, the lack of anti-mullerian hormone and testosterone is what beings the differentiation between the male and female genital development. At this point of time the Wolffian duct degenerates but the Mullerian ducts remain, in contrast to the male gonadal development. It is the Mullerian ducts that develop into the internal genital organs, the upper part into the fallopian tubes, and the lower part into the uterus and the vagina. <ref><pubmed>13230915</pubmed></ref><br />
<br />
During the 10th week, the ovaries become recognisable with the gonadal cords extending into the surface of the ovary. It is within this foetal developmental phase, beginning in the 16th week, that the gonadal cords commence degeneration forming primordial oocytes, referred to as oogonium. These oogonia, surrounded by a thin layer of epithelial cells, are the primordial follicles that a formed by mitosis.<br />
<br />
[[File:Bailey329.jpg|600px]]<br />
<br />
'''Transverse section of the ovary of a fox embryo'''<br />
<br />
===References===<br />
<references/><br />
'''Textbook''' [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466393265-4#4-u1.0-B978-1-4377-2002-0..00012-6--f0150 Moore: The Developing Human Chapter 12]<br />
* ''Note: Access to UNSW database requires a valid UNSW username and zPass''<br />
<br />
==Assessment Lab 9==<br />
===Peer review===<br />
<br />
'''Group 1 — Respiratory'''<br />
<br />
The introduction is shaping quite well. The information used are all relevant and provide an overall understanding of the respiratory system. It is great how you have divided the system into the two main parts, the conducting zone and respiratory zone, providing information and images for both. With that said, the images contain no caption or any description when clicked on and more work is needed in this area as explaining the images/slides will heighten the educational aim of the project. Furthermore, as Mark Hill has mentioned, you must cover all the components required in uploading and using an image, such as adding the copyright information. <br />
<br />
Presenting the lung development stages in a table format is very clever and the table constructed contains valuable information simplifying the developmental stages of the respiratory system. You have gone one step further than the required by showing that development does not only occur embryonically but up to 8 years of age. Good work. In terms of the references in this section, they all seem to be fine, however I am unable to click on the “Lung Development” link, which returns with “object not found.” So please fix that issue as the reader/marker must be able to validate all the references if need be.<br />
<br />
The current research section of this project page seems promising with a wide range of information. The foundations and structure are present however more information is required, which I know will be added before final submission. Identical to the introduction, it is good that you have divided the section into subsections based on the current research style and understanding that physiologically the lungs can be divided into the conduction system and functional unit. Numbering and dot points may be used, but I highly recommend that it is not used throughout the whole section. Moreover, your addition of an image highlighting Schematic lung disease and normal vs diseased lung models is appropriate for current research and models, however it should not be placed at the end under the references, you need to find a place between a paragraph that discusses or introduces this model. Lastly, there is a small formatting error in the middle of this section, I assume that is where an image should be located however check if you have written the command correctly. <br />
<br />
It is obvious that the historical section is well researched and that a number of articles have been referenced. The use dot points and dates are great and simple to understand, however if you make a timeline and paragraphs, the page might look more professional. You have the information required to create a simple timeline and paragraphs that follow. Great historical images used however the first lacks any description and the second lacks a reference. <br />
<br />
A vast range of abnormalities are addressed with references and thorough research into each. Some require more information, but overall all abnormalities are mentioned at a substantial extent with both full sentences and dot points. <br />
<br />
Overall this group has provided a well researched project, certain formatting errors need to be addressed and some more information can be added, otherwise good work!<br />
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'''Group 2 — Renal'''<br />
<br />
The introduction successfully touches on the project as a whole, including describing the system and its development, and the abnormalities that may arise. However it has failed to mention the importance of historical and current research. Also adding an image of the renal system or the renal units in particular will heighten the readers interest in this project.<br />
<br />
There seems to be no information under the historical findings subheading, it might be hard to find research papers on this system, however a good start would be reading Mark Hill’s page on the renal development.<br />
<br />
A very brief developmental timeline, however it does simply provide the information required to understanding the timeframe of renal development. More information about the structures mentioned in this timeline is required, this can be added within the timeline or following it.<br />
<br />
The current research model section needs more information, if you are unable to find enough to make a substantial section then a possibility to work around that is to integrate the various research models with the organ sections. However, if more information can be obtained then this section should be left and continued as the image is correctly included and the information is written at a high standard.<br />
<br />
The division of this page into the various organs in the renal system, the kidney, urethra, and ureter is clever as providing information on all in one section may be overwhelming. Each of these organs are well researched and written about. The layout looks fine with the paragraphs placed under subheadings and an abundant amount of images are located next to their corresponding information. Some images do not have a description, it is best to add a description, even a short one, to guide the reader and pinpoint the reason for uploading. An error has occurred for the first image under the Kidney section which has been removed by the administrator. Please take care with copyright. <br />
<br />
I really like the abnormality section and the information added thus far. It is evident that you plan to continue as this section is not finished, however with what is there, great work. Both images used contain captions and clearly understood descriptions. One fault is the presence of references in this section. The group has one reference heading at the end of the project, however some of the references doubled up within the abnormalities section. One that note, please look carefully through the referencing list as you have the same articles more than once in the list, for example 23 and 24. There is a way of merging them together and having superscripts indicate that this article has been cited more than once, use article 28 and 30 as examples. <br />
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'''Group 3 — Gastrointestinal'''<br />
<br />
The overview is quite short and lacks citations and images, however this is understandable seeing as it is a draft copy, but please make sure the overview informations are cited and images are included. The information uploaded so far is structured based on the division of the gut into fore-gut, mid-gut and hind-gut, and very easy to follow.<br />
<br />
An extensive timeline, however the presentation can be improved as this timeline takes a lot of space and consists of a single word or a sentence. Maybe adding more information in the timeline or condensing the timeline in a table format.<br />
<br />
I don’t understand the recent findings section as only one research paper has been considered. If more will be added then that is fine however when writing about these findings it’s good to incorporate it with other findings rather than simply summarising the results of one article. <br />
<br />
Foregut, midgut and hindgut are well covered including innervations and structures of those areas. A range of format is used such as table, dot point and full paragraphs, which neatly tie all the information together and allows for a break in between paragraphs. Student redrawn images are a great source and you have referenced from where you have obtained the original image. No images are used for the foregut even though you have mentioned a few organs in detail. Furthermore, it is best to keep your formatting consistent as the dot points in the foregut section differs to those in midgut.<br />
<br />
Detailed examples of deformities are present in the gastrointestinal system, however more deformities should be looked at and included. Deformities are also mentioned under the subheading of hindgut (Anorectal deformities, cloacal extrophy, and developmental problems), which might be best moved to the deformities block of the project page. This redrawn image is clear and labelled, however there is no reference. <br />
<br />
Overall the project page is interesting, easy to comprehend and follow, however certain layout issues should be addressed and more information added. <br />
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'''Group 5 — Integumentary''' <br />
<br />
The introduction covers all the topics of the project, however it does so briefly. Merging the development overview with the introduction will hide the fact that the introduction paragraph is short as this whole section will become one large detailed introduction about the integumentary system. The development overview is detailed and separated in terms of the structures found in the system. This is great, however less dot points should be used as it looks more like notes than presentable information. The creation of this timeline table is amazing and addition of the images according to the weeks is a well generated idea. Not all the images are described, so please do so for the final copy as it is essential that images of histological slides are describes as they can be confusion and difficult to understand. The information about hair and its adjacent image is the scaffold that should be followed throughout the whole section, as it has been written concisely and easily understandable. The hair development stages image is adequately describes and references with the copyright statement. Well done.<br />
<br />
I appreciate the uniqueness in the layout of the recent findings, however I find it slightly overwhelming and out of place. Possibly adding a collapse and expand option to each article is beneficial. The summaries of the findings are in-depth and it is obvious that the author of this summary understands the topic.<br />
<br />
A great start in historic findings with information present for a wide range of structures in this system. With that said, each section requires more research, however you are on the right path in finding articles greater than 50 years old. Only one image is attempted to be added, it is hard to find copyright granted images or historical drawings, but redrawing those original images is vital in providing solid historical information. In terms of the referencing, if you are unable to find a PMID for a certain article then manually add the reference and the URL link as you have but adhere to correct formatting.<br />
<br />
Each abnormality is consistent with detailed information, statistics and a described image. The writing style is consistent and the image uploads with captions are correctly completed. Great work. The information is frequently cited emphasising efficient research ability. On that note, the references are correctly numbered and superscripts used instead of repeating the reference. <br />
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'''Group 6 — Endocrine'''<br />
<br />
An introduction has not yet been added, however when doing so aim to mention the gist of the project and the manner in which is has been divided so that the reader/marker can effectively understand what is in this project. The wikipage is separated into the numerous endocrine organs, which is great as a future student can easily navigate to the organ of interest. <br />
<br />
As it is only a draft copy it is assumed that improvement and adding of information will take place leading to the submission of the final as there are subheadings such as “Recent findings” that have been left blank. With what is currently present, each organ contains well researched information. In the beginning two organs, the pineal gland and hypothalamus, there is a subheading for abnormalities, however there is also a section towards the end of the wikipage solely for abnormalities, so refrain from doubling up on the information and either place all the abnormalities in one section or separate the malformations in terms of their respective structure. References are also seen at the end of each section or subsection and no in-text citation has been used yet, so it might be easier to cite the dot points or information as you go so you can remember where you got that from instead of trying to find that piece in the numerous research articles you have. Once that has been done, it will be best to relocate all the references at the end of the page, where you have already made the heading.<br />
<br />
The structure is consistent throughout the page with each organ having a timeline and most containing an image and a table. This makes the project appealing and easy to read and understand. All the images uploaded contain comprehensive information and thus I am able to decipher the image and as a result enriches the learning aims of this assignment. The creation of a timeline for each organ is clever as each exhibits its own developmental process. The separation into many smaller timelines allows for specific events to be included that would otherwise overload a collective timeline. The setup of a table under the organisation of hormone, cells and function further simplifies an extremely complicated developmental system. As a student learning about the endocrine system I would be relieved to discover tables and content of this standard and structure. <br />
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'''Group 7 — Neural (CNS)'''<br />
<br />
Solid introduction, it is well conveyed and divided into the two main organs of the CNS, the brain and the spinal cord. You have not just listed the two organs but also introduced both individually, describing their components and functions. Nice work.<br />
<br />
The layout of this page is well thought through as you it begins with the overall neural development in the foetal period, then delves into the development of the two main organs, firstly the brain development, followed by the spinal cord development. This makes the project easy to understand as it is well organised. Within each subsection there has been images uploaded and tables added in addition to the information in both paragraph and dot point format. Majority of the images uploaded contain a description as well as the caption, however some descriptions require more to help clarify the image and for some no description is present, such as the image of the newborn with a giant occipital encephalocele. All have a caption, however I recommend you change the formatting of the image so that the caption is location just under the image and not within the text as you have done. <br />
<br />
A timeline of neural development is added at the beginning in the form of a drawing and another timeline, more specific to sulcation and gyration, is added under brain development. These are great to use as it collaborates all the information into a clear and comprehensive piece. <br />
<br />
The spinal cord development and meninges development lack information at this stage, so when filling up this section, it will be best to ensure you are consistent with the formatting and follow what has been used in the brain development section. Add as many tables, timelines and images as possible as this simplifies the information and enriches the page in terms of interest and completing the objectives of this assignment. The same goes for current research models and findings, I can see you have many references ready to be used and that this section has a lot of information. So that the project does not become overwhelming, it is not necessary to summarise or present all the findings, but only chose the most important and influential. You can also merge some research together if they focus on similar or identical concepts. <br />
<br />
The abnormalities section is shaping up well. You have included many abnormalities that can occur in this system, so if you are able to write about each and include an image, then that will be great. Possibly refrain from writing it all in dot points, but that could only be the case because it is a draft copy. There is an error in an image uploaded about the facial characteristics associated with foetal alcohol syndrome. It returns with permission error so before uploading ensure that you are not breaching any copyright laws. You may even draw it or find another image similar that allows you to use it. <br />
<br />
Listing all the references at the end of the page is a great idea. Some references are listed more than once because you have cited them in more than one place throughout the assignment. Such examples are 7 and 8, and 9 and 10. There is a command that allows you to use superscript where the one reference is listed with many superscripts, each corresponding to the different areas in which you have cited that article. <br />
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'''Group 8 — Musculoskeletal'''<br />
<br />
The Making Gains section is quite funny but as you said, this is not Broscience and I’m sure it will be removed for the final submission. Once that is removed, begin the project with an introduction and the developmental general timeline. The main idea of the timeline is present, however when constructing one, use specific weeks within the foetal period and what developmental changes occur in those weeks. The information found under Background Embryonic development may be used to form the introduction, but if you are going to do that do not make the introduction as detailed as this section is, particularly in terms of the transcription factors and signalling molecules, they can be moved and added into the other sections that look at the various musculoskeletal developments individually.<br />
<br />
It is evident that there is great understanding of this topic and that it is only a case of further research and addition of those information to complete the sections. Certain sections lack information all together, such as the Third Trimester Muscular development and Recent findings, whereas other sections only contain the research articles and no summaries of them such as Abnormalities. However I understand this is a draft and that all those areas will be addressed adequately, contributing to the final copy. <br />
<br />
Only the Background Embryonic development and Molecular and Cellular regulation of foetal myogenesis have in text citations, whereas the other sections that do contain information are not cited. It might become difficult to later find the correct article from which you obtained the information so it is advised to cite the text while adding it. In terms of the citations present, there is no need for a comma between the superscripts and you have also allocated two sections to references, one subsequent to Abnormalities and another at the bottom of the page, it is best to collate all the references in one list at the end of the page. This is also the case for Abnormalities as there are two subheadings for it, merge them into one. <br />
<br />
No images, tables, or timelines are added. The information you have now is well written and divided into small paragraphs, which is a good way of presenting the information, however other forms such as images and tables should be used. A timeline should be added under the Muscle development General Timeline subheading, this may be done as a table or a drawing and uploaded as it simplifies the information and breaks the page from continuous writing. <br />
<br />
Overall this group project page is great, containing all the headings and articles present. It is only a matter of summarising those articles and adding the information. All the information present thus far is appropriate and emphasises great research skills.<br />
<br />
==Assessment Lab 10==<br />
'''Neural crest contribution to lingual mesenchyme, epithelium and developing taste papillae and taste buds'''<br />
<br />
The study by Liu ''et al.'' aimed to discover if neural-crest derived cells contribute to the tongue mesenchyme and epithelium including taste papillae and taste buds. To test this, they utilised tissues from four different transgenic mice, separated by Cre recombinase enzyme, ''Wnt1-Cre'' and ''P0-Cre'', and further divided into two reporter lines, ''R26R lacZ'' and ''ZEG'' double reporter, producing four unique mouse lines (''Wnt1-Cre/R26R'', ''Wnt1-Cre/ZEG'', ''P0-Cre/R26R'' and ''P0-Cre/ZEG''). This then allowed Liu and his colleagues to quantitatively examine the expression of all the papillae, as previous research indicated that some of the papillae contain a distinct test array and require a different method of analysis. <br />
<br />
The mice population consisted of embryonic and postnatal mice, up to 10 days old, with their litter collected and genotyped via polymerase chain reaction (PCR). A control group was included with their litter also collected. Various experiments were carried out to test for the four types of lingual papillae; fungiform, filiform, foliate and circumvallate. <br />
<br />
X-Gal staining and labelling was used to test for fungiform papillae in the ''P0-Cre/R26R'' mouse tongue. The taste buds were then divided into three categories based on their expression rate under light microscopy. Immunohistochemistry was also employed in this study, with slides treated with primary and secondary antibodies to illicit an immunoreaction that could be quantitatively recorded. <br />
<br />
The embryonic mice sample and the newborn mice (P1) that were treated with ''Wnt1-Cre'' were examined for the location of the neural crest-derived cells. Upon completion, it was found that the neural crest-derived cells were primarily located in the lingual mesenchyme of both the embryonic and postnatal mice, however it was shown that as the tongue develops, the cells become more localised, immediately under the lingual epithelium. This was uniform with the findings on the tongues of the ''Wnt1-Cre/ZEG'' type mice, and thus Liu ''et al.'' concluded that these neural crest-derived cells are abundant within the papilla mesenchyme and in the core of the taste papillae. However, a different conclusion was reached for the tongue epithelium of the ''Wnt1-Cre'' type population, where these neural crest-derived cells were rarely found. <br />
<br />
The fungiform papillae were tested in the ''P0-Cre'' line mice. The distribution pattern of the neural crest-derived cells in the mesenchyme was similar to that in the ''Wnt1-Cre'' samples. A different result, however, was obtained for the epithelium, as the desired cells were found to be located in the epithelium and the taste buds of the tongue, indicating that neural crest-cells contributed greatly to the fungiform papillae.<br />
<br />
Antibodies were added into samples of developed tongues and no Cre immunoreactivity took place in those tissues, highlighting the validity of the study in tracing the cell lineage and removing doubts that ectopic ''Cre'' activity was in fact responsible for the results and not true ''P0''-expressing cells.<br />
<br />
Base on their findings, Liu et al. proposed that neural crest cell from the neural tube migrate to the developing tongue mesenchyme and epithelium. They further explained that subsequent to migration into the epithelium, these cells acquire different phenotypes and differentiate into taste papillae. The taste papillae interact with the neural crest-derived cells that remain in the mesenchyme, which have roles in the development and maintenance of the taste papillae.<br />
<br />
<pubmed>22659543</pubmed><br />
<br />
==Assessment Lab 11==</div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1605442014 Group Project 92014-10-24T12:16:54Z<p>Z3415716: /* Male Genital Development */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
This page is the second page of the [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_4 Group 4 Project]<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It is through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
Majority of the findings led to a proposal of a theory of that organ or the system, with some of these theories still accepted today while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian ducts.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
[[File:Mullerian ducts development.jpeg|400px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
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><br />
<br />
According to the works of the early embryologists, Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also known that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina, indicating that the development of the hymen is a process irrespective of vagina development <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening at the junction of the labia minora, is the most sensitive sexual organ of a female and has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
[[File:Prostate.jpeg|300px|right|thumb|The prostate with the adjoining seminal vesicles and vas deferens]]<br />
<br />
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 in the understanding of the development of the gland. <ref><pubmed>18462432</pubmed></ref> <ref><pubmed>13948442</pubmed></ref> <ref><pubmed>18942121</pubmed></ref><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustration of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1611 ||bgcolor="F5FAFF"| Caspar Batholin, described the prostate as a spongy double organ that is continuous with the urethra, secreting protective substances.<br />
|-<br />
|bgcolor="FCFCFC"| 1674 ||bgcolor="FCFCFC"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="F5FAFF"| 1678 ||bgcolor="F5FAFF"| The first illustration of the prostate with the seminal vesicles and seminal ducts attached. This diagram was published by a Dutch anatomist Reinier De Graaf.<br />
|-<br />
|bgcolor="FCFCFC"| 1792 ||bgcolor="FCFCFC"| William Cheselden, an English anatomists and surgeon, challenged the theory that the prostate was two organs, stating that it may in fact one gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1800 ||bgcolor="F5FAFF"| The double gland idea was disproven with the discovery that the perceived two glands had identical morphology and thus were one gland. <br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debates was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum, as a vascular and fibrous foetal structure, and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated was introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed glans penis, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divide the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
[[File:Prepuce.jpeg|500px|centre|thumb|The steps of the developing prepuce in the male foetus condensed into three overall events]]<br />
<br />
{|class="wikitable mw-collapsible mw-collapsed"<br />
! '''Further information on the historical teachings of the genital system'''<br />
|- bgcolor="A3BFB1"<br />
|<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Human_Embryology_and_Morphology_9 The Urogenital System (1902)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Manual_of_Human_Embryology_19 The Development of the Urinogenital Organs (1912)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Text-Book_of_Embryology_15 The Development of the Urogenital System (1921)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Contributions_to_Embryology_Carnegie_Institution_No.61 The Development of the External Genitalia in the Human Embryo (1921)]<br />
|}<br />
<br />
==Abnormalities==<br />
<br />
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>. <br />
The content will cover most common abnormalities and then also the rare cases. <br />
Most genital abnormalities have a high risk in affecting fertility of both sexes. <br />
Currently there are a variety of methods applied to ensure that infertility can be treated and this will be mentioned. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout the child's life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia <ref>Schoenwolf, GC., Bleyl, S.B., Brauer, P.R., Francis-West, P.H., (2008). Larsen's Human Embryology, 4th ed. Chapter 15 Development of the Urogenital System. New York; Edinburgh: Churchill Livingstone, an imprint of Elsevier.</ref><br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. The congenital disorder affects 1 in 5,000 females <ref>http://www.urologyhealth.org/urology/index.cfm?article=50</ref>.<br />
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>.<br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>. [[File:WomenwithSwyerSyndrome.png|285px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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>. The syndrome affects 1 in 30,000 people <ref>http://ghr.nlm.nih.gov/condition/swyer-syndrome</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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=magenta>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
A metabolic endocrine disorder with an immense variety of phenotypes presented. The disorder shows an imbalance in female sex hormones and a resistance to insulin. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. It is most common in 5-10% of women in their reproductive age <ref>http://www.myvmc.com/diseases/polycystic-ovarian-syndrome-pcos/</ref>. The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
Involves the absence of both or single testis to descend into the scrotum, the testes can be ectopic,<br />
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 condition is prevalent in 2-4% of infant males <ref>http://livehealthy.chron.com/cryptorchidism-infertility-1080.html</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>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>. [[File:Hypospadia classifications.jpg|280px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
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 <br />
<ref><pubmed>24936573</pubmed></ref>. Generally occurs in 1 of 125-300 male births <ref>http://www.hypospadiasuk.co.uk/statistics-about-hypospadias/</ref>. <br />
The surgical methods currently used to treat distal hypospadias, include tabularized incised plate and meatal advancement and glansplasty intergrated repair. <br />
For proximal forms two staged procedures are employed. <ref><pubmed>25023236</pubmed></ref><br />
<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome]]<br />
<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
<br />
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>. The disorder occurs among 1 in 500-1,000 male births <ref>http://ghr.nlm.nih.gov/condition/klinefelter-syndrome</ref>. An early diagnosis is important in order for treatment to be commenced right away. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=mediumslateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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. It occur is about 1 in 15,000 live births <ref>http://www.patient.co.uk/health/congenital-adrenal-hyperplasia-leaflet</ref>. 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>.<br />
[[File:Hydrocele.jpg|300px|thumb|right|A fetal ultrasound showing Hydrocele surrounding the testis]]<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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. The condition is prevalent in about 1-3% of births <ref><pubmed>http://bestpractice.bmj.com/best-practice/monograph/1104/basics/epidemiology.html</ref>. To manage the condition treatments focus on ensuring draining any excess fluid and inhibiting reaccumulation. <br />
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>.<br />
[[File:Ovotestes.jpg|180px|thumb|left|Tissue in True Hermaphroditism disorder, showing the Ovotestes that comprises of primary follicles and seminiferous tubules.]]<br />
<br />
====<font color=mediumslateblue>True Hermaphroditism</font>==== <br />
<br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. The disorder occur in 1 of 1,500-2,000 births <ref>http://www.isna.org/faq/frequency</ref>.<br />
Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. <br />
Each case is determined differently as there are many factors to consider when choosing the gender identity. <br />
This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=blueviolet>Also related include;</font><br />
|- <br />
| <font color=mediumslateblue>'''Kallmann syndrome'''</font><br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hypogonadotropic hypogonadism</font>====<br />
<br />
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). The incidence is about 1 in 2,000 births <ref>http://www.rightdiagnosis.com/h/hypogonadotropic_hypogonadism_syndactyly/prevalence.htm</ref>. <br />
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>.<br />
|}<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1605412014 Group Project 92014-10-24T11:59:51Z<p>Z3415716: /* Female Genital Development */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
This page is the second page of the [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_4 Group 4 Project]<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It is through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
Majority of the findings led to a proposal of a theory of that organ or the system, with some of these theories still accepted today while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian ducts.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
[[File:Mullerian ducts development.jpeg|400px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
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><br />
<br />
According to the works of the early embryologists, Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also known that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina, indicating that the development of the hymen is a process irrespective of vagina development <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening at the junction of the labia minora, is the most sensitive sexual organ of a female and has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
[[File:Prostate.jpeg|300px|right|thumb|The prostate with the adjoining seminal vesicles and vas deferens]]<br />
<br />
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> <ref><pubmed>18942121</pubmed></ref><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1611 ||bgcolor="F5FAFF"| Caspar Batholin, described the prostate as a spongy double organ that is continuous with the urethra, secreting protective substances.<br />
|-<br />
|bgcolor="FCFCFC"| 1674 ||bgcolor="FCFCFC"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="F5FAFF"| 1678 ||bgcolor="F5FAFF"| The first illustration of the prostate with the seminal vesicles and seminal ducts attached. This diagram was published by a Dutch anatomist Reinier De Graaf.<br />
|-<br />
|bgcolor="FCFCFC"| 1792 ||bgcolor="FCFCFC"| William Cheselden, an English anatomists and surgeon, challenged the theory that the prostate was two organs, stating that it may in fact be one gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1800 ||bgcolor="F5FAFF"| The double gland idea was disproven with the discovery that the perceived two glands had identical morphology and thus were one gland. <br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divide the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
[[File:Prepuce.jpeg|500px|centre|thumb|The steps of the developing prepuce in the male foetus condensed into three overall events]]<br />
<br />
{|class="wikitable mw-collapsible mw-collapsed"<br />
! '''Further information on the historical teachings of the genital system'''<br />
|- bgcolor="F5FFFA"<br />
|<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Human_Embryology_and_Morphology_9 The Urogenital System (1902)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Manual_of_Human_Embryology_19 The Development of the Urinogenital Organs (1912)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Text-Book_of_Embryology_15 The Development of the Urogenital System (1921)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Contributions_to_Embryology_Carnegie_Institution_No.61 The Development of the External Genitalia in the Human Embryo (1921)]<br />
|}<br />
<br />
==Abnormalities==<br />
<br />
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>. <br />
The content will cover most common abnormalities and then also the rare cases. <br />
Most genital abnormalities have a high risk in affecting fertility of both sexes. <br />
Currently there are a variety of methods applied to ensure that infertility can be treated and this will be mentioned. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout the child's life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia <ref>Schoenwolf, GC., Bleyl, S.B., Brauer, P.R., Francis-West, P.H., (2008). Larsen's Human Embryology, 4th ed. Chapter 15 Development of the Urogenital System. New York; Edinburgh: Churchill Livingstone, an imprint of Elsevier.</ref><br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. The congenital disorder affects 1 in 5,000 females <ref>http://www.urologyhealth.org/urology/index.cfm?article=50</ref>.<br />
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>.<br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>. [[File:WomenwithSwyerSyndrome.png|285px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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>. The syndrome affects 1 in 30,000 people <ref>http://ghr.nlm.nih.gov/condition/swyer-syndrome</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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=magenta>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
A metabolic endocrine disorder with an immense variety of phenotypes presented. The disorder shows an imbalance in female sex hormones and a resistance to insulin. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. It is most common in 5-10% of women in their reproductive age <ref>http://www.myvmc.com/diseases/polycystic-ovarian-syndrome-pcos/</ref>. The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
Involves the absence of both or single testis to descend into the scrotum, the testes can be ectopic,<br />
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 condition is prevalent in 2-4% of infant males <ref>http://livehealthy.chron.com/cryptorchidism-infertility-1080.html</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>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>. [[File:Hypospadia classifications.jpg|280px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
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 <br />
<ref><pubmed>24936573</pubmed></ref>. Generally occurs in 1 of 125-300 male births <ref>http://www.hypospadiasuk.co.uk/statistics-about-hypospadias/</ref>. <br />
The surgical methods currently used to treat distal hypospadias, include tabularized incised plate and meatal advancement and glansplasty intergrated repair. <br />
For proximal forms two staged procedures are employed. <ref><pubmed>25023236</pubmed></ref><br />
<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome]]<br />
<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
<br />
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>. The disorder occurs among 1 in 500-1,000 male births <ref>http://ghr.nlm.nih.gov/condition/klinefelter-syndrome</ref>. An early diagnosis is important in order for treatment to be commenced right away. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=mediumslateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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. It occur is about 1 in 15,000 live births <ref>http://www.patient.co.uk/health/congenital-adrenal-hyperplasia-leaflet</ref>. 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>.<br />
[[File:Hydrocele.jpg|300px|thumb|right|A fetal ultrasound showing Hydrocele surrounding the testis]]<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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. The condition is prevalent in about 1-3% of births <ref><pubmed>http://bestpractice.bmj.com/best-practice/monograph/1104/basics/epidemiology.html</ref>. To manage the condition treatments focus on ensuring draining any excess fluid and inhibiting reaccumulation. <br />
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>.<br />
[[File:Ovotestes.jpg|180px|thumb|left|Tissue in True Hermaphroditism disorder, showing the Ovotestes that comprises of primary follicles and seminiferous tubules.]]<br />
<br />
====<font color=mediumslateblue>True Hermaphroditism</font>==== <br />
<br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. The disorder occur in 1 of 1,500-2,000 births <ref>http://www.isna.org/faq/frequency</ref>.<br />
Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. <br />
Each case is determined differently as there are many factors to consider when choosing the gender identity. <br />
This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=blueviolet>Also related include;</font><br />
|- <br />
| <font color=mediumslateblue>'''Kallmann syndrome'''</font><br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hypogonadotropic hypogonadism</font>====<br />
<br />
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). The incidence is about 1 in 2,000 births <ref>http://www.rightdiagnosis.com/h/hypogonadotropic_hypogonadism_syndactyly/prevalence.htm</ref>. <br />
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>.<br />
|}<br />
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==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1603072014 Group Project 92014-10-24T09:58:04Z<p>Z3415716: /* Historic Finding */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
This page is the second page of the [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_4 Group 4 Project]<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It is through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
[[File:Mullerian ducts development.jpeg|400px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
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><br />
<br />
According to the works of the early embryologists, Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
[[File:Prostate.jpeg|300px|right|thumb|The prostate with the adjoining seminal vesicles and vas deferens]]<br />
<br />
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> <ref><pubmed>18942121</pubmed></ref><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1611 ||bgcolor="F5FAFF"| Caspar Batholin, described the prostate as a spongy double organ that is continuous with the urethra, secreting protective substances.<br />
|-<br />
|bgcolor="FCFCFC"| 1674 ||bgcolor="FCFCFC"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="F5FAFF"| 1678 ||bgcolor="F5FAFF"| The first illustration of the prostate with the seminal vesicles and seminal ducts attached. This diagram was published by a Dutch anatomist Reinier De Graaf.<br />
|-<br />
|bgcolor="FCFCFC"| 1792 ||bgcolor="FCFCFC"| William Cheselden, an English anatomists and surgeon, challenged the theory that the prostate was two organs, stating that it may in fact be one gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1800 ||bgcolor="F5FAFF"| The double gland idea was disproven with the discovery that the perceived two glands had identical morphology and thus were one gland. <br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divide the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
[[File:Prepuce.jpeg|500px|centre|thumb|The steps of the developing prepuce in the male foetus condensed into three overall events]]<br />
<br />
{|class="wikitable mw-collapsible mw-collapsed"<br />
! '''Further information on the historical teachings of the genital system'''<br />
|- bgcolor="F5FFFA"<br />
|<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Human_Embryology_and_Morphology_9 The Urogenital System (1902)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Manual_of_Human_Embryology_19 The Development of the Urinogenital Organs (1912)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Text-Book_of_Embryology_15 The Development of the Urogenital System (1921)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Contributions_to_Embryology_Carnegie_Institution_No.61 The Development of the External Genitalia in the Human Embryo (1921)]<br />
|}<br />
<br />
==Abnormalities==<br />
<br />
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>. <br />
The content will cover most common abnormalities and then also the rare cases. <br />
Most genital abnormalities have a high risk in affecting fertility of both sexes. <br />
Currently there are a variety of methods applied to ensure that infertility can be treated and this will be mentioned. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout the child's life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia <ref>Schoenwolf, GC., Bleyl, S.B., Brauer, P.R., Francis-West, P.H., (2008). Larsen's Human Embryology, 4th ed. Chapter 15 Development of the Urogenital System. New York; Edinburgh: Churchill Livingstone, an imprint of Elsevier.</ref><br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. The congenital disorder affects 1 in 5,000 females <ref>http://www.urologyhealth.org/urology/index.cfm?article=50</ref>.<br />
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>.<br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>.<br />
[[File:WomenwithSwyerSyndrome.png|285px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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>. The syndrome affects 1 in 30,000 people <ref>http://ghr.nlm.nih.gov/condition/swyer-syndrome</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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=magenta>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
A metabolic endocrine disorder with an immense variety of phenotypes presented. The disorder shows an imbalance in female sex hormones and a resistance to insulin. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. It is most common in 5-10% of women in their reproductive age <ref>http://www.myvmc.com/diseases/polycystic-ovarian-syndrome-pcos/</ref>. The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
Involves the absence of both or single testis to descend into the scrotum, the testes can be ectopic,<br />
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 condition is prevalent in 2-4% of infant males <ref>http://livehealthy.chron.com/cryptorchidism-infertility-1080.html</ref>.<br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
[[File:Hypospadia classifications.jpg|300px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
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 <br />
<ref><pubmed>24936573</pubmed></ref>. Generally occurs in 1 of 125-300 male births <ref>http://www.hypospadiasuk.co.uk/statistics-about-hypospadias/</ref>. <br />
The surgical methods currently used to treat distal hypospadias, include tabularized incised plate and meatal advancement and glansplasty intergrated repair. <br />
For proximal forms two staged procedures are employed. <ref><pubmed>25023236</pubmed></ref><br />
<br />
[[File:Klinefelter.jpg|300px|left|thumb|Characteristics presented among men with Klinefelter Syndrome]]<br />
<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
<br />
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>. The disorder occurs among 1 in 500-1,000 male births <ref>http://ghr.nlm.nih.gov/condition/klinefelter-syndrome</ref>. An early diagnosis is important in order for treatment to be commenced right away. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=mediumslateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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. It occur is about 1 in 15,000 live births <ref>http://www.patient.co.uk/health/congenital-adrenal-hyperplasia-leaflet</ref>. 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>.<br />
[[File:Hydrocele.jpg|300px|thumb|right|A fetal ultrasound showing Hydrocele surrounding the testis]]<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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. The condition is prevalent in about 1-3% of births <ref><pubmed>http://bestpractice.bmj.com/best-practice/monograph/1104/basics/epidemiology.html</ref>. To manage the condition treatments focus on ensuring draining any excess fluid and inhibiting reaccumulation. <br />
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>.<br />
[[File:Ovotestes.jpg|180px|thumb|left|Tissue in True Hermaphroditism disorder, showing the Ovotestes that comprises of primary follicles and seminiferous tubules.]]<br />
<br />
====<font color=mediumslateblue>True Hermaphroditism</font>==== <br />
<br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. The disorder occur in 1 of 1,500-2,000 births <ref>http://www.isna.org/faq/frequency</ref>.<br />
Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. <br />
Each case is determined differently as there are many factors to consider when choosing the gender identity. <br />
This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=blueviolet>Also related include;</font><br />
|- <br />
| <font color=mediumslateblue>'''Kallmann syndrome'''</font><br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hypogonadotropic hypogonadism</font>====<br />
<br />
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). The incidence is about 1 in 2,000 births <ref>http://www.rightdiagnosis.com/h/hypogonadotropic_hypogonadism_syndactyly/prevalence.htm</ref>. <br />
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>.<br />
|}<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Prepuce.jpeg&diff=159977File:Prepuce.jpeg2014-10-24T07:27:28Z<p>Z3415716: </p>
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<div>A summary of the steps of prepuce development as described by Hunter in 1935. The drawings resemble and illustrate the observations of the foetal penis at different gestational age, depicting that the prepuce is a gradually growing structure during foetal growth. <br />
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The three images (A, B, C) show the overall continuous change of the penis in terms of the prepuce.<br />
* A - Before prepuce development. The glans penis is fully exposed as the prepuce growth has not yet occurred. <br />
* B - Prepuce development. The developing prepuce layer form folds due to its rapid rate of growth and begins to cover the glans penis posteriorly. <br />
* C - Completion of the prepuce. By this stage, the epithelial cells have migrated forming a superficial layer that covers the entire glans penis. This is the penis-type observed at birth. <br />
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This diagram is an adaptation from <ref><pubmed>17104576</pubmed></ref><br />
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===Reference===<br />
<references/><br />
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===Copyright===<br />
Beginning six months after publication, I z3417458 grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode<br />
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{{Template:Student Image}}</div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_4&diff=1599712014 Group Project 42014-10-24T07:25:51Z<p>Z3415716: /* Introduction */</p>
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<div>{{ANAT2341Project2014header}}<br />
=Genital=<br />
==Introduction==<br />
<br />
[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]<br />
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Genital system development occurs in both the embryonic and foetal phase of development. By the commencement of the foetal period, sexual determination and initial growth of the different gonads occur <ref name=Hill2014>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>. It is within the foetal period that the internal and external genital organs develop <ref name=Hill2014>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>. This page focuses on the foetal developmental processes, exploring the current and historical models and understanding, alongside the congenital abnormalities. <br />
<br />
Today there is an innumerable amount of research articles focused on foetal genital growth, with some addressing the system as a whole <ref name=PMID14641326><pubmed>14641326</pubmed></ref> and others investigating certain genital organs <ref name=PMID13362960><pubmed>13362960</pubmed></ref>. Current models and understandings have been obtained from both human <ref name=PMID11315960><pubmed>11315960</pubmed></ref> and animal populations <ref name=PMID13362960><pubmed>13362960</pubmed></ref>, and this page will outline some of the important current research.<br />
<br />
Research into foetal genital development can be traced to as early as the 16th century<ref name=PMID18462432><pubmed>18462432</pubmed></ref> with anatomists proposing theories and constructing models, proven to being critical in obtaining the in-depth information known today. This page will mention some of these historical findings in both the female and male genital system. <br />
<br />
This project will end with discussing some of the congenital abnormalities of the genital system, mentioning both the malformations that are most common <ref name=PMID16006950><pubmed>16006950</pubmed></ref> and those that are rare <ref name=PMID23635766><pubmed>23635766</pubmed></ref>.<br />
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==System Development==<br />
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[[File:Paramesonephric duct.jpg|200px|thumb|Paramesonephric duct development]]<br />
[[File:Infant ovary.jpg|200px|thumb|Histological image of primordial follicles in infant ovary]]<br />
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'''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><br />
{| class="wikitable" <br />
|-bgcolor="purple"|align="centre"<br />
|'''Week''' || '''Development'''<br />
|-bgcolor="lavender"<br />
| 3-4 || Primordial germ cells migrate during gastrulation<br />
|-<br />
| 4 || Intermediate mesoderm, pronephros primordium<br />
|-bgcolor="lavender"<br />
| 5 || Mesonephros and mesonephric duct<br />
|-<br />
| 6 || Ureteric bud, metanephros, genital ridge<br />
|-bgcolor="lavender"<br />
| 7 || Cloacal divison, gonadal primordium - indifferent to first appearance of testis cords<br />
Female - Paramesonephric duct preservation or regression begins<br />
|-<br />
| 8 || Paramesonephric duct, clear gonadal differentiation<br />
|-bgcolor="lavender"<br />
| 9 || Paramesonephric duct fusion in the female forming the uterus and lack of fusion laterally forming the fallopian tubes. Also forms vagina.<br />
|-<br />
| 15 || Primary follicles (ovary)<br />
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.<br />
Both male and female gonads undergo descent. <br />
|-bgcolor="lavender"<br />
| Puberty || Development of secondary sexual characteristics<br />
Female - start of menstruation, first egg released.<br />
Male - development of course voice, body hair and sperm formation.<br />
|-<br />
|}<br />
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'''Related video'''<br />
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<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media><br />
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===Development of Internal Genitalia===<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE'''<br />
|bgcolor="violet"|'''FEMALE'''<br />
|-<br />
|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><br />
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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><br />
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<br />
<br />
''Fetal Male Glandular Development''<br />
* 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<br />
* 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><br />
* 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.<br />
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| 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><br />
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<br />
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.<br />
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<br />
''Female Glandular Development''<br />
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* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.<br />
* 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><br />
|-<br />
|- style="height:10px" <br />
| style="width:50%"| <br />
|}<br />
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===Development of the External Genitalia ===<br />
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{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''<br />
|- bgcolor="lavender"<br />
|<br />
# 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><br />
# 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.<br />
# 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.<br />
# 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><br />
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
|}<br />
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[[File:External genitalia current model.jpg|400px|centre|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]<br />
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<br />
'''The current model for fetal development of the external genitalia in humans and mice:'''<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE MODEL'''<br />
|bgcolor="violet"|'''FEMALE MODEL'''<br />
<br />
|-<br />
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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).<br />
# 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><br />
# 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><br />
# 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).<br />
# 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.<br />
# 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><br />
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[[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]]<br />
<br />
* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.<br />
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.<br />
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.<br />
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* 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.<br />
<br />
* 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.<br />
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.<br />
* 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><br />
* 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><br />
*: 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><br />
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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.<br />
# The urogenital folds remain apart and unfused to form the labia majora.<ref name=PMID11315960><pubmed>11315960</pubmed></ref><br />
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
<br />
* 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.<br />
* The tubercle itself goes on to form the mons pubis.<br />
* 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.<br />
* 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><br />
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[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]<br />
|-<br />
|- style="height:10px"<br />
| style="width:50%"|<br />
|}<br />
<br />
===Descent of the Gonads===<br />
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[[File:Testis-descent end.jpg|200px|thumb|right|Descent of testes]]<br />
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'''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><br />
<br />
'''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><br />
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<br />
==Current Research, Models and Findings==<br />
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===Current Models===<br />
<br />
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><br />
<br />
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><br />
<br />
Some examples of different animal models used in research involving fetal development of male and female genital systems are:<br />
<br />
* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref><br />
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref><br />
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref><br />
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref><br />
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref><br />
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref><br />
<br />
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><br />
<br />
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><br />
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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]]<br />
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===Current Research and Findings===<br />
====Male====<br />
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{|<br />
|-bgcolor="aliceblue"<br />
|<br />
[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]<br />
<br />
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><br />
<br />
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><br />
|}<br />
<br />
[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]<br />
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{|<br />
|-bgcolor="aliceblue"<br />
|<br />
[[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]]<br />
<br />
'''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><br />
<br />
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><br />
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>.<br />
Therefore, the aim of the present study was to investigate the linkage between exposures of the fetus to POPs and risk of developing hypospadias.<br />
<br />
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.<br />
<br />
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.<br />
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{|<br />
|-bgcolor="aliceblue"<br />
|<br />
'''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><br />
<br />
[[File:Male testosterone and AMH level graph.jpg|thumb|300px|right|Graph showing male testosterone and AMH levels]]<br />
<br />
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: <br />
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.<br />
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.<br />
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.<br />
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.<br />
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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.<br />
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Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.<br />
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.<br />
<br />
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).<br />
<br />
Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.<br />
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.<br />
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.<br />
<br />
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.<br />
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. <br />
<br />
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.<br />
|}<br />
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<br />
<br />
<br />
{|<br />
|-bgcolor="aliceblue"<br />
|<br />
'''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><br />
<br />
[[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]]<br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
|}<br />
<br />
====Female====<br />
----<br />
<br />
<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref><br />
<br />
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.<br />
<br />
[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]<br />
<br />
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. <br />
<br />
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.<br />
<br />
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><br />
<br />
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.<br />
|}<br />
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<br />
<br />
----<br />
<br />
<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref><br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
|}<br />
<br />
<br />
<br />
----<br />
<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
'''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><br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
|}<br />
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----<br />
<br />
<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
<br />
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> <br />
<br />
[[File:Human Y chromosome SRY region.jpg|400px|right|thumb| Human Y chromosome showing SRY gene]]<br />
<br />
Some critical genes involved in the testicular and ovarian pathways include:<br />
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref><br />
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref><br />
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
<br />
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><br />
<br />
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. <br />
<br />
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. <br />
<br />
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.<br />
<br />
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.<br />
|}<br />
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<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! '''Other current research findings and interesting reads:'''<br />
|- <br />
| * 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><br />
<br />
<pubmed>21584884</pubmed><br />
<pubmed>18367374</pubmed><br />
<pubmed>15086026</pubmed><br />
<pubmed>14641326</pubmed><br />
<pubmed>11684660</pubmed><br />
<pubmed>22127979</pubmed><br />
<pubmed>24631756</pubmed><br />
<pubmed>23192465</pubmed><br />
|}<br />
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<br />
==Historic Findings==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for Historical Findings<br />
<br />
==Abnormalities==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for foetal genital abnormalities<br />
<br />
==References==<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_4&diff=1599682014 Group Project 42014-10-24T07:23:34Z<p>Z3415716: /* Introduction */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
=Genital=<br />
==Introduction==<br />
<br />
[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]<br />
<br />
Genital system development occurs in both the embryonic and foetal phase of development. By the commencement of the foetal period, sexual determination and initial growth of the different gonads occur <ref name=Hill2014>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>. It is within the foetal period that the internal and external genital organs develop <ref name=Hill2014>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>. This page focuses on the foetal developmental processes, exploring the current and historical models and understanding, alongside the congenital abnormalities. <br />
<br />
Today there is an innumerable amount of research articles focused on foetal genital growth, with some addressing the system as a whole <ref name=PMID14641326><pubmed>14641326</pubmed></ref> and others investigating certain genital organs <ref name=PMID13362960><pubmed>13362960</pubmed></ref>. Current models and understandings have been obtained from both human <ref name=PMID11315960><pubmed>11315960</pubmed></ref> and animal populations <ref name=PMID13362960><pubmed>13362960</pubmed></ref>, and this page will outline some of the important current research.<br />
<br />
Research into foetal genital development can be traced to as early as the 16th century<ref name=PMID18462432><pubmed>18462432</pubmed></ref> with anatomists proposing theories and constructing models, proven to being critical in obtaining the in-depth information known today. This page will mention some of these historical findings in both the female and male genital system. <br />
<br />
This project will end with discussing some of the congenital abnormalities of the genital system, mentioning both the malformations that are most common <ref name=PMID16006950><pubmed>16006950</pubmed></ref> and those that are rare <ref name=PMID23635766><pubmed>23635766</pubmed></ref><br />
<br />
==System Development==<br />
<br />
[[File:Paramesonephric duct.jpg|200px|thumb|Paramesonephric duct development]]<br />
[[File:Infant ovary.jpg|200px|thumb|Histological image of primordial follicles in infant ovary]]<br />
<br />
'''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><br />
{| class="wikitable" <br />
|-bgcolor="purple"|align="centre"<br />
|'''Week''' || '''Development'''<br />
|-bgcolor="lavender"<br />
| 3-4 || Primordial germ cells migrate during gastrulation<br />
|-<br />
| 4 || Intermediate mesoderm, pronephros primordium<br />
|-bgcolor="lavender"<br />
| 5 || Mesonephros and mesonephric duct<br />
|-<br />
| 6 || Ureteric bud, metanephros, genital ridge<br />
|-bgcolor="lavender"<br />
| 7 || Cloacal divison, gonadal primordium - indifferent to first appearance of testis cords<br />
Female - Paramesonephric duct preservation or regression begins<br />
|-<br />
| 8 || Paramesonephric duct, clear gonadal differentiation<br />
|-bgcolor="lavender"<br />
| 9 || Paramesonephric duct fusion in the female forming the uterus and lack of fusion laterally forming the fallopian tubes. Also forms vagina.<br />
|-<br />
| 15 || Primary follicles (ovary)<br />
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.<br />
Both male and female gonads undergo descent. <br />
|-bgcolor="lavender"<br />
| Puberty || Development of secondary sexual characteristics<br />
Female - start of menstruation, first egg released.<br />
Male - development of course voice, body hair and sperm formation.<br />
|-<br />
|}<br />
<br />
<br />
'''Related video'''<br />
<br />
<br />
<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media><br />
<br />
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===Development of Internal Genitalia===<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE'''<br />
|bgcolor="violet"|'''FEMALE'''<br />
|-<br />
|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><br />
<br />
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><br />
<br />
<br />
<br />
''Fetal Male Glandular Development''<br />
* 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<br />
* 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><br />
* 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.<br />
<br />
<br />
<br />
| 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><br />
<br />
<br />
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.<br />
<br />
<br />
''Female Glandular Development''<br />
<br />
* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.<br />
* 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><br />
|-<br />
|- style="height:10px" <br />
| style="width:50%"| <br />
|}<br />
<br />
===Development of the External Genitalia ===<br />
<br />
{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''<br />
|- bgcolor="lavender"<br />
|<br />
# 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><br />
# 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.<br />
# 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.<br />
# 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><br />
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
|}<br />
<br />
[[File:External genitalia current model.jpg|400px|centre|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]<br />
<br />
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<br />
<br />
'''The current model for fetal development of the external genitalia in humans and mice:'''<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE MODEL'''<br />
|bgcolor="violet"|'''FEMALE MODEL'''<br />
<br />
|-<br />
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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).<br />
# 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><br />
# 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><br />
# 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).<br />
# 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.<br />
# 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><br />
<br />
[[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]]<br />
<br />
* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.<br />
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.<br />
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.<br />
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* 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.<br />
<br />
* 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.<br />
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.<br />
* 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><br />
* 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><br />
*: 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><br />
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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.<br />
# The urogenital folds remain apart and unfused to form the labia majora.<ref name=PMID11315960><pubmed>11315960</pubmed></ref><br />
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
<br />
* 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.<br />
* The tubercle itself goes on to form the mons pubis.<br />
* 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.<br />
* 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><br />
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[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]<br />
|-<br />
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|}<br />
<br />
===Descent of the Gonads===<br />
<br />
[[File:Testis-descent end.jpg|200px|thumb|right|Descent of testes]]<br />
<br />
'''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><br />
<br />
'''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><br />
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<br />
==Current Research, Models and Findings==<br />
<br />
===Current Models===<br />
<br />
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><br />
<br />
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><br />
<br />
Some examples of different animal models used in research involving fetal development of male and female genital systems are:<br />
<br />
* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref><br />
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref><br />
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref><br />
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref><br />
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref><br />
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref><br />
<br />
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><br />
<br />
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><br />
<br />
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]]<br />
<br />
===Current Research and Findings===<br />
====Male====<br />
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{|<br />
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[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]<br />
<br />
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><br />
<br />
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><br />
|}<br />
<br />
[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]<br />
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{|<br />
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[[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]]<br />
<br />
'''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><br />
<br />
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><br />
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>.<br />
Therefore, the aim of the present study was to investigate the linkage between exposures of the fetus to POPs and risk of developing hypospadias.<br />
<br />
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.<br />
<br />
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.<br />
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{|<br />
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'''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><br />
<br />
[[File:Male testosterone and AMH level graph.jpg|thumb|300px|right|Graph showing male testosterone and AMH levels]]<br />
<br />
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: <br />
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.<br />
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.<br />
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.<br />
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.<br />
<br />
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.<br />
<br />
Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.<br />
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.<br />
<br />
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).<br />
<br />
Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.<br />
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.<br />
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.<br />
<br />
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.<br />
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. <br />
<br />
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.<br />
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{|<br />
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'''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><br />
<br />
[[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]]<br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
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====Female====<br />
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{|<br />
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'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref><br />
<br />
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.<br />
<br />
[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]<br />
<br />
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. <br />
<br />
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.<br />
<br />
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><br />
<br />
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.<br />
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{|<br />
|-bgcolor="lavenderblush"<br />
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'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref><br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
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{|<br />
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'''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><br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
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{|<br />
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'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
<br />
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> <br />
<br />
[[File:Human Y chromosome SRY region.jpg|400px|right|thumb| Human Y chromosome showing SRY gene]]<br />
<br />
Some critical genes involved in the testicular and ovarian pathways include:<br />
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref><br />
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref><br />
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
<br />
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><br />
<br />
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. <br />
<br />
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. <br />
<br />
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.<br />
<br />
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.<br />
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{| class="wikitable mw-collapsible mw-collapsed"<br />
! '''Other current research findings and interesting reads:'''<br />
|- <br />
| * 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><br />
<br />
<pubmed>21584884</pubmed><br />
<pubmed>18367374</pubmed><br />
<pubmed>15086026</pubmed><br />
<pubmed>14641326</pubmed><br />
<pubmed>11684660</pubmed><br />
<pubmed>22127979</pubmed><br />
<pubmed>24631756</pubmed><br />
<pubmed>23192465</pubmed><br />
|}<br />
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==Historic Findings==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for Historical Findings<br />
<br />
==Abnormalities==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for foetal genital abnormalities<br />
<br />
==References==<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_4&diff=1599592014 Group Project 42014-10-24T07:18:17Z<p>Z3415716: /* Introduction */</p>
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<div>{{ANAT2341Project2014header}}<br />
=Genital=<br />
==Introduction==<br />
<br />
[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]<br />
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Genital system development occurs in both the embryonic and foetal phase of development. By the commencement of the foetal period, sexual determination and initial growth of the different gonads occur <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>. It is within the foetal period that the internal and external genital organs develop <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>. This page focuses on the foetal developmental processes, exploring the current and historical models and understanding, alongside the congenital abnormalities. <br />
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Today there is an innumerable amount of research articles focused on foetal genital growth, with some addressing the system as a whole <ref name=PMID14641326><pubmed>14641326</pubmed></ref> and others investigating certain genital organs <ref name=PMID13362960><pubmed>13362960</pubmed></ref>. Current models and understandings have been obtained from both human <ref name=PMID11315960><pubmed>11315960</pubmed></ref> and animal populations <ref name=PMID13362960><pubmed>13362960</pubmed></ref>, and this page will outline some of the important current research.<br />
<br />
Research into foetal genital development can be traced to as early as the 16th century<ref name=PMID18462432><pubmed>18462432</pubmed></ref> with anatomists proposing theories and constructing models, proven to being critical in obtaining the in-depth information known today. This page will mention some of these historical findings in both the female and male genital system. <br />
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This project will end with discussing some of the congenital abnormalities of the genital system, mentioning both the malformations are most common <ref name=PMID16006950><pubmed>16006950</pubmed></ref> and rare <ref name=PMID23635766><pubmed>23635766</pubmed></ref><br />
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==System Development==<br />
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[[File:Paramesonephric duct.jpg|200px|thumb|Paramesonephric duct development]]<br />
[[File:Infant ovary.jpg|200px|thumb|Histological image of primordial follicles in infant ovary]]<br />
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'''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><br />
{| class="wikitable" <br />
|-bgcolor="purple"|align="centre"<br />
|'''Week''' || '''Development'''<br />
|-bgcolor="lavender"<br />
| 3-4 || Primordial germ cells migrate during gastrulation<br />
|-<br />
| 4 || Intermediate mesoderm, pronephros primordium<br />
|-bgcolor="lavender"<br />
| 5 || Mesonephros and mesonephric duct<br />
|-<br />
| 6 || Ureteric bud, metanephros, genital ridge<br />
|-bgcolor="lavender"<br />
| 7 || Cloacal divison, gonadal primordium - indifferent to first appearance of testis cords<br />
Female - Paramesonephric duct preservation or regression begins<br />
|-<br />
| 8 || Paramesonephric duct, clear gonadal differentiation<br />
|-bgcolor="lavender"<br />
| 9 || Paramesonephric duct fusion in the female forming the uterus and lack of fusion laterally forming the fallopian tubes. Also forms vagina.<br />
|-<br />
| 15 || Primary follicles (ovary)<br />
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.<br />
Both male and female gonads undergo descent. <br />
|-bgcolor="lavender"<br />
| Puberty || Development of secondary sexual characteristics<br />
Female - start of menstruation, first egg released.<br />
Male - development of course voice, body hair and sperm formation.<br />
|-<br />
|}<br />
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<br />
'''Related video'''<br />
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<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media><br />
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===Development of Internal Genitalia===<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE'''<br />
|bgcolor="violet"|'''FEMALE'''<br />
|-<br />
|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><br />
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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><br />
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''Fetal Male Glandular Development''<br />
* 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<br />
* 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><br />
* 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.<br />
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| 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><br />
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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.<br />
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''Female Glandular Development''<br />
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* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.<br />
* 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><br />
|-<br />
|- style="height:10px" <br />
| style="width:50%"| <br />
|}<br />
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===Development of the External Genitalia ===<br />
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{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''<br />
|- bgcolor="lavender"<br />
|<br />
# 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><br />
# 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.<br />
# 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.<br />
# 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><br />
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
|}<br />
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[[File:External genitalia current model.jpg|400px|centre|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]<br />
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'''The current model for fetal development of the external genitalia in humans and mice:'''<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE MODEL'''<br />
|bgcolor="violet"|'''FEMALE MODEL'''<br />
<br />
|-<br />
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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).<br />
# 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><br />
# 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><br />
# 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).<br />
# 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.<br />
# 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><br />
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[[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]]<br />
<br />
* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.<br />
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.<br />
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.<br />
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* 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.<br />
<br />
* 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.<br />
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.<br />
* 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><br />
* 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><br />
*: 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><br />
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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.<br />
# The urogenital folds remain apart and unfused to form the labia majora.<ref name=PMID11315960><pubmed>11315960</pubmed></ref><br />
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
<br />
* 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.<br />
* The tubercle itself goes on to form the mons pubis.<br />
* 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.<br />
* 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><br />
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[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]<br />
|-<br />
|- style="height:10px"<br />
| style="width:50%"|<br />
|}<br />
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===Descent of the Gonads===<br />
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[[File:Testis-descent end.jpg|200px|thumb|right|Descent of testes]]<br />
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'''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><br />
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'''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><br />
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==Current Research, Models and Findings==<br />
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===Current Models===<br />
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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><br />
<br />
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><br />
<br />
Some examples of different animal models used in research involving fetal development of male and female genital systems are:<br />
<br />
* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref><br />
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref><br />
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref><br />
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref><br />
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref><br />
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref><br />
<br />
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><br />
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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><br />
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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]]<br />
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===Current Research and Findings===<br />
====Male====<br />
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{|<br />
|-bgcolor="aliceblue"<br />
|<br />
[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]<br />
<br />
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><br />
<br />
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><br />
|}<br />
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[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]<br />
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{|<br />
|-bgcolor="aliceblue"<br />
|<br />
[[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]]<br />
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'''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><br />
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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><br />
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>.<br />
Therefore, the aim of the present study was to investigate the linkage between exposures of the fetus to POPs and risk of developing hypospadias.<br />
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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.<br />
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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.<br />
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{|<br />
|-bgcolor="aliceblue"<br />
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'''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><br />
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[[File:Male testosterone and AMH level graph.jpg|thumb|300px|right|Graph showing male testosterone and AMH levels]]<br />
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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: <br />
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.<br />
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.<br />
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.<br />
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.<br />
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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.<br />
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Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.<br />
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.<br />
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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).<br />
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Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.<br />
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.<br />
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.<br />
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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.<br />
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. <br />
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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.<br />
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{|<br />
|-bgcolor="aliceblue"<br />
|<br />
'''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><br />
<br />
[[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]]<br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
|}<br />
<br />
====Female====<br />
----<br />
<br />
<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref><br />
<br />
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.<br />
<br />
[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]<br />
<br />
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. <br />
<br />
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.<br />
<br />
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><br />
<br />
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.<br />
|}<br />
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{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref><br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
|}<br />
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{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
'''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><br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
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{|<br />
|-bgcolor="lavenderblush"<br />
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'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
<br />
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> <br />
<br />
[[File:Human Y chromosome SRY region.jpg|400px|right|thumb| Human Y chromosome showing SRY gene]]<br />
<br />
Some critical genes involved in the testicular and ovarian pathways include:<br />
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref><br />
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref><br />
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
<br />
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><br />
<br />
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. <br />
<br />
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. <br />
<br />
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.<br />
<br />
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.<br />
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{| class="wikitable mw-collapsible mw-collapsed"<br />
! '''Other current research findings and interesting reads:'''<br />
|- <br />
| * 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><br />
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<pubmed>21584884</pubmed><br />
<pubmed>18367374</pubmed><br />
<pubmed>15086026</pubmed><br />
<pubmed>14641326</pubmed><br />
<pubmed>11684660</pubmed><br />
<pubmed>22127979</pubmed><br />
<pubmed>24631756</pubmed><br />
<pubmed>23192465</pubmed><br />
|}<br />
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==Historic Findings==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for Historical Findings<br />
<br />
==Abnormalities==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for foetal genital abnormalities<br />
<br />
==References==<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_4&diff=1598632014 Group Project 42014-10-24T06:25:38Z<p>Z3415716: /* System Development */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
=Genital=<br />
==Introduction==<br />
<br />
[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]<br />
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<br />
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.<br />
<br />
==System Development==<br />
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[[File:Paramesonephric duct.jpg|200px|thumb|Paramesonephric duct development]]<br />
[[File:Infant ovary.jpg|200px|thumb|Histological image of primordial follicles in infant ovary]]<br />
<br />
'''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><br />
{| class="wikitable" <br />
|-bgcolor="purple"|align="centre"<br />
|'''Week''' || '''Development'''<br />
|-bgcolor="lavender"<br />
| 3-4 || Primordial germ cells migrate during gastrulation<br />
|-<br />
| 4 || Intermediate mesoderm, pronephros primordium<br />
|-bgcolor="lavender"<br />
| 5 || Mesonephros and mesonephric duct<br />
|-<br />
| 6 || Ureteric bud, metanephros, genital ridge<br />
|-bgcolor="lavender"<br />
| 7 || Cloacal divison, gonadal primordium - indifferent to first appearance of testis cords<br />
Female - Paramesonephric duct preservation or regression begins<br />
|-<br />
| 8 || Paramesonephric duct, clear gonadal differentiation<br />
|-bgcolor="lavender"<br />
| 9 || Paramesonephric duct fusion in the female forming the uterus and lack of fusion laterally forming the fallopian tubes. Also forms vagina.<br />
|-<br />
| 15 || Primary follicles (ovary)<br />
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.<br />
Both male and female gonads undergo descent. <br />
|-bgcolor="lavender"<br />
| Puberty || Development of secondary sexual characteristics<br />
Female - start of menstruation, first egg released.<br />
Male - development of course voice, body hair and sperm formation.<br />
|-<br />
|}<br />
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'''Related video'''<br />
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<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media><br />
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===Development of Internal Genitalia===<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE'''<br />
|bgcolor="violet"|'''FEMALE'''<br />
|-<br />
|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><br />
<br />
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><br />
<br />
<br />
<br />
''Fetal Male Glandular Development''<br />
* 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<br />
* 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><br />
* 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.<br />
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| 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><br />
<br />
<br />
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.<br />
<br />
<br />
''Female Glandular Development''<br />
<br />
* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.<br />
* 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><br />
|-<br />
|- style="height:10px" <br />
| style="width:50%"| <br />
|}<br />
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===Development of the External Genitalia ===<br />
<br />
{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''<br />
|- bgcolor="lavender"<br />
|<br />
# 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><br />
# 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.<br />
# 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.<br />
# 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><br />
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
|}<br />
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[[File:External genitalia current model.jpg|400px|centre|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]<br />
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'''The current model for fetal development of the external genitalia in humans and mice:'''<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE MODEL'''<br />
|bgcolor="violet"|'''FEMALE MODEL'''<br />
<br />
|-<br />
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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).<br />
# 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><br />
# 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><br />
# 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).<br />
# 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.<br />
# 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><br />
<br />
[[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]]<br />
<br />
* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.<br />
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.<br />
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.<br />
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* 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.<br />
<br />
* 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.<br />
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.<br />
* 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><br />
* 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><br />
*: 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><br />
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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.<br />
# The urogenital folds remain apart and unfused to form the labia majora.<ref name=PMID11315960><pubmed>11315960</pubmed></ref><br />
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
<br />
* 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.<br />
* The tubercle itself goes on to form the mons pubis.<br />
* 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.<br />
* 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><br />
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[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]<br />
|-<br />
|- style="height:10px"<br />
| style="width:50%"|<br />
|}<br />
<br />
===Descent of the Gonads===<br />
<br />
[[File:Testis-descent end.jpg|200px|thumb|right|Descent of testes]]<br />
<br />
'''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><br />
<br />
'''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><br />
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==Current Research, Models and Findings==<br />
<br />
===Current Models===<br />
<br />
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><br />
<br />
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><br />
<br />
Some examples of different animal models used in research involving fetal development of male and female genital systems are:<br />
<br />
* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref><br />
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref><br />
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref><br />
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref><br />
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref><br />
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref><br />
<br />
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><br />
<br />
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><br />
<br />
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]]<br />
<br />
===Current Research and Findings===<br />
====Male====<br />
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{|<br />
|-bgcolor="aliceblue"<br />
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[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]<br />
<br />
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><br />
<br />
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><br />
|}<br />
<br />
[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]<br />
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{|<br />
|-bgcolor="aliceblue"<br />
|<br />
[[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]]<br />
<br />
'''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><br />
<br />
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><br />
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>.<br />
Therefore, the aim of the present study was to investigate the linkage between exposures of the fetus to POPs and risk of developing hypospadias.<br />
<br />
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.<br />
<br />
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.<br />
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{|<br />
|-bgcolor="aliceblue"<br />
|<br />
'''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><br />
<br />
[[File:Male testosterone and AMH level graph.jpg|thumb|300px|right|Graph showing male testosterone and AMH levels]]<br />
<br />
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: <br />
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.<br />
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.<br />
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.<br />
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.<br />
<br />
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.<br />
<br />
Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.<br />
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.<br />
<br />
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).<br />
<br />
Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.<br />
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.<br />
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.<br />
<br />
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.<br />
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. <br />
<br />
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.<br />
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{|<br />
|-bgcolor="aliceblue"<br />
|<br />
'''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><br />
<br />
[[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]]<br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
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====Female====<br />
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{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref><br />
<br />
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.<br />
<br />
[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]<br />
<br />
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. <br />
<br />
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.<br />
<br />
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><br />
<br />
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.<br />
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{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref><br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
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<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
'''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><br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
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<br />
{|<br />
|-bgcolor="lavenderblush"<br />
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'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
<br />
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> <br />
<br />
[[File:Human Y chromosome SRY region.jpg|400px|right|thumb| Human Y chromosome showing SRY gene]]<br />
<br />
Some critical genes involved in the testicular and ovarian pathways include:<br />
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref><br />
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref><br />
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
<br />
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><br />
<br />
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. <br />
<br />
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. <br />
<br />
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.<br />
<br />
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.<br />
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{| class="wikitable mw-collapsible mw-collapsed"<br />
! '''Other current research findings and interesting reads:'''<br />
|- <br />
| * 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><br />
<br />
<pubmed>21584884</pubmed><br />
<pubmed>18367374</pubmed><br />
<pubmed>15086026</pubmed><br />
<pubmed>14641326</pubmed><br />
<pubmed>11684660</pubmed><br />
<pubmed>22127979</pubmed><br />
<pubmed>24631756</pubmed><br />
<pubmed>23192465</pubmed><br />
|}<br />
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==Historic Findings==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for Historical Findings<br />
<br />
==Abnormalities==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for foetal genital abnormalities<br />
<br />
==References==<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_4&diff=1598542014 Group Project 42014-10-24T06:21:23Z<p>Z3415716: /* Development of the External Genitalia */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
=Genital=<br />
==Introduction==<br />
<br />
[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]<br />
<br />
<br />
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.<br />
<br />
==System Development==<br />
<br />
[[File:Paramesonephric duct.jpg|200px|thumb|Paramesonephric duct development]]<br />
[[File:Infant ovary.jpg|200px|thumb|Histological image of primordial follicles in infant ovary]]<br />
<br />
'''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><br />
{| class="wikitable" <br />
|-bgcolor="purple"|align="centre"<br />
|'''Week''' || '''Development'''<br />
|-bgcolor="lavender"<br />
| 3-4 || Primordial germ cells migrate during gastrulation<br />
|-<br />
| 4 || Intermediate mesoderm, pronephros primordium<br />
|-bgcolor="lavender"<br />
| 5 || Mesonephros and mesonephric duct<br />
|-<br />
| 6 || Ureteric bud, metanephros, genital ridge<br />
|-bgcolor="lavender"<br />
| 7 || Cloacal divison, gonadal primordium - indifferent to first appearance of testis cords<br />
Female - Paramesonephric duct preservation or regression begins<br />
|-<br />
| 8 || Paramesonephric duct, clear gonadal differentiation<br />
|-bgcolor="lavender"<br />
| 9 || Paramesonephric duct fusion in the female forming the uterus and lack of fusion laterally forming the fallopian tubes. Also forms vagina.<br />
|-<br />
| 15 || Primary follicles (ovary)<br />
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.<br />
Both male and female gonads undergo descent. <br />
|-bgcolor="lavender"<br />
| Puberty || Development of secondary sexual characteristics<br />
Female - start of menstruation, first egg released.<br />
Male - development of course voice, body hair and sperm formation.<br />
|-<br />
|}<br />
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'''Related video'''<br />
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<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media><br />
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===Development of Internal Genitalia===<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE'''<br />
|bgcolor="violet"|'''FEMALE'''<br />
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|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><br />
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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><br />
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''Fetal Male Glandular Development''<br />
* 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<br />
* 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><br />
* 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.<br />
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| 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><br />
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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.<br />
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''Female Glandular Development''<br />
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* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.<br />
* 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><br />
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===Development of the External Genitalia ===<br />
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{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''<br />
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# 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><br />
# 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.<br />
# 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.<br />
# 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><br />
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
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[[File:External genitalia current model.jpg|400px|centre|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]<br />
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'''The current model for fetal development of the external genitalia in humans and mice:'''<br />
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|bgcolor="lightskyblue"|'''MALE MODEL'''<br />
|bgcolor="violet"|'''FEMALE MODEL'''<br />
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|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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).<br />
# 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><br />
# 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><br />
# 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).<br />
# 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.<br />
# 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><br />
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[[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]]<br />
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* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.<br />
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.<br />
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.<br />
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* 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.<br />
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* 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.<br />
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.<br />
* 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><br />
* 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><br />
*: 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><br />
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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.<br />
# The urogenital folds remain apart and unfused to form the labia majora.<ref name=PMID11315960><pubmed>11315960</pubmed></ref><br />
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
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* 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.<br />
* The tubercle itself goes on to form the mons pubis.<br />
* 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.<br />
* 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><br />
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[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]<br />
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===Descent of the Gonads===<br />
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[[File:Testis-descent end.jpg|200px|thumb|right|Descent of testes]]<br />
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'''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><br />
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'''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><br />
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==Current Research, Models and Findings==<br />
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===Current Models===<br />
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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><br />
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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><br />
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Some examples of different animal models used in research involving fetal development of male and female genital systems are:<br />
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* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref><br />
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref><br />
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref><br />
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref><br />
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref><br />
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref><br />
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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><br />
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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><br />
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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]]<br />
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===Current Research and Findings===<br />
====Male====<br />
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{|<br />
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[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]<br />
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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><br />
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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><br />
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[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]<br />
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[[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]]<br />
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'''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><br />
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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><br />
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>.<br />
Therefore, the aim of the present study was to investigate the linkage between exposures of the fetus to POPs and risk of developing hypospadias.<br />
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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.<br />
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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.<br />
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'''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><br />
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[[File:Male testosterone and AMH level graph.jpg|thumb|300px|right|Graph showing male testosterone and AMH levels]]<br />
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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: <br />
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.<br />
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.<br />
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.<br />
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.<br />
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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.<br />
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Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.<br />
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.<br />
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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).<br />
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Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.<br />
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.<br />
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.<br />
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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.<br />
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. <br />
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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.<br />
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'''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><br />
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[[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]]<br />
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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.<br />
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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.<br />
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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.<br />
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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. <br />
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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.<br />
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====Female====<br />
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'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref><br />
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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.<br />
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[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]<br />
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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. <br />
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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.<br />
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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><br />
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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.<br />
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{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref><br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
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{|<br />
|-bgcolor="lavenderblush"<br />
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'''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><br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
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{|<br />
|-bgcolor="lavenderblush"<br />
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'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
<br />
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> <br />
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[[File:Human Y chromosome SRY region.jpg|400px|right|thumb| Human Y chromosome showing SRY gene]]<br />
<br />
Some critical genes involved in the testicular and ovarian pathways include:<br />
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref><br />
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref><br />
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
<br />
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><br />
<br />
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. <br />
<br />
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. <br />
<br />
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.<br />
<br />
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.<br />
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{| class="wikitable mw-collapsible mw-collapsed"<br />
! '''Other current research findings and interesting reads:'''<br />
|- <br />
| * 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><br />
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<pubmed>21584884</pubmed><br />
<pubmed>18367374</pubmed><br />
<pubmed>15086026</pubmed><br />
<pubmed>14641326</pubmed><br />
<pubmed>11684660</pubmed><br />
<pubmed>22127979</pubmed><br />
<pubmed>24631756</pubmed><br />
<pubmed>23192465</pubmed><br />
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==Historic Findings==<br />
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Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for Historical Findings<br />
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==Abnormalities==<br />
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Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for foetal genital abnormalities<br />
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==References==<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_4&diff=1598452014 Group Project 42014-10-24T06:19:05Z<p>Z3415716: /* Development of the External Genitalia */</p>
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<div>{{ANAT2341Project2014header}}<br />
=Genital=<br />
==Introduction==<br />
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[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]<br />
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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.<br />
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==System Development==<br />
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[[File:Paramesonephric duct.jpg|200px|thumb|Paramesonephric duct development]]<br />
[[File:Infant ovary.jpg|200px|thumb|Histological image of primordial follicles in infant ovary]]<br />
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'''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><br />
{| class="wikitable" <br />
|-bgcolor="purple"|align="centre"<br />
|'''Week''' || '''Development'''<br />
|-bgcolor="lavender"<br />
| 3-4 || Primordial germ cells migrate during gastrulation<br />
|-<br />
| 4 || Intermediate mesoderm, pronephros primordium<br />
|-bgcolor="lavender"<br />
| 5 || Mesonephros and mesonephric duct<br />
|-<br />
| 6 || Ureteric bud, metanephros, genital ridge<br />
|-bgcolor="lavender"<br />
| 7 || Cloacal divison, gonadal primordium - indifferent to first appearance of testis cords<br />
Female - Paramesonephric duct preservation or regression begins<br />
|-<br />
| 8 || Paramesonephric duct, clear gonadal differentiation<br />
|-bgcolor="lavender"<br />
| 9 || Paramesonephric duct fusion in the female forming the uterus and lack of fusion laterally forming the fallopian tubes. Also forms vagina.<br />
|-<br />
| 15 || Primary follicles (ovary)<br />
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.<br />
Both male and female gonads undergo descent. <br />
|-bgcolor="lavender"<br />
| Puberty || Development of secondary sexual characteristics<br />
Female - start of menstruation, first egg released.<br />
Male - development of course voice, body hair and sperm formation.<br />
|-<br />
|}<br />
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'''Related video'''<br />
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<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media><br />
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{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Embryonic Period – Genital Development''<br />
|- bgcolor="lavender"<br />
|<br />
# Genital System development begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally on the coelomic cavity<br />
# 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<br />
# 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 <br />
|}<br />
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===Development of Internal Genitalia===<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE'''<br />
|bgcolor="violet"|'''FEMALE'''<br />
|-<br />
|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><br />
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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><br />
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''Fetal Male Glandular Development''<br />
* 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<br />
* 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><br />
* 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.<br />
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| 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><br />
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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.<br />
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''Female Glandular Development''<br />
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* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.<br />
* 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><br />
|-<br />
|- style="height:10px" <br />
| style="width:50%"| <br />
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===Development of the External Genitalia ===<br />
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[[File:External genitalia current model.jpg|400px|centre|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]<br />
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'''The current model for embryonic development of the external genitalia in humans and mice:'''<br />
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{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''<br />
|- bgcolor="lavender"<br />
|<br />
# 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><br />
# 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.<br />
# 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.<br />
# 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><br />
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
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'''The current model for fetal development of the external genitalia in humans and mice:'''<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE MODEL'''<br />
|bgcolor="violet"|'''FEMALE MODEL'''<br />
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|-<br />
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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).<br />
# 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><br />
# 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><br />
# 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).<br />
# 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.<br />
# 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><br />
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[[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]]<br />
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* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.<br />
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.<br />
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.<br />
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* 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.<br />
<br />
* 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.<br />
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.<br />
* 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><br />
* 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><br />
*: 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><br />
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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.<br />
# The urogenital folds remain apart and unfused to form the labia majora.<ref name=PMID11315960><pubmed>11315960</pubmed></ref><br />
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
<br />
* 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.<br />
* The tubercle itself goes on to form the mons pubis.<br />
* 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.<br />
* 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><br />
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[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]<br />
|-<br />
|- style="height:10px"<br />
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|}<br />
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===Descent of the Gonads===<br />
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[[File:Testis-descent end.jpg|200px|thumb|right|Descent of testes]]<br />
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'''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><br />
<br />
'''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><br />
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==Current Research, Models and Findings==<br />
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===Current Models===<br />
<br />
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><br />
<br />
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><br />
<br />
Some examples of different animal models used in research involving fetal development of male and female genital systems are:<br />
<br />
* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref><br />
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref><br />
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref><br />
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref><br />
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref><br />
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref><br />
<br />
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><br />
<br />
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><br />
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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]]<br />
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===Current Research and Findings===<br />
====Male====<br />
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{|<br />
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[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]<br />
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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><br />
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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><br />
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[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]<br />
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[[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]]<br />
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'''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><br />
<br />
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><br />
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>.<br />
Therefore, the aim of the present study was to investigate the linkage between exposures of the fetus to POPs and risk of developing hypospadias.<br />
<br />
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.<br />
<br />
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.<br />
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'''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><br />
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[[File:Male testosterone and AMH level graph.jpg|thumb|300px|right|Graph showing male testosterone and AMH levels]]<br />
<br />
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: <br />
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.<br />
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.<br />
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.<br />
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.<br />
<br />
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.<br />
<br />
Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.<br />
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.<br />
<br />
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).<br />
<br />
Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.<br />
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.<br />
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.<br />
<br />
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.<br />
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. <br />
<br />
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.<br />
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{|<br />
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'''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><br />
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[[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]]<br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
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====Female====<br />
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{|<br />
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'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref><br />
<br />
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.<br />
<br />
[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]<br />
<br />
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. <br />
<br />
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.<br />
<br />
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><br />
<br />
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.<br />
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{|<br />
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'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref><br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
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'''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><br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
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'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
<br />
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> <br />
<br />
[[File:Human Y chromosome SRY region.jpg|400px|right|thumb| Human Y chromosome showing SRY gene]]<br />
<br />
Some critical genes involved in the testicular and ovarian pathways include:<br />
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref><br />
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref><br />
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
<br />
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><br />
<br />
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. <br />
<br />
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. <br />
<br />
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.<br />
<br />
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.<br />
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{| class="wikitable mw-collapsible mw-collapsed"<br />
! '''Other current research findings and interesting reads:'''<br />
|- <br />
| * 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><br />
<br />
<pubmed>21584884</pubmed><br />
<pubmed>18367374</pubmed><br />
<pubmed>15086026</pubmed><br />
<pubmed>14641326</pubmed><br />
<pubmed>11684660</pubmed><br />
<pubmed>22127979</pubmed><br />
<pubmed>24631756</pubmed><br />
<pubmed>23192465</pubmed><br />
|}<br />
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==Historic Findings==<br />
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Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for Historical Findings<br />
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==Abnormalities==<br />
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Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for foetal genital abnormalities<br />
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==References==<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_4&diff=1598392014 Group Project 42014-10-24T06:16:29Z<p>Z3415716: /* Development of the External Genitalia */</p>
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<div>{{ANAT2341Project2014header}}<br />
=Genital=<br />
==Introduction==<br />
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[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]<br />
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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.<br />
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==System Development==<br />
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[[File:Paramesonephric duct.jpg|200px|thumb|Paramesonephric duct development]]<br />
[[File:Infant ovary.jpg|200px|thumb|Histological image of primordial follicles in infant ovary]]<br />
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'''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><br />
{| class="wikitable" <br />
|-bgcolor="purple"|align="centre"<br />
|'''Week''' || '''Development'''<br />
|-bgcolor="lavender"<br />
| 3-4 || Primordial germ cells migrate during gastrulation<br />
|-<br />
| 4 || Intermediate mesoderm, pronephros primordium<br />
|-bgcolor="lavender"<br />
| 5 || Mesonephros and mesonephric duct<br />
|-<br />
| 6 || Ureteric bud, metanephros, genital ridge<br />
|-bgcolor="lavender"<br />
| 7 || Cloacal divison, gonadal primordium - indifferent to first appearance of testis cords<br />
Female - Paramesonephric duct preservation or regression begins<br />
|-<br />
| 8 || Paramesonephric duct, clear gonadal differentiation<br />
|-bgcolor="lavender"<br />
| 9 || Paramesonephric duct fusion in the female forming the uterus and lack of fusion laterally forming the fallopian tubes. Also forms vagina.<br />
|-<br />
| 15 || Primary follicles (ovary)<br />
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.<br />
Both male and female gonads undergo descent. <br />
|-bgcolor="lavender"<br />
| Puberty || Development of secondary sexual characteristics<br />
Female - start of menstruation, first egg released.<br />
Male - development of course voice, body hair and sperm formation.<br />
|-<br />
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'''Related video'''<br />
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<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media><br />
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{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Embryonic Period – Genital Development''<br />
|- bgcolor="lavender"<br />
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# Genital System development begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally on the coelomic cavity<br />
# 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<br />
# 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 <br />
|}<br />
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===Development of Internal Genitalia===<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE'''<br />
|bgcolor="violet"|'''FEMALE'''<br />
|-<br />
|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><br />
<br />
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><br />
<br />
<br />
<br />
''Fetal Male Glandular Development''<br />
* 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<br />
* 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><br />
* 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.<br />
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<br />
<br />
| 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><br />
<br />
<br />
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.<br />
<br />
<br />
''Female Glandular Development''<br />
<br />
* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.<br />
* 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><br />
|-<br />
|- style="height:10px" <br />
| style="width:50%"| <br />
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===Development of the External Genitalia ===<br />
<br />
[[File:External genitalia current model.jpg|400px|right|centre|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]<br />
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'''The current model for embryonic development of the external genitalia in humans and mice:'''<br />
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! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''<br />
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# 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><br />
# 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.<br />
# 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.<br />
# 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><br />
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
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'''The current model for fetal development of the external genitalia in humans and mice:'''<br />
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|bgcolor="lightskyblue"|'''MALE MODEL'''<br />
|bgcolor="violet"|'''FEMALE MODEL'''<br />
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|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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).<br />
# 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><br />
# 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><br />
# 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).<br />
# 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.<br />
# 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><br />
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[[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]]<br />
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* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.<br />
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.<br />
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.<br />
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* 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.<br />
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* 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.<br />
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.<br />
* 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><br />
* 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><br />
*: 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><br />
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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.<br />
# The urogenital folds remain apart and unfused to form the labia majora.<ref name=PMID11315960><pubmed>11315960</pubmed></ref><br />
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
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* 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.<br />
* The tubercle itself goes on to form the mons pubis.<br />
* 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.<br />
* 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><br />
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[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]<br />
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===Descent of the Gonads===<br />
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[[File:Testis-descent end.jpg|200px|thumb|right|Descent of testes]]<br />
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'''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><br />
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'''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><br />
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==Current Research, Models and Findings==<br />
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===Current Models===<br />
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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><br />
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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><br />
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Some examples of different animal models used in research involving fetal development of male and female genital systems are:<br />
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* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref><br />
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref><br />
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref><br />
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref><br />
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref><br />
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref><br />
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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><br />
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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><br />
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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]]<br />
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===Current Research and Findings===<br />
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[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]<br />
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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><br />
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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><br />
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[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]<br />
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[[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]]<br />
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'''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><br />
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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><br />
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>.<br />
Therefore, the aim of the present study was to investigate the linkage between exposures of the fetus to POPs and risk of developing hypospadias.<br />
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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.<br />
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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.<br />
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'''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><br />
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[[File:Male testosterone and AMH level graph.jpg|thumb|300px|right|Graph showing male testosterone and AMH levels]]<br />
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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: <br />
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.<br />
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.<br />
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.<br />
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.<br />
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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.<br />
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Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.<br />
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.<br />
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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).<br />
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Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.<br />
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.<br />
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.<br />
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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.<br />
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. <br />
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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.<br />
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'''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><br />
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[[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]]<br />
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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.<br />
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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.<br />
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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.<br />
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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. <br />
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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.<br />
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'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref><br />
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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.<br />
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[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]<br />
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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. <br />
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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.<br />
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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><br />
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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.<br />
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'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref><br />
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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.<br />
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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.<br />
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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. <br />
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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.<br />
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'''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><br />
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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.<br />
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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.<br />
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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.<br />
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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. <br />
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'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
<br />
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> <br />
<br />
[[File:Human Y chromosome SRY region.jpg|400px|right|thumb| Human Y chromosome showing SRY gene]]<br />
<br />
Some critical genes involved in the testicular and ovarian pathways include:<br />
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref><br />
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref><br />
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
<br />
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><br />
<br />
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. <br />
<br />
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. <br />
<br />
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.<br />
<br />
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.<br />
|}<br />
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{| class="wikitable mw-collapsible mw-collapsed"<br />
! '''Other current research findings and interesting reads:'''<br />
|- <br />
| * 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><br />
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<pubmed>21584884</pubmed><br />
<pubmed>18367374</pubmed><br />
<pubmed>15086026</pubmed><br />
<pubmed>14641326</pubmed><br />
<pubmed>11684660</pubmed><br />
<pubmed>22127979</pubmed><br />
<pubmed>24631756</pubmed><br />
<pubmed>23192465</pubmed><br />
|}<br />
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==Historic Findings==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for Historical Findings<br />
<br />
==Abnormalities==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for foetal genital abnormalities<br />
<br />
==References==<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_4&diff=1598332014 Group Project 42014-10-24T06:13:42Z<p>Z3415716: /* System Development */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
=Genital=<br />
==Introduction==<br />
<br />
[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]<br />
<br />
<br />
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.<br />
<br />
==System Development==<br />
<br />
[[File:Paramesonephric duct.jpg|200px|thumb|Paramesonephric duct development]]<br />
[[File:Infant ovary.jpg|200px|thumb|Histological image of primordial follicles in infant ovary]]<br />
<br />
'''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><br />
{| class="wikitable" <br />
|-bgcolor="purple"|align="centre"<br />
|'''Week''' || '''Development'''<br />
|-bgcolor="lavender"<br />
| 3-4 || Primordial germ cells migrate during gastrulation<br />
|-<br />
| 4 || Intermediate mesoderm, pronephros primordium<br />
|-bgcolor="lavender"<br />
| 5 || Mesonephros and mesonephric duct<br />
|-<br />
| 6 || Ureteric bud, metanephros, genital ridge<br />
|-bgcolor="lavender"<br />
| 7 || Cloacal divison, gonadal primordium - indifferent to first appearance of testis cords<br />
Female - Paramesonephric duct preservation or regression begins<br />
|-<br />
| 8 || Paramesonephric duct, clear gonadal differentiation<br />
|-bgcolor="lavender"<br />
| 9 || Paramesonephric duct fusion in the female forming the uterus and lack of fusion laterally forming the fallopian tubes. Also forms vagina.<br />
|-<br />
| 15 || Primary follicles (ovary)<br />
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.<br />
Both male and female gonads undergo descent. <br />
|-bgcolor="lavender"<br />
| Puberty || Development of secondary sexual characteristics<br />
Female - start of menstruation, first egg released.<br />
Male - development of course voice, body hair and sperm formation.<br />
|-<br />
|}<br />
<br />
<br />
'''Related video'''<br />
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<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media><br />
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<br />
{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Embryonic Period – Genital Development''<br />
|- bgcolor="lavender"<br />
|<br />
# Genital System development begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally on the coelomic cavity<br />
# 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<br />
# 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 <br />
|}<br />
<br />
<br />
===Development of Internal Genitalia===<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE'''<br />
|bgcolor="violet"|'''FEMALE'''<br />
|-<br />
|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><br />
<br />
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><br />
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''Fetal Male Glandular Development''<br />
* 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<br />
* 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><br />
* 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.<br />
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| 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><br />
<br />
<br />
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.<br />
<br />
<br />
''Female Glandular Development''<br />
<br />
* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.<br />
* 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><br />
|-<br />
|- style="height:10px" <br />
| style="width:50%"| <br />
|}<br />
<br />
===Development of the External Genitalia ===<br />
<br />
[[File:External genitalia current model.jpg|400px|right|centre|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]<br />
<br />
'''The current model for embryonic development of the external genitalia in humans and mice:'''<br />
<br />
{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''<br />
|- bgcolor="lavender"<br />
|<br />
# 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><br />
# 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.<br />
# 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.<br />
# 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><br />
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
|}<br />
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'''The current model for fetal development of the external genitalia in humans and mice:'''<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE MODEL'''<br />
|bgcolor="violet"|'''FEMALE MODEL'''<br />
<br />
|-<br />
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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).<br />
# 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><br />
# 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><br />
# 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).<br />
# 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.<br />
# 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><br />
<br />
[[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]]<br />
<br />
* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.<br />
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.<br />
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.<br />
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* 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.<br />
<br />
* 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.<br />
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.<br />
* 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><br />
* 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><br />
*: 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><br />
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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.<br />
# The urogenital folds remain apart and unfused to form the labia majora.<ref name=PMID11315960><pubmed>11315960</pubmed></ref><br />
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
<br />
* 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.<br />
* The tubercle itself goes on to form the mons pubis.<br />
* 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.<br />
* 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><br />
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[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]<br />
|-<br />
|- style="height:10px"<br />
| style="width:50%"|<br />
|}<br />
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<br />
===Descent of the Gonads===<br />
<br />
[[File:Testis-descent end.jpg|200px|thumb|right|Descent of testes]]<br />
<br />
'''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><br />
<br />
'''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><br />
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<br />
==Current Research, Models and Findings==<br />
<br />
===Current Models===<br />
<br />
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><br />
<br />
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><br />
<br />
Some examples of different animal models used in research involving fetal development of male and female genital systems are:<br />
<br />
* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref><br />
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref><br />
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref><br />
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref><br />
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref><br />
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref><br />
<br />
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><br />
<br />
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><br />
<br />
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]]<br />
<br />
===Current Research and Findings===<br />
====Male====<br />
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{|<br />
|-bgcolor="aliceblue"<br />
|<br />
[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]<br />
<br />
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><br />
<br />
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><br />
|}<br />
<br />
[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]<br />
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{|<br />
|-bgcolor="aliceblue"<br />
|<br />
[[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]]<br />
<br />
'''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><br />
<br />
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><br />
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>.<br />
Therefore, the aim of the present study was to investigate the linkage between exposures of the fetus to POPs and risk of developing hypospadias.<br />
<br />
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.<br />
<br />
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.<br />
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'''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><br />
<br />
[[File:Male testosterone and AMH level graph.jpg|thumb|300px|right|Graph showing male testosterone and AMH levels]]<br />
<br />
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: <br />
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.<br />
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.<br />
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.<br />
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.<br />
<br />
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.<br />
<br />
Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.<br />
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.<br />
<br />
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).<br />
<br />
Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.<br />
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.<br />
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.<br />
<br />
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.<br />
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. <br />
<br />
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.<br />
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{|<br />
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'''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><br />
<br />
[[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]]<br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
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<br />
====Female====<br />
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{|<br />
|-bgcolor="lavenderblush"<br />
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'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref><br />
<br />
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.<br />
<br />
[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]<br />
<br />
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. <br />
<br />
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.<br />
<br />
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><br />
<br />
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.<br />
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{|<br />
|-bgcolor="lavenderblush"<br />
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'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref><br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
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{|<br />
|-bgcolor="lavenderblush"<br />
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'''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><br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
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{|<br />
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'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
<br />
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> <br />
<br />
[[File:Human Y chromosome SRY region.jpg|400px|right|thumb| Human Y chromosome showing SRY gene]]<br />
<br />
Some critical genes involved in the testicular and ovarian pathways include:<br />
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref><br />
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref><br />
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
<br />
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><br />
<br />
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. <br />
<br />
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. <br />
<br />
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.<br />
<br />
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.<br />
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{| class="wikitable mw-collapsible mw-collapsed"<br />
! '''Other current research findings and interesting reads:'''<br />
|- <br />
| * 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><br />
<br />
<pubmed>21584884</pubmed><br />
<pubmed>18367374</pubmed><br />
<pubmed>15086026</pubmed><br />
<pubmed>14641326</pubmed><br />
<pubmed>11684660</pubmed><br />
<pubmed>22127979</pubmed><br />
<pubmed>24631756</pubmed><br />
<pubmed>23192465</pubmed><br />
|}<br />
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<br />
==Historic Findings==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for Historical Findings<br />
<br />
==Abnormalities==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for foetal genital abnormalities<br />
<br />
==References==<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1597972014 Group Project 92014-10-24T06:04:18Z<p>Z3415716: /* Historic Finding */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
This page is the second page of the [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_4 Group 4 Project]<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
[[File:Mullerian ducts development.jpeg|400px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
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><br />
<br />
According to the works of the early embryologists, Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
[[File:Prostate.jpeg|300px|right|thumb|The prostate with the adjoining seminal vesicles and vas deferens]]<br />
<br />
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> <ref><pubmed>18942121</pubmed></ref><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1611 ||bgcolor="F5FAFF"| Caspar Batholin, described the prostate as a spongy double organ that is continuous with the urethra, secreting protective substances.<br />
|-<br />
|bgcolor="FCFCFC"| 1674 ||bgcolor="FCFCFC"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="F5FAFF"| 1678 ||bgcolor="F5FAFF"| The first illustration of the prostate with the seminal vesicles and seminal ducts attached. This diagram was published by a Dutch anatomist Reinier De Graaf.<br />
|-<br />
|bgcolor="FCFCFC"| 1792 ||bgcolor="FCFCFC"| William Cheselden, an English anatomists and surgeon, challenged the theory that the prostate was two organs, stating that it may in fact be one gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1800 ||bgcolor="F5FAFF"| The double gland idea was disproven with the discovery that the perceived two glands had identical morphology and thus were one gland. <br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divide the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
[[File:Prepuce.jpeg|500px|centre|thumb|The steps of the developing prepuce in the male foetus condensed into three overall events]]<br />
<br />
{|class="wikitable mw-collapsible mw-collapsed"<br />
! '''Further information on the historical teachings of the genital system'''<br />
|- bgcolor="F5FFFA"<br />
|<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Human_Embryology_and_Morphology_9 The Urogenital System (1902)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Manual_of_Human_Embryology_19 The Development of the Urinogenital Organs (1912)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Text-Book_of_Embryology_15 The Development of the Urogenital System (1921)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Contributions_to_Embryology_Carnegie_Institution_No.61 The Development of the External Genitalia in the Human Embryo (1921)]<br />
|}<br />
<br />
==Abnormalities==<br />
<br />
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>. <br />
The content will cover most common abnormalities and then also the rare cases. <br />
Most genital abnormalities have a high risk in affecting fertility of both sexes. <br />
Currently there are a variety of methods applied to ensure that infertility can be treated and this will be mentioned. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout the child's life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia <ref>Schoenwolf, GC., Bleyl, S.B., Brauer, P.R., Francis-West, P.H., (2008). Larsen's Human Embryology, 4th ed. Chapter 15 Development of the Urogenital System. New York; Edinburgh: Churchill Livingstone, an imprint of Elsevier.</ref><br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. The congenital disorder affects 1 in 5,000 females <ref>http://www.urologyhealth.org/urology/index.cfm?article=50</ref>.<br />
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>.<br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>.<br />
<br />
[[File:WomenwithSwyerSyndrome.png|290px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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>. The syndrome affects 1 in 30,000 people <ref>http://ghr.nlm.nih.gov/condition/swyer-syndrome</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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=magenta>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
A metabolic endocrine disorder with an immense variety of phenotypes presented. The disorder shows an imbalance in female sex hormones and a resistance to insulin. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. It is most common in 5-10% of women in their reproductive age <ref>http://www.myvmc.com/diseases/polycystic-ovarian-syndrome-pcos/</ref>. The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
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 condition is prevalent in 2-4% of infant males <ref>http://livehealthy.chron.com/cryptorchidism-infertility-1080.html</ref>.<br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
[[File:Hypospadia classifications.jpg|300px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
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 <br />
<ref><pubmed>24936573</pubmed></ref>. Generally occurs in 1 of 125-300 male births <ref>http://www.hypospadiasuk.co.uk/statistics-about-hypospadias/</ref>. <br />
The surgical methods currently used to treat distal hypospadias, include tabularized incised plate and meatal advancement and glansplasty intergrated repair. <br />
For proximal forms two staged procedures are employed. <ref><pubmed>25023236</pubmed></ref><br />
<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
<br />
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>. The disorder occurs among 1 in 500-1,000 male births <ref>http://ghr.nlm.nih.gov/condition/klinefelter-syndrome</ref>. An early diagnosis is important in order for treatment to be commenced right away. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=mediumslateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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. It occur is about 1 in 15,000 live births <ref>http://www.patient.co.uk/health/congenital-adrenal-hyperplasia-leaflet</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
[[File:Hydrocele.jpg|300px|thumb|right|A fetal ultrasound showing Hydrocele surrounding the testis]]<br />
<br />
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. The condition is prevalent in about 1-3% of births <ref><pubmed>http://bestpractice.bmj.com/best-practice/monograph/1104/basics/epidemiology.html</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>True Hermaphroditism</font>==== <br />
<br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. The disorder occur in 1 of 1,500-2,000 births <ref>http://www.isna.org/faq/frequency</ref>.<br />
Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. <br />
Each case is determined differently as there are many factors to consider when choosing the gender identity. <br />
This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=blueviolet>Also related include;</font><br />
|- <br />
| <font color=mediumslateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hypogonadotropic hypogonadism</font>====<br />
<br />
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). The incidence is about 1 in 2,000 births <ref>http://www.rightdiagnosis.com/h/hypogonadotropic_hypogonadism_syndactyly/prevalence.htm</ref>. <br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1597732014 Group Project 92014-10-24T06:00:50Z<p>Z3415716: /* Historic Finding */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
This page is the second page of the [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_4 Group 4 Project]<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
[[File:Mullerian ducts development.jpeg|400px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
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><br />
<br />
According to the works of the early embryologists, Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
[[File:Prostate.jpeg|300px|right|thumb|The prostate with the adjoining seminal vesicles and vas deferens]]<br />
<br />
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> <ref><pubmed>18942121</pubmed></ref><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1611 ||bgcolor="F5FAFF"| Caspar Batholin, described the prostate as a spongy double organ that is continuous with the urethra, secreting protective substances.<br />
|-<br />
|bgcolor="FCFCFC"| 1674 ||bgcolor="FCFCFC"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="F5FAFF"| 1678 ||bgcolor="F5FAFF"| The first illustration of the prostate with the seminal vesicles and seminal ducts attached. This diagram was published by a Dutch anatomist Reinier De Graaf.<br />
|-<br />
|bgcolor="FCFCFC"| 1792 ||bgcolor="FCFCFC"| William Cheselden, an English anatomists and surgeon, challenged the theory that the prostate was two organs, stating that it may in fact be one gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1800 ||bgcolor="F5FAFF"| The double gland idea was disproven with the discovery that the perceived two glands had identical morphology and thus were one gland. <br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divide the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
[[File:Prepuce.jpeg|500px|centre|thumb|The steps of the developing prepuce in the male foetus condensed into three overall events]]<br />
<br />
{|class="wikitable mw-collapsible mw-collapsed"<br />
! '''Links to pages of history journals of on the genital system'''<br />
|- bgcolor="F5FFFA"<br />
|<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Human_Embryology_and_Morphology_9 The Urogenital System (1902)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Manual_of_Human_Embryology_19 The Development of the Urinogenital Organs (1912)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Text-Book_of_Embryology_15 The Development of the Urogenital System (1921)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Contributions_to_Embryology_Carnegie_Institution_No.61 The Development of the External Genitalia in the Human Embryo (1921)]<br />
|}<br />
<br />
==Abnormalities==<br />
<br />
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>. <br />
The content will cover most common abnormalities and then also the rare cases. <br />
Most genital abnormalities have a high risk in affecting fertility of both sexes. <br />
Currently there are a variety of methods applied to ensure that infertility can be treated and this will be mentioned. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout the child's life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia <ref>Schoenwolf, GC., Bleyl, S.B., Brauer, P.R., Francis-West, P.H., (2008). Larsen's Human Embryology, 4th ed. Chapter 15 Development of the Urogenital System. New York; Edinburgh: Churchill Livingstone, an imprint of Elsevier.</ref><br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. The congenital disorder affects 1 in 5,000 females <ref>http://www.urologyhealth.org/urology/index.cfm?article=50</ref>.<br />
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>.<br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>.<br />
<br />
[[File:WomenwithSwyerSyndrome.png|290px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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>. The syndrome affects 1 in 30,000 people <ref>http://ghr.nlm.nih.gov/condition/swyer-syndrome</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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=magenta>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
A metabolic endocrine disorder with an immense variety of phenotypes presented. The disorder shows an imbalance in female sex hormones and a resistance to insulin. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. It is most common in 5-10% of women in their reproductive age <ref>http://www.myvmc.com/diseases/polycystic-ovarian-syndrome-pcos/</ref>. The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
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 condition is prevalent in 2-4% of infant males <ref>http://livehealthy.chron.com/cryptorchidism-infertility-1080.html</ref>.<br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
[[File:Hypospadia classifications.jpg|300px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
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 <br />
<ref><pubmed>24936573</pubmed></ref>. Generally occurs in 1 of 125-300 male births <ref>http://www.hypospadiasuk.co.uk/statistics-about-hypospadias/</ref>. <br />
The surgical methods currently used to treat distal hypospadias, include tabularized incised plate and meatal advancement and glansplasty intergrated repair. <br />
For proximal forms two staged procedures are employed. <ref><pubmed>25023236</pubmed></ref><br />
<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
<br />
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>. The disorder occurs among 1 in 500-1,000 male births <ref>http://ghr.nlm.nih.gov/condition/klinefelter-syndrome</ref>. An early diagnosis is important in order for treatment to be commenced right away. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=mediumslateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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. It occur is about 1 in 15,000 live births <ref>http://www.patient.co.uk/health/congenital-adrenal-hyperplasia-leaflet</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
[[File:Hydrocele.jpg|300px|thumb|right|A fetal ultrasound showing Hydrocele surrounding the testis]]<br />
<br />
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. The condition is prevalent in about 1-3% of births <ref><pubmed>http://bestpractice.bmj.com/best-practice/monograph/1104/basics/epidemiology.html</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>True Hermaphroditism</font>==== <br />
<br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. The disorder occur in 1 of 1,500-2,000 births <ref>http://www.isna.org/faq/frequency</ref>.<br />
Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. <br />
Each case is determined differently as there are many factors to consider when choosing the gender identity. <br />
This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=blueviolet>Also related include;</font><br />
|- <br />
| <font color=mediumslateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hypogonadotropic hypogonadism</font>====<br />
<br />
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). The incidence is about 1 in 2,000 births <ref>http://www.rightdiagnosis.com/h/hypogonadotropic_hypogonadism_syndactyly/prevalence.htm</ref>. <br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1597672014 Group Project 92014-10-24T05:56:51Z<p>Z3415716: /* Historic Finding */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
This page is the second page of the [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_4 Group 4 Project]<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
[[File:Mullerian ducts development.jpeg|400px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
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><br />
<br />
According to the works of the early embryologists, Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
[[File:Prostate.jpeg|300px|right|thumb|The prostate with the adjoining seminal vesicles and vas deferens]]<br />
<br />
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> <ref><pubmed>18942121</pubmed></ref><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1611 ||bgcolor="F5FAFF"| Caspar Batholin, described the prostate as a spongy double organ that is continuous with the urethra, secreting protective substances.<br />
|-<br />
|bgcolor="FCFCFC"| 1674 ||bgcolor="FCFCFC"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="F5FAFF"| 1678 ||bgcolor="F5FAFF"| The first illustration of the prostate with the seminal vesicles and seminal ducts attached. This diagram was published by a Dutch anatomist Reinier De Graaf.<br />
|-<br />
|bgcolor="FCFCFC"| 1792 ||bgcolor="FCFCFC"| William Cheselden, an English anatomists and surgeon, challenged the theory that the prostate was two organs, stating that it may in fact be one gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1800 ||bgcolor="F5FAFF"| The double gland idea was disproven with the discovery that the perceived two glands had identical morphology and thus were one gland. <br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divide the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
[[File:Prepuce.jpeg|500px|centre|thumb|The steps of the developing prepuce in the male foetus condensed into three overall events]]<br />
<br />
{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Historical ''<br />
|- bgcolor="F5FFFA"<br />
|<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Human_Embryology_and_Morphology_9 The Urogenital System (1902)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Manual_of_Human_Embryology_19 The Development of the Urinogenital Organs (1912)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Text-Book_of_Embryology_15 The Development of the Urogenital System (1921)]<br />
* [https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Contributions_to_Embryology_Carnegie_Institution_No.61 The Development of the External Genitalia in the Human Embryo (1921)]<br />
|}<br />
<br />
==Abnormalities==<br />
<br />
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>. <br />
The content will cover most common abnormalities and then also the rare cases. <br />
Most genital abnormalities have a high risk in affecting fertility of both sexes. <br />
Currently there are a variety of methods applied to ensure that infertility can be treated and this will be mentioned. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout the child's life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia <ref>Schoenwolf, GC., Bleyl, S.B., Brauer, P.R., Francis-West, P.H., (2008). Larsen's Human Embryology, 4th ed. Chapter 15 Development of the Urogenital System. New York; Edinburgh: Churchill Livingstone, an imprint of Elsevier.</ref><br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. The congenital disorder affects 1 in 5,000 females <ref>http://www.urologyhealth.org/urology/index.cfm?article=50</ref>.<br />
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>.<br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>.<br />
<br />
[[File:WomenwithSwyerSyndrome.png|290px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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>. The syndrome affects 1 in 30,000 people <ref>http://ghr.nlm.nih.gov/condition/swyer-syndrome</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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=magenta>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
A metabolic endocrine disorder with an immense variety of phenotypes presented. The disorder shows an imbalance in female sex hormones and a resistance to insulin. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. It is most common in 5-10% of women in their reproductive age <ref>http://www.myvmc.com/diseases/polycystic-ovarian-syndrome-pcos/</ref>. The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
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 condition is prevalent in 2-4% of infant males <ref>http://livehealthy.chron.com/cryptorchidism-infertility-1080.html</ref>.<br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
[[File:Hypospadia classifications.jpg|300px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
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 <br />
<ref><pubmed>24936573</pubmed></ref>. Generally occurs in 1 of 125-300 male births <ref>http://www.hypospadiasuk.co.uk/statistics-about-hypospadias/</ref>. <br />
The surgical methods currently used to treat distal hypospadias, include tabularized incised plate and meatal advancement and glansplasty intergrated repair. <br />
For proximal forms two staged procedures are employed. <ref><pubmed>25023236</pubmed></ref><br />
<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
<br />
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>. The disorder occurs among 1 in 500-1,000 male births <ref>http://ghr.nlm.nih.gov/condition/klinefelter-syndrome</ref>. An early diagnosis is important in order for treatment to be commenced right away. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=mediumslateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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. It occur is about 1 in 15,000 live births <ref>http://www.patient.co.uk/health/congenital-adrenal-hyperplasia-leaflet</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
[[File:Hydrocele.jpg|300px|thumb|right|A fetal ultrasound showing Hydrocele surrounding the testis]]<br />
<br />
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. The condition is prevalent in about 1-3% of births <ref><pubmed>http://bestpractice.bmj.com/best-practice/monograph/1104/basics/epidemiology.html</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>True Hermaphroditism</font>==== <br />
<br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. The disorder occur in 1 of 1,500-2,000 births <ref>http://www.isna.org/faq/frequency</ref>.<br />
Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. <br />
Each case is determined differently as there are many factors to consider when choosing the gender identity. <br />
This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=blueviolet>Also related include;</font><br />
|- <br />
| <font color=mediumslateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hypogonadotropic hypogonadism</font>====<br />
<br />
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). The incidence is about 1 in 2,000 births <ref>http://www.rightdiagnosis.com/h/hypogonadotropic_hypogonadism_syndactyly/prevalence.htm</ref>. <br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1597192014 Group Project 92014-10-24T05:41:18Z<p>Z3415716: /* The Prostate */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
This page is the second page of the [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_4 Group 4 Project]<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
[[File:Mullerian ducts development.jpeg|400px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
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><br />
<br />
According to the works of the early embryologists, Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
[[File:Prostate.jpeg|300px|right|thumb|The prostate with the adjoining seminal vesicles and vas deferens]]<br />
<br />
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> <ref><pubmed>18942121</pubmed></ref><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1611 ||bgcolor="F5FAFF"| Caspar Batholin, described the prostate as a spongy double organ that is continuous with the urethra, secreting protective substances.<br />
|-<br />
|bgcolor="FCFCFC"| 1674 ||bgcolor="FCFCFC"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="F5FAFF"| 1678 ||bgcolor="F5FAFF"| The first illustration of the prostate with the seminal vesicles and seminal ducts attached. This diagram was published by a Dutch anatomist Reinier De Graaf.<br />
|-<br />
|bgcolor="FCFCFC"| 1792 ||bgcolor="FCFCFC"| William Cheselden, an English anatomists and surgeon, challenged the theory that the prostate was two organs, stating that it may in fact be one gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1800 ||bgcolor="F5FAFF"| The double gland idea was disproven with the discovery that the perceived two glands had identical morphology and thus were one gland. <br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divide the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
[[File:Prepuce.jpeg|500px|centre|thumb|The steps of the developing prepuce in the male foetus condensed into three overall events]]<br />
<br />
==Abnormalities==<br />
<br />
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>. <br />
The content will cover most common abnormalities and then also the rare cases. <br />
Most genital abnormalities have a high risk in affecting fertility of both sexes. <br />
Currently there are a variety of methods applied to ensure that infertility can be treated and this will be mentioned. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout the child's life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia <ref>Schoenwolf, GC., Bleyl, S.B., Brauer, P.R., Francis-West, P.H., (2008). Larsen's Human Embryology, 4th ed. Chapter 15 Development of the Urogenital System. New York; Edinburgh: Churchill Livingstone, an imprint of Elsevier.</ref><br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. The congenital disorder affects 1 in 5,000 females <ref>http://www.urologyhealth.org/urology/index.cfm?article=50</ref>.<br />
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>.<br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>.<br />
<br />
[[File:WomenwithSwyerSyndrome.png|290px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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>. The syndrome affects 1 in 30,000 people <ref>http://ghr.nlm.nih.gov/condition/swyer-syndrome</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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=magenta>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
A metabolic endocrine disorder with an immense variety of phenotypes presented. The disorder shows an imbalance in female sex hormones and a resistance to insulin. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. It is most common in 5-10% of women in their reproductive age <ref>http://www.myvmc.com/diseases/polycystic-ovarian-syndrome-pcos/</ref>. The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
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 condition is prevalent in 2-4% of infant males <ref>http://livehealthy.chron.com/cryptorchidism-infertility-1080.html</ref>.<br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
[[File:Hypospadia classifications.jpg|300px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
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 <br />
<ref><pubmed>24936573</pubmed></ref>. Generally occurs in 1 of 125-300 male births <ref>http://www.hypospadiasuk.co.uk/statistics-about-hypospadias/</ref>. <br />
The surgical methods currently used to treat distal hypospadias, include tabularized incised plate and meatal advancement and glansplasty intergrated repair. <br />
For proximal forms two staged procedures are employed. <ref><pubmed>25023236</pubmed></ref><br />
<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
<br />
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>. The disorder occurs among 1 in 500-1,000 male births <ref>http://ghr.nlm.nih.gov/condition/klinefelter-syndrome</ref>. An early diagnosis is important in order for treatment to be commenced right away. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=mediumslateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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. It occur is about 1 in 15,000 live births <ref>http://www.patient.co.uk/health/congenital-adrenal-hyperplasia-leaflet</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
[[File:Hydrocele.jpg|300px|thumb|right|A fetal ultrasound showing Hydrocele surrounding the testis]]<br />
<br />
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. The condition is prevalent in about 1-3% of births <ref><pubmed>http://bestpractice.bmj.com/best-practice/monograph/1104/basics/epidemiology.html</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>True Hermaphroditism</font>==== <br />
<br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. The disorder occur in 1 of 1,500-2,000 births <ref>http://www.isna.org/faq/frequency</ref>.<br />
Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. <br />
Each case is determined differently as there are many factors to consider when choosing the gender identity. <br />
This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=blueviolet>Also related include;</font><br />
|- <br />
| <font color=mediumslateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hypogonadotropic hypogonadism</font>====<br />
<br />
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). The incidence is about 1 in 2,000 births <ref>http://www.rightdiagnosis.com/h/hypogonadotropic_hypogonadism_syndactyly/prevalence.htm</ref>. <br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Prostate.jpeg&diff=159716File:Prostate.jpeg2014-10-24T05:38:39Z<p>Z3415716: </p>
<hr />
<div>This drawing is of the prostate with the seminal vesicles and vas deferens, as first described by Reinier De Graaf, a Dutch anatomists, in 1678. It shows the structures all attaching and places them in their respective positions in relation to the prostate gland. Prior to his work, the prostate and its adjoining ducts and structures were considered separately. <br />
This diagram is a based on De Graaf's illustration as published in <ref><pubmed>18942121</pubmed></ref><br />
<br />
===Reference===<br />
<references/><br />
<br />
===Copyright===<br />
<br />
Beginning six months after publication, I z3415716 grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode<br />
<br />
{{Template:Student Image}}</div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Prostate.jpeg&diff=159713File:Prostate.jpeg2014-10-24T05:37:36Z<p>Z3415716: This drawing is of the prostate with the seminal vesicles and vas deferens, as first described by Reinier De Graaf, a Dutch anatomists, in 1678. It shows the structures all attaching and places them in their respective positions in relation to the pros...</p>
<hr />
<div>This drawing is of the prostate with the seminal vesicles and vas deferens, as first described by Reinier De Graaf, a Dutch anatomists, in 1678. It shows the structures all attaching and places them in their respective positions in relation to the prostate gland. Prior to his work, the prostate and its adjoining ducts and structures were considered separately. <br />
This diagram is a based on De Graaf's illustration as published in <ref>18942121</pubmed></ref><br />
<br />
===Reference===<br />
<references/><br />
<br />
===Copyright===<br />
<br />
Beginning six months after publication, I z3415716 grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode<br />
<br />
{{Template:Student Image}}</div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1596892014 Group Project 92014-10-24T05:29:38Z<p>Z3415716: /* Female Genital Development */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
This page is the second page of the [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_4 Group 4 Project]<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
[[File:Mullerian ducts development.jpeg|400px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
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><br />
<br />
According to the works of the early embryologists, Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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> <ref><pubmed>18942121</pubmed></ref><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1611 ||bgcolor="F5FAFF"| Caspar Batholin, described the prostate as a spongy double organ that is continuous with the urethra, secreting protective substances.<br />
|-<br />
|bgcolor="FCFCFC"| 1674 ||bgcolor="FCFCFC"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="F5FAFF"| 1678 ||bgcolor="F5FAFF"| The first illustration of the prostate with the seminal vesicles and seminal ducts attached. This diagram was published by a Dutch anatomist Reinier De Graaf.<br />
|-<br />
|bgcolor="FCFCFC"| 1792 ||bgcolor="FCFCFC"| William Cheselden, an English anatomists and surgeon, challenged the theory that the prostate was two organs, stating that it may in fact be one gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1800 ||bgcolor="F5FAFF"| The double gland idea was disproven with the discovery that the perceived two glands had identical morphology and thus were one gland. <br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divide the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
[[File:Prepuce.jpeg|500px|centre|thumb|The steps of the developing prepuce in the male foetus condensed into three overall events]]<br />
<br />
==Abnormalities==<br />
<br />
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>. <br />
The content will cover most common abnormalities and then also the rare cases. <br />
Most genital abnormalities have a high risk in affecting fertility of both sexes. <br />
Currently there are a variety of methods applied to ensure that infertility can be treated and this will be mentioned. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout the child's life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia <ref>Schoenwolf, GC., Bleyl, S.B., Brauer, P.R., Francis-West, P.H., (2008). Larsen's Human Embryology, 4th ed. Chapter 15 Development of the Urogenital System. New York; Edinburgh: Churchill Livingstone, an imprint of Elsevier.</ref><br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. The congenital disorder affects 1 in 5,000 females <ref>http://www.urologyhealth.org/urology/index.cfm?article=50</ref>.<br />
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>.<br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>.<br />
<br />
[[File:WomenwithSwyerSyndrome.png|290px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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>. The syndrome affects 1 in 30,000 people <ref>http://ghr.nlm.nih.gov/condition/swyer-syndrome</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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=magenta>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
A metabolic endocrine disorder with an immense variety of phenotypes presented. The disorder shows an imbalance in female sex hormones and a resistance to insulin. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. It is most common in 5-10% of women in their reproductive age <ref>http://www.myvmc.com/diseases/polycystic-ovarian-syndrome-pcos/</ref>. The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
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 condition is prevalent in 2-4% of infant males <ref>http://livehealthy.chron.com/cryptorchidism-infertility-1080.html</ref>.<br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
[[File:Hypospadia classifications.jpg|300px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
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 <br />
<ref><pubmed>24936573</pubmed></ref>. Generally occurs in 1 of 125-300 male births <ref>http://www.hypospadiasuk.co.uk/statistics-about-hypospadias/</ref>. <br />
The surgical methods currently used to treat distal hypospadias, include tabularized incised plate and meatal advancement and glansplasty intergrated repair. <br />
For proximal forms two staged procedures are employed. <ref><pubmed>25023236</pubmed></ref><br />
<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
<br />
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>. The disorder occurs among 1 in 500-1,000 male births <ref>http://ghr.nlm.nih.gov/condition/klinefelter-syndrome</ref>. An early diagnosis is important in order for treatment to be commenced right away. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=mediumslateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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. It occur is about 1 in 15,000 live births <ref>http://www.patient.co.uk/health/congenital-adrenal-hyperplasia-leaflet</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
[[File:Hydrocele.jpg|300px|thumb|right|A fetal ultrasound showing Hydrocele surrounding the testis]]<br />
<br />
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. The condition is prevalent in about 1-3% of births <ref><pubmed>http://bestpractice.bmj.com/best-practice/monograph/1104/basics/epidemiology.html</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>True Hermaphroditism</font>==== <br />
<br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. The disorder occur in 1 of 1,500-2,000 births <ref>http://www.isna.org/faq/frequency</ref>.<br />
Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. <br />
Each case is determined differently as there are many factors to consider when choosing the gender identity. <br />
This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=blueviolet>Also related include;</font><br />
|- <br />
| <font color=mediumslateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hypogonadotropic hypogonadism</font>====<br />
<br />
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). The incidence is about 1 in 2,000 births <ref>http://www.rightdiagnosis.com/h/hypogonadotropic_hypogonadism_syndactyly/prevalence.htm</ref>. <br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1595902014 Group Project 92014-10-24T04:52:39Z<p>Z3415716: /* The Prostate */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
This page is the second page of the [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_4 Group 4 Project]<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
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><br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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> <ref><pubmed>18942121</pubmed></ref><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1611 ||bgcolor="F5FAFF"| Caspar Batholin, described the prostate as a spongy double organ that is continuous with the urethra, secreting protective substances.<br />
|-<br />
|bgcolor="FCFCFC"| 1674 ||bgcolor="FCFCFC"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="F5FAFF"| 1678 ||bgcolor="F5FAFF"| The first illustration of the prostate with the seminal vesicles and seminal ducts attached. This diagram was published by a Dutch anatomist Reinier De Graaf.<br />
|-<br />
|bgcolor="FCFCFC"| 1792 ||bgcolor="FCFCFC"| William Cheselden, an English anatomists and surgeon, challenged the theory that the prostate was two organs, stating that it may in fact be one gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1800 ||bgcolor="F5FAFF"| The double gland idea was disproven with the discovery that the perceived two glands had identical morphology and thus were one gland. <br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divide the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
[[File:Prepuce.jpeg|500px|centre|thumb|The steps of the developing prepuce in the male foetus condensed into three overall events]]<br />
<br />
==Abnormalities==<br />
<br />
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>. <br />
The content will cover most common abnormalities and then also the rare cases. <br />
Most genital abnormalities have a high risk in affecting fertility of both sexes. <br />
Currently there are a variety of methods applied to ensure that infertility can be treated and this will be mentioned. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout the child's life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia <ref>Schoenwolf, GC., Bleyl, S.B., Brauer, P.R., Francis-West, P.H., (2008). Larsen's Human Embryology, 4th ed. Chapter 15 Development of the Urogenital System. New York; Edinburgh: Churchill Livingstone, an imprint of Elsevier.</ref><br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. The congenital disorder affects 1 in 5,000 females <ref>http://www.urologyhealth.org/urology/index.cfm?article=50</ref>.<br />
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>.<br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>.<br />
<br />
[[File:WomenwithSwyerSyndrome.png|290px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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>. The syndrome affects 1 in 30,000 people <ref>http://ghr.nlm.nih.gov/condition/swyer-syndrome</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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=magenta>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
A metabolic endocrine disorder with an immense variety of phenotypes presented. The disorder shows an imbalance in female sex hormones and a resistance to insulin. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. It is most common in 5-10% of women in their reproductive age <ref>http://www.myvmc.com/diseases/polycystic-ovarian-syndrome-pcos/</ref>. The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
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 condition is prevalent in 2-4% of infant males <ref>http://livehealthy.chron.com/cryptorchidism-infertility-1080.html</ref>.<br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
[[File:Hypospadia classifications.jpg|300px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
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 <br />
<ref><pubmed>24936573</pubmed></ref>. Generally occurs in 1 of 125-300 male births <ref>http://www.hypospadiasuk.co.uk/statistics-about-hypospadias/</ref>. <br />
The surgical methods currently used to treat distal hypospadias, include tabularized incised plate and meatal advancement and glansplasty intergrated repair. <br />
For proximal forms two staged procedures are employed. <ref><pubmed>25023236</pubmed></ref><br />
<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
<br />
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>. The disorder occurs among 1 in 500-1,000 male births <ref>http://ghr.nlm.nih.gov/condition/klinefelter-syndrome</ref>. An early diagnosis is important in order for treatment to be commenced right away. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=mediumslateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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. It occur is about 1 in 15,000 live births <ref>http://www.patient.co.uk/health/congenital-adrenal-hyperplasia-leaflet</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
[[File:Hydrocele.jpg|300px|thumb|right|A fetal ultrasound showing Hydrocele surrounding the testis]]<br />
<br />
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. The condition is prevalent in about 1-3% of births <ref><pubmed>http://bestpractice.bmj.com/best-practice/monograph/1104/basics/epidemiology.html</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>True Hermaphroditism</font>==== <br />
<br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. The disorder occur in 1 of 1,500-2,000 births <ref>http://www.isna.org/faq/frequency</ref>.<br />
Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. <br />
Each case is determined differently as there are many factors to consider when choosing the gender identity. <br />
This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=blueviolet>Also related include;</font><br />
|- <br />
| <font color=mediumslateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hypogonadotropic hypogonadism</font>====<br />
<br />
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). The incidence is about 1 in 2,000 births <ref>http://www.rightdiagnosis.com/h/hypogonadotropic_hypogonadism_syndactyly/prevalence.htm</ref>. <br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Prepuce.jpeg&diff=159509File:Prepuce.jpeg2014-10-24T04:18:40Z<p>Z3415716: </p>
<hr />
<div>A summary the steps of prepuce development as described by Hunter in 1935. The drawings resemble and illustrate the observations of the foetal penis at different gestational age, depicting that the prepuce is a gradually growing structure during foetal growth. <br />
<br />
The three images (A, B, C) show the overall continuous change of the penis in terms of the prepuce.<br />
* A - Before prepuce development. The glans penis is fully exposed as the prepuce growth has not yet occurred. <br />
* B - Prepuce development. The developing prepuce layer form folds due to its rapid rate of growth and begins to cover the glans penis posteriorly. <br />
* C - Completion of the prepuce. By this stage, the epithelial cells have migrated forming a superficial layer that covers the entire glans penis. This is the penis-type observed at birth. <br />
<br />
This diagram is an adaptation from <ref><pubmed>17104576</pubmed></ref><br />
<br />
===Reference===<br />
<references/><br />
<br />
===Copyright===<br />
Beginning six months after publication, I z3417458 grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode<br />
<br />
{{Template:Student Image}}</div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1595032014 Group Project 92014-10-24T04:13:58Z<p>Z3415716: /* The prepuce */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
This page is the second page of the [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_4 Group 4 Project]<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
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><br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divide the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
[[File:Prepuce.jpeg|500px|centre|thumb|The steps of the developing prepuce in the male foetus condensed into three overall events]]<br />
<br />
==Abnormalities==<br />
<br />
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>. <br />
The content will cover most common abnormalities and then also the rare cases. <br />
Most genital abnormalities have a high risk in affecting fertility of both sexes. <br />
Currently there are a variety of methods applied to ensure that infertility can be treated and this will be mentioned. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout the child's life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia <ref>Schoenwolf, GC., Bleyl, S.B., Brauer, P.R., Francis-West, P.H., (2008). Larsen's Human Embryology, 4th ed. Chapter 15 Development of the Urogenital System. New York; Edinburgh: Churchill Livingstone, an imprint of Elsevier.</ref><br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. The congenital disorder affects 1 in 5,000 females <ref>http://www.urologyhealth.org/urology/index.cfm?article=50</ref>.<br />
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>.<br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>.<br />
<br />
[[File:WomenwithSwyerSyndrome.png|290px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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>. The syndrome affects 1 in 30,000 people <ref>http://ghr.nlm.nih.gov/condition/swyer-syndrome</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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=magenta>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
A metabolic endocrine disorder with an immense variety of phenotypes presented. The disorder shows an imbalance in female sex hormones and a resistance to insulin. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. It is most common in 5-10% of women in their reproductive age <ref>http://www.myvmc.com/diseases/polycystic-ovarian-syndrome-pcos/</ref>. The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
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 condition is prevalent in 2-4% of infant males <ref>http://livehealthy.chron.com/cryptorchidism-infertility-1080.html</ref>.<br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
[[File:Hypospadia classifications.jpg|300px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
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 <br />
<ref><pubmed>24936573</pubmed></ref>. Generally occurs in 1 of 125-300 male births <ref>http://www.hypospadiasuk.co.uk/statistics-about-hypospadias/</ref>. <br />
The surgical methods currently used to treat distal hypospadias, include tabularized incised plate and meatal advancement and glansplasty intergrated repair. <br />
For proximal forms two staged procedures are employed. <ref><pubmed>25023236</pubmed></ref><br />
<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
<br />
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>. The disorder occurs among 1 in 500-1,000 male births <ref>http://ghr.nlm.nih.gov/condition/klinefelter-syndrome</ref>. An early diagnosis is important in order for treatment to be commenced right away. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=mediumslateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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. It occur is about 1 in 15,000 live births <ref>http://www.patient.co.uk/health/congenital-adrenal-hyperplasia-leaflet</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
[[File:Hydrocele.jpg|300px|thumb|right|A fetal ultrasound showing Hydrocele surrounding the testis]]<br />
<br />
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. The condition is prevalent in about 1-3% of births <ref><pubmed>http://bestpractice.bmj.com/best-practice/monograph/1104/basics/epidemiology.html</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>True Hermaphroditism</font>==== <br />
<br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. The disorder occur in 1 of 1,500-2,000 births <ref>http://www.isna.org/faq/frequency</ref>.<br />
Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. <br />
Each case is determined differently as there are many factors to consider when choosing the gender identity. <br />
This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=blueviolet>Also related include;</font><br />
|- <br />
| <font color=mediumslateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hypogonadotropic hypogonadism</font>====<br />
<br />
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). The incidence is about 1 in 2,000 births <ref>http://www.rightdiagnosis.com/h/hypogonadotropic_hypogonadism_syndactyly/prevalence.htm</ref>. <br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Prepuce.jpeg&diff=159500File:Prepuce.jpeg2014-10-24T04:12:12Z<p>Z3415716: </p>
<hr />
<div>A summary the steps of prepuce development as described by Hunter in 1935. The drawings resemble and illustrate the observations of the foetal penis at different gestational age, depicting that the prepuce is a gradually growing structure during embryogenesis. <br />
<br />
The three images (A, B, C) show the overall continuous change of the penis in terms of the prepuce.<br />
* A - Before prepuce development. The glans penis is fully exposed as the prepuce growth has not yet occurred. <br />
* B - Prepuce development. The developing prepuce layer form folds due to its rapid rate of growth and begins to cover the glans penis posteriorly. <br />
* C - Completion of the prepuce. By this stage, the epithelial cells have migrated forming a superficial layer that covers the entire glans penis. This is the penis-type observed at birth. <br />
<br />
This diagram is an adaptation from <ref><pubmed>17104576</pubmed></ref><br />
<br />
===Reference===<br />
<references/><br />
<br />
===Copyright===<br />
Beginning six months after publication, I z3417458 grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode<br />
<br />
{{Template:Student Image}}</div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1594912014 Group Project 92014-10-24T04:04:28Z<p>Z3415716: /* The prepuce */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
This page is the second page of the [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_4 Group 4 Project]<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
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><br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divide the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
[[File:Prepuce.jpeg|400px|centre|thumb|The steps of the developing prepuce in the male foetus condensed into three overall events]]<br />
<br />
==Abnormalities==<br />
<br />
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>. <br />
The content will cover most common abnormalities and then also the rare cases. <br />
Most genital abnormalities have a high risk in affecting fertility of both sexes. <br />
Currently there are a variety of methods applied to ensure that infertility can be treated and this will be mentioned. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout the child's life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia <ref>Schoenwolf, GC., Bleyl, S.B., Brauer, P.R., Francis-West, P.H., (2008). Larsen's Human Embryology, 4th ed. Chapter 15 Development of the Urogenital System. New York; Edinburgh: Churchill Livingstone, an imprint of Elsevier.</ref><br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. The congenital disorder affects 1 in 5,000 females <ref>http://www.urologyhealth.org/urology/index.cfm?article=50</ref>.<br />
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>.<br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>.<br />
<br />
[[File:WomenwithSwyerSyndrome.png|290px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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>. The syndrome affects 1 in 30,000 people <ref>http://ghr.nlm.nih.gov/condition/swyer-syndrome</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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=magenta>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
A metabolic endocrine disorder with an immense variety of phenotypes presented. The disorder shows an imbalance in female sex hormones and a resistance to insulin. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. It is most common in 5-10% of women in their reproductive age <ref>http://www.myvmc.com/diseases/polycystic-ovarian-syndrome-pcos/</ref>. The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
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 condition is prevalent in 2-4% of infant males <ref>http://livehealthy.chron.com/cryptorchidism-infertility-1080.html</ref>.<br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
[[File:Hypospadia classifications.jpg|300px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
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 <br />
<ref><pubmed>24936573</pubmed></ref>. Generally occurs in 1 of 125-300 male births <ref>http://www.hypospadiasuk.co.uk/statistics-about-hypospadias/</ref>. <br />
The surgical methods currently used to treat distal hypospadias, include tabularized incised plate and meatal advancement and glansplasty intergrated repair. <br />
For proximal forms two staged procedures are employed. <ref><pubmed>25023236</pubmed></ref><br />
<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
<br />
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>. The disorder occurs among 1 in 500-1,000 male births <ref>http://ghr.nlm.nih.gov/condition/klinefelter-syndrome</ref>. An early diagnosis is important in order for treatment to be commenced right away. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=mediumslateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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. It occur is about 1 in 15,000 live births <ref>http://www.patient.co.uk/health/congenital-adrenal-hyperplasia-leaflet</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
[[File:Hydrocele.jpg|300px|thumb|right|A fetal ultrasound showing Hydrocele surrounding the testis]]<br />
<br />
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. The condition is prevalent in about 1-3% of births <ref><pubmed>http://bestpractice.bmj.com/best-practice/monograph/1104/basics/epidemiology.html</ref>. 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>.<br />
<br />
====<font color=mediumslateblue>True Hermaphroditism</font>==== <br />
<br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. The disorder occur in 1 of 1,500-2,000 births <ref>http://www.isna.org/faq/frequency</ref>.<br />
Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. <br />
Each case is determined differently as there are many factors to consider when choosing the gender identity. <br />
This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=blueviolet>Also related include;</font><br />
|- <br />
| <font color=mediumslateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hypogonadotropic hypogonadism</font>====<br />
<br />
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). The incidence is about 1 in 2,000 births <ref>http://www.rightdiagnosis.com/h/hypogonadotropic_hypogonadism_syndactyly/prevalence.htm</ref>. <br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Prepuce.jpeg&diff=159473File:Prepuce.jpeg2014-10-24T03:58:22Z<p>Z3415716: </p>
<hr />
<div>A summary the steps of prepuce development as described by Hunter in 1935. The drawings resemble and illustrate the observations of the foetal penis at different gestational age, depicting that the prepuce is a gradually growing structure during embryogenesis. <br />
<br />
The three images (A, B, C) show the overall continuous change of the prepuce.<br />
* A - describes the penis with an undeveloped prepuce and a fully exposed penis glans.<br />
* B - Shows the developing prepuce layer, that begins to cover the glans penis posteriorly, forming folds due to its rapid rate of growth.<br />
* C - By this stage, the epithelial cells have migrated forming a superficial layer that covers the entire glans penis. This is penis-type observed at birth. <br />
<br />
This diagram is an adaptation from <ref><pubmed>17104576</pubmed></ref><br />
<br />
===Reference===<br />
<references/><br />
<br />
===Copyright===<br />
Beginning six months after publication, I z3417458 grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode<br />
<br />
{{Template:Student Image}}</div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Prepuce.jpeg&diff=159464File:Prepuce.jpeg2014-10-24T03:55:39Z<p>Z3415716: A summary the steps of prepuce development as described by Hunter in 1935. The drawing resemble and illustrates the observations of the foetal penis at different gestational, depicting that the prepuce is a gradually growing structure during embryogene...</p>
<hr />
<div>A summary the steps of prepuce development as described by Hunter in 1935. The drawing resemble and illustrates the observations of the foetal penis at different gestational, depicting that the prepuce is a gradually growing structure during embryogenesis. <br />
The three images (A, B, C) show the overall continuous change of the prepuce.<br />
A described the penis with undeveloped prepuce and a fully exposed penis glans.<br />
Shows the developing prepuce layer that begins to cover the glans penis posteriorly and forms folds due to its rapid rate of growth.<br />
By this stage, the epithelial cells have migrated forming a superficial layer that covers the entire glans penis. This is penis-type observed at birth. <br />
This diagram is an adaptation from <ref><pubmed>17104576</pubmed></ref><br />
<br />
===Reference===<br />
<references/><br />
<br />
===Copyright===<br />
Beginning six months after publication, I z3417458 grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode<br />
<br />
{{Template:Student Image}}</div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_4&diff=1593292014 Group Project 42014-10-24T03:30:08Z<p>Z3415716: /* Abnormalities */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
=Genital=<br />
==Introduction==<br />
<br />
[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]<br />
<br />
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.<br />
<br />
==System Development==<br />
<br />
{| class="wikitable" <br />
|-bgcolor="purple"|align="centre"<br />
|'''Week''' || '''Development'''|||'''Image'''<br />
|-bgcolor="lavender"<br />
| 3-4 || Primordial germ cells migrate during gastrulation<br />
|-<br />
| 4 || Intermediate mesoderm, pronephros primordium<br />
|-bgcolor="lavender"<br />
| 5 || Mesonephros and mesonephric duct<br />
|-<br />
| 6 || Ureteric bud, metanephros, genital ridge<br />
|-bgcolor="lavender"<br />
| 7 || Cloacal divison, gonadal primordium - indifferent to first appearance of testis cords<br />
Female - Paramesonephric duct preservation or regression begins<br />
<br />
|-<br />
| 8 || Paramesonephric duct, clear gonadal differentiation<br />
|-bgcolor="lavender"<br />
| 9 || Paramesonephric duct fusion in the female forming the uterus and lack of fusion laterally forming the fallopian tubes. Also forms vagina.<br />
|[[File:Paramesonephric duct.jpg|200px]]<br />
|-<br />
| 15 || Primary follicles (ovary)<br />
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.<br />
Both male and female gonads undergo descent. <br />
|[[File:Infant ovary.jpg|200px]]<br />
[[File:Testis-descent end.jpg|200px]]<br />
|-bgcolor="lavender"<br />
| Puberty || Development of secondary sexual characteristics<br />
Female - start of menstruation, first egg released.<br />
Male - development of course voice, body hair and sperm formation.<br />
|-<br />
|}<br />
<br />
'''Related video'''<br />
<br />
<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media><br />
<br />
<br />
{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Embryonic Period – Genital Development''<br />
|- bgcolor="lavender"<br />
|<br />
# Genital System development begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally on the coelomic cavity<br />
# 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<br />
# 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 <br />
|}<br />
<br />
<br />
===Internal Genital Development===<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE'''<br />
|bgcolor="violet"|'''FEMALE'''<br />
|-<br />
|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><br />
<br />
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><br />
<br />
<br />
<br />
''Fetal Male Glandular Development''<br />
* 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<br />
* 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><br />
* 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.<br />
<br />
<br />
<br />
| 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><br />
<br />
<br />
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.<br />
<br />
<br />
''Female Glandular Development''<br />
<br />
* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.<br />
* 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><br />
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[[File:External genitalia current model.jpg|300px|right|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]<br />
<br />
===Development of the External Genitalia ===<br />
<br />
'''The current model for embryonic development of the external genitalia in humans and mice:'''<br />
<br />
{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''<br />
|- bgcolor="lavender"<br />
|<br />
# 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><br />
# 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.<br />
# 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.<br />
# 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><br />
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
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'''The current model for fetal development of the external genitalia in humans and mice:'''<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE MODEL'''<br />
|bgcolor="violet"|'''FEMALE MODEL'''<br />
<br />
|-<br />
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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).<br />
# 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><br />
# 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><br />
# 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).<br />
# 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.<br />
# 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><br />
<br />
[[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]]<br />
<br />
* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.<br />
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.<br />
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.<br />
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* 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.<br />
<br />
* 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.<br />
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.<br />
* 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><br />
* 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><br />
*: 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><br />
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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.<br />
# The urogenital folds remain apart and unfused to form the labia majora.<ref name=PMID11315960><pubmed>11315960</pubmed></ref><br />
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
<br />
* 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.<br />
* The tubercle itself goes on to form the mons pubis.<br />
* 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.<br />
* 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><br />
<br />
[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]<br />
|-<br />
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==Current Research, Models and Findings==<br />
<br />
===Current Models===<br />
<br />
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><br />
<br />
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><br />
<br />
Some examples of different animal models used in research involving fetal development of male and female genital systems are:<br />
<br />
* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref><br />
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref><br />
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref><br />
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref><br />
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref><br />
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref><br />
<br />
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><br />
<br />
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><br />
<br />
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]]<br />
<br />
===Current Research and Findings===<br />
====Male====<br />
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{|<br />
|-bgcolor="aliceblue"<br />
|<br />
[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]<br />
<br />
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><br />
<br />
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><br />
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[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]<br />
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{|<br />
|-bgcolor="aliceblue"<br />
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[[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]]<br />
<br />
'''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><br />
<br />
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><br />
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>.<br />
Therefore, the aim of the present study was to investigate the linkage between exposures of the fetus to POPs and risk of developing hypospadias.<br />
<br />
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.<br />
<br />
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.<br />
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{|<br />
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'''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><br />
<br />
[[File:Male testosterone and AMH level graph.jpg|thumb|300px|right|Graph showing male testosterone and AMH levels]]<br />
<br />
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: <br />
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.<br />
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.<br />
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.<br />
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.<br />
<br />
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.<br />
<br />
Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.<br />
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.<br />
<br />
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).<br />
<br />
Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.<br />
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.<br />
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.<br />
<br />
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.<br />
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. <br />
<br />
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.<br />
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{|<br />
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'''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><br />
<br />
[[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]]<br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
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====Female====<br />
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{|<br />
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'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref><br />
<br />
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.<br />
<br />
[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]<br />
<br />
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. <br />
<br />
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.<br />
<br />
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><br />
<br />
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.<br />
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'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref><br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
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|-bgcolor="lavenderblush"<br />
|<br />
'''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><br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
|}<br />
<br />
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<br />
----<br />
<br />
<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
<br />
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> <br />
<br />
[[File:Human Y chromosome SRY region.jpg|400px|right|thumb| Human Y chromosome showing SRY gene]]<br />
<br />
Some critical genes involved in the testicular and ovarian pathways include:<br />
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref><br />
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref><br />
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
<br />
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><br />
<br />
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. <br />
<br />
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. <br />
<br />
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.<br />
<br />
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.<br />
|}<br />
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<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! '''Other current research findings and interesting reads:'''<br />
|- <br />
| * 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><br />
<br />
<pubmed>21584884</pubmed><br />
<pubmed>18367374</pubmed><br />
<pubmed>15086026</pubmed><br />
<pubmed>14641326</pubmed><br />
<pubmed>11684660</pubmed><br />
<pubmed>22127979</pubmed><br />
<pubmed>24631756</pubmed><br />
<pubmed>23192465</pubmed><br />
|}<br />
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<br />
==Historic Findings==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for Historical Findings<br />
<br />
==Abnormalities==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for foetal genital abnormalities<br />
<br />
==References==<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_4&diff=1593112014 Group Project 42014-10-24T03:28:04Z<p>Z3415716: /* Historic Finding */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
=Genital=<br />
==Introduction==<br />
<br />
[[File:SexualDifferentation.jpg|300px|right|thumb|The stages in sexual differentiation of the female and male reproductive system]]<br />
<br />
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.<br />
<br />
==System Development==<br />
<br />
{| class="wikitable" <br />
|-bgcolor="purple"|align="centre"<br />
|'''Week''' || '''Development'''|||'''Image'''<br />
|-bgcolor="lavender"<br />
| 3-4 || Primordial germ cells migrate during gastrulation<br />
|-<br />
| 4 || Intermediate mesoderm, pronephros primordium<br />
|-bgcolor="lavender"<br />
| 5 || Mesonephros and mesonephric duct<br />
|-<br />
| 6 || Ureteric bud, metanephros, genital ridge<br />
|-bgcolor="lavender"<br />
| 7 || Cloacal divison, gonadal primordium - indifferent to first appearance of testis cords<br />
Female - Paramesonephric duct preservation or regression begins<br />
<br />
|-<br />
| 8 || Paramesonephric duct, clear gonadal differentiation<br />
|-bgcolor="lavender"<br />
| 9 || Paramesonephric duct fusion in the female forming the uterus and lack of fusion laterally forming the fallopian tubes. Also forms vagina.<br />
|[[File:Paramesonephric duct.jpg|200px]]<br />
|-<br />
| 15 || Primary follicles (ovary)<br />
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.<br />
Both male and female gonads undergo descent. <br />
|[[File:Infant ovary.jpg|200px]]<br />
[[File:Testis-descent end.jpg|200px]]<br />
|-bgcolor="lavender"<br />
| Puberty || Development of secondary sexual characteristics<br />
Female - start of menstruation, first egg released.<br />
Male - development of course voice, body hair and sperm formation.<br />
|-<br />
|}<br />
<br />
'''Related video'''<br />
<br />
<html5media>https://www.youtube.com/watch?v=MureNA-RSZM</html5media><br />
<br />
<br />
{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Embryonic Period – Genital Development''<br />
|- bgcolor="lavender"<br />
|<br />
# Genital System development begins from a thickening of the epithelium surrounding the mesonephros, which lies dorsally on the coelomic cavity<br />
# 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<br />
# 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 <br />
|}<br />
<br />
<br />
===Internal Genital Development===<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE'''<br />
|bgcolor="violet"|'''FEMALE'''<br />
|-<br />
|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><br />
<br />
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><br />
<br />
<br />
<br />
''Fetal Male Glandular Development''<br />
* 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<br />
* 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><br />
* 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.<br />
<br />
<br />
<br />
| 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><br />
<br />
<br />
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.<br />
<br />
<br />
''Female Glandular Development''<br />
<br />
* The urethra develops outgrowths which form the mucus secreting '''urethral glands''' and paraurtehral glands.<br />
* 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><br />
|-<br />
|- style="height:10px" <br />
| style="width:50%"| <br />
|}<br />
<br />
[[File:External genitalia current model.jpg|300px|right|thumb|Flow Diagram of the current model of embryonic and fetal development of the external genitalia]]<br />
<br />
===Development of the External Genitalia ===<br />
<br />
'''The current model for embryonic development of the external genitalia in humans and mice:'''<br />
<br />
{|class="wikitable mw-collapsible mw-collapsed"<br />
! ''Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE''<br />
|- bgcolor="lavender"<br />
|<br />
# 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><br />
# 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.<br />
# 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.<br />
# 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><br />
# The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
|}<br />
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<br />
'''The current model for fetal development of the external genitalia in humans and mice:'''<br />
{| style="width:100%"<br />
|bgcolor="lightskyblue"|'''MALE MODEL'''<br />
|bgcolor="violet"|'''FEMALE MODEL'''<br />
<br />
|-<br />
|bgcolor="aliceblue"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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).<br />
# 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><br />
# 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><br />
# 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).<br />
# 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.<br />
# 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><br />
<br />
[[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]]<br />
<br />
* Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.<br />
* The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.<br />
* Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.<br />
* During development, the mesoderm separates into connective tissues and dermis.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* 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.<br />
<br />
* 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.<br />
* In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.<br />
* 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><br />
* 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><br />
*: 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><br />
| bgcolor="lavenderblush"|'''''Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION'''''<br />
# 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.<br />
# The urogenital folds remain apart and unfused to form the labia majora.<ref name=PMID11315960><pubmed>11315960</pubmed></ref><br />
# The genital swellings also remain apart and unfused to form the labia minora.<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
<br />
* 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.<br />
* The tubercle itself goes on to form the mons pubis.<br />
* 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.<br />
* 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><br />
<br />
[[File:Clitoris.jpg|600px|thumb|center|Stages in the Development of the External Sexual Organs in the Male and Female]]<br />
|-<br />
|- style="height:10px"<br />
| style="width:50%"|<br />
|}<br />
<br />
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<br />
==Current Research, Models and Findings==<br />
<br />
===Current Models===<br />
<br />
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><br />
<br />
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><br />
<br />
Some examples of different animal models used in research involving fetal development of male and female genital systems are:<br />
<br />
* Sheep<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
* Mouse<ref name=PMID14641326><pubmed>14641326</pubmed></ref><br />
* Dogs<ref name=PMID13362960><pubmed>13362960</pubmed></ref><br />
* Porcine<ref name=PMID23571006><pubmed>23571006</pubmed></ref><br />
* Rats<ref name=PMID22248293><pubmed>22248293</pubmed></ref><br />
* Monkeys<ref name=PMID21710394><pubmed>21710394</pubmed></ref><br />
* Bovine<ref name=PMID20347535><pubmed>20347535</pubmed></ref><br />
* Goats<ref name=PMID22006251><pubmed>22006251</pubmed></ref><br />
<br />
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><br />
<br />
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><br />
<br />
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]]<br />
<br />
===Current Research and Findings===<br />
====Male====<br />
----<br />
{|<br />
|-bgcolor="aliceblue"<br />
|<br />
[[File:Hypospadias.jpg|400px|thumb|right|Different types of hypospadias]]<br />
<br />
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><br />
<br />
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><br />
|}<br />
<br />
[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]<br />
<br />
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<br />
<br />
{|<br />
|-bgcolor="aliceblue"<br />
|<br />
[[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]]<br />
<br />
'''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><br />
<br />
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><br />
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>.<br />
Therefore, the aim of the present study was to investigate the linkage between exposures of the fetus to POPs and risk of developing hypospadias.<br />
<br />
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.<br />
<br />
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.<br />
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'''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><br />
<br />
[[File:Male testosterone and AMH level graph.jpg|thumb|300px|right|Graph showing male testosterone and AMH levels]]<br />
<br />
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: <br />
*Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.<br />
*Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.<br />
*Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.<br />
*Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.<br />
<br />
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.<br />
<br />
Cryptorchidism is the failure of descent of the testis and is the most common congenital malformation in males.<br />
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.<br />
<br />
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).<br />
<br />
Testicular cells were counted using histology and image analysis and the hormones were assayed in the medium.<br />
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.<br />
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.<br />
<br />
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.<br />
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. <br />
<br />
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.<br />
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'''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><br />
<br />
[[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]]<br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
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====Female====<br />
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{|<br />
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'''Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)'''<ref name=PMID21584884><pubmed>21584884</pubmed></ref><br />
<br />
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.<br />
<br />
[[File:Ultrasound male.jpg|200px|thumb|left|Ultrasound of male fetus]]<br />
<br />
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. <br />
<br />
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.<br />
<br />
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><br />
<br />
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.<br />
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{|<br />
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'''In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)'''<ref name=PMID16585961><pubmed>16585961</pubmed></ref><br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
<br />
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.<br />
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'''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><br />
<br />
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.<br />
<br />
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.<br />
<br />
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.<br />
<br />
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. <br />
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'''Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)'''<ref name=PMID21223560><pubmed>21223560</pubmed></ref><br />
<br />
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> <br />
<br />
[[File:Human Y chromosome SRY region.jpg|400px|right|thumb| Human Y chromosome showing SRY gene]]<br />
<br />
Some critical genes involved in the testicular and ovarian pathways include:<br />
*SRY gene (sex-determining region of the Y-chromosome) <ref name=PMID2247149><pubmed>2247149</pubmed></ref><br />
*Rspol gene (R-spondin homolog)<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
*Wnt4 – wongless-related MMTV integration site 4)<ref name=PMID18250097><pubmed>18250097</pubmed></ref><br />
*Beta-catenin<ref name=PMID18250098><pubmed>18250098</pubmed></ref><br />
<br />
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><br />
<br />
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. <br />
<br />
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. <br />
<br />
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.<br />
<br />
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.<br />
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{| class="wikitable mw-collapsible mw-collapsed"<br />
! '''Other current research findings and interesting reads:'''<br />
|- <br />
| * 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><br />
<br />
<pubmed>21584884</pubmed><br />
<pubmed>18367374</pubmed><br />
<pubmed>15086026</pubmed><br />
<pubmed>14641326</pubmed><br />
<pubmed>11684660</pubmed><br />
<pubmed>22127979</pubmed><br />
<pubmed>24631756</pubmed><br />
<pubmed>23192465</pubmed><br />
|}<br />
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<br />
==Historic Findings==<br />
<br />
Click [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9 here] for Historical Findings<br />
<br />
==Abnormalities==<br />
<br />
[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_9]<br />
<br />
==References==<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1583782014 Group Project 92014-10-23T22:59:13Z<p>Z3415716: /* Genital */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
This page is the second page of the [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_4 Group 4 Project]<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
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><br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divide the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
Most genital abnormalities have a high risk in affecting fertility of both sexes. <br />
Currently there are a variety of methods applied to ensure that infertility can be treated and this will be mentioned. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout the child's life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia <ref>Schoenwolf, GC., Bleyl, S.B., Brauer, P.R., Francis-West, P.H., (2008). Larsen's Human Embryology, 4th ed. Chapter 15 Development of the Urogenital System. New York; Edinburgh: Churchill Livingstone, an imprint of Elsevier.</ref><br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>.<br />
<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=magenta>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=mediumslateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>True Hermaphroditism</font>==== <br />
<br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=blueviolet>Also related include;</font><br />
|- <br />
| <font color=mediumslateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1582882014 Group Project 92014-10-23T22:34:04Z<p>Z3415716: /* The prepuce */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
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><br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divide the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
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. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout their life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia<br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>.<br />
<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=magenta>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=mediumslateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>True Hermaphroditism</font>==== <br />
<br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=blueviolet>Also related include;</font><br />
|- <br />
| <font color=mediumslateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Keibel%27s_model_of_urogenital_organs.jpg&diff=158198File:Keibel's model of urogenital organs.jpg2014-10-23T21:54:48Z<p>Z3415716: /* Reference */</p>
<hr />
<div>This model by the German anatomists and embryologists Franz Keibel marks the location of the later developed hymen, the Mullerian eminence, with an X, at the junction of the urogenital sinus and the Mullerian ducts. It also contains the Mullerian ducts before differentiation into the female genital organs, and the lateral Wolffian ducts before degeneration later in the foetal period. <br />
<br />
===Reference===<br />
<pubmed>17232227</pubmed><br />
<br />
===Copyright===<br />
Model and article published prior to 1923, therefore copyright has expired allowing public use.<br />
<br />
{{Template:Student Image}}</div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1581592014 Group Project 92014-10-23T21:46:23Z<p>Z3415716: /* Female Genital Development */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
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><br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divided the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
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. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout their life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia<br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>.<br />
<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=magenta>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|280px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=slateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=slateblue>True Hermaphroditism</font>==== <br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| <font color=slateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=darkorchid>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1581352014 Group Project 92014-10-23T21:39:19Z<p>Z3415716: /* The hymen */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
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><br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>.<br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divided the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
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. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout their life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia<br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>.<br />
<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=violet>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=dodgerblue>Also related include;</font><br />
|- <br />
| <font color=lightskyblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=slateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=slateblue>True Hermaphroditism</font>==== <br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| <font color=slateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=darkorchid>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1580962014 Group Project 92014-10-23T21:34:49Z<p>Z3415716: /* Historic Finding */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
{{Historic Disclaimer}}<br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
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><br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
<br />
[[File:Keibel's model of urogenital organs.jpg|300px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>. <br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divided the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
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. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout their life. <br />
<br />
===<font color=magenta>FEMALE</font>===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia<br />
<br />
====<font color=violet>Mullerian agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Vaginal agenesis</font>==== <br />
<br />
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>. <br />
<br />
====<font color=violet>Turners Syndrome</font>====<br />
<br />
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>.<br />
<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
====<font color=violet>Swyer Syndrome</font>==== <br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=violet>Also related include;</font><br />
|- <br />
| | <font color=violet>'''Polycystic Ovarian Syndrome'''</font><br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
====<font color=lightskyblue>Cryptorchidism</font>====<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
====<font color=lightskyblue>Hypospadias</font>====<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
====<font color=lightskyblue>Klinefelter</font>====<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
====<font color=lightskyblue>Peyronie's Disease</font>====<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=lightskyblue>Also related include;</font><br />
|- <br />
| <font color=dodgerblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=slateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=slateblue>True Hermaphroditism</font>==== <br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| <font color=slateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=darkorchid>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Mullerian_ducts_development.jpeg&diff=157637File:Mullerian ducts development.jpeg2014-10-23T14:05:07Z<p>Z3415716: Z3415716 uploaded a new version of &quot;File:Mullerian ducts development.jpeg&quot;</p>
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<div>This is a diagram illustrating the origin of the female genital organs from the Mullerian ducts, in accordance with the anatomists of the 17th and 18th century. The Mullerian ducts (A) are separated into an upper and lower part, both developing into the mature internal female organs (B). The lower part is the origin of the vagina and uterus, whereas the upper part is the origin of the uterine tube.<br />
This drawing is an adaption from <ref><pubmed>13230915</pubmed></ref><br />
<br />
===Reference===<br />
<references/><br />
<br />
===Copyright===<br />
<br />
Beginning six months after publication, I z3415716 grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode<br />
<br />
{{Template:Student Image}}</div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1575892014 Group Project 92014-10-23T13:42:17Z<p>Z3415716: /* Historic Finding */</p>
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<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
==Historic Finding==<br />
<br />
The development of the genital system has been a focus of scientific research and literature for many centuries, with anatomists publishing articles on both the male and female reproductive system. Historical findings are based mainly on dissections and observation of foetal and deceased neonates in comparison to the current emphasis on molecular research. The different research methods and findings have been published in worldwide journals over hundreds of years, with articles considering the system as a whole or specifically analysing one organ. It through the previous work of these academics that embryology has developed to the complex, abundant study it is today. <br />
<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
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><br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>. <br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divided the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
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. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout their life. <br />
<br />
===FEMALE===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia<br />
<br />
====Mullerian agenesis====<br />
<br />
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>. <br />
<br />
====Vaginal agenesis====<br />
<br />
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>. <br />
<br />
====Turners syndrome====<br />
<br />
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>.<br />
<br />
====Swyer Syndrome====<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| '''Polycystic Ovarian Syndrome'''<br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
===<font color=lightskyblue>Cryptorchidism</font>===<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
===<font color=lightskyblue>Hypospadias</font>===<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
===<font color=lightskyblue>Klinefelter</font>===<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
===<font color=lightskyblue>Peyronie's Disease</font>===<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=lightskyblue>Also related include;</font><br />
|- <br />
| <font color=dodgerblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=slateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=slateblue>True Hermaphroditism</font>==== <br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| <font color=slateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=darkorchid>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1575172014 Group Project 92014-10-23T13:07:29Z<p>Z3415716: /* Testicular descent */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
==Historic Finding==<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
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><br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>. <br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divided the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
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. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout their life. <br />
<br />
===FEMALE===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia<br />
<br />
====Mullerian agenesis====<br />
<br />
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>. <br />
<br />
====Vaginal agenesis====<br />
<br />
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>. <br />
<br />
====Turners syndrome====<br />
<br />
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>.<br />
<br />
====Swyer Syndrome====<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| '''Polycystic Ovarian Syndrome'''<br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
===<font color=lightskyblue>Cryptorchidism</font>===<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
===<font color=lightskyblue>Hypospadias</font>===<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
===<font color=lightskyblue>Klinefelter</font>===<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
===<font color=lightskyblue>Peyronie's Disease</font>===<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=lightskyblue>Also related include;</font><br />
|- <br />
| <font color=dodgerblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=slateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=slateblue>True Hermaphroditism</font>==== <br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| <font color=slateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=darkorchid>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1575082014 Group Project 92014-10-23T13:01:23Z<p>Z3415716: /* Testicular descent */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
==Historic Finding==<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
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><br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>. <br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divided the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
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. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout their life. <br />
<br />
===FEMALE===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia<br />
<br />
====Mullerian agenesis====<br />
<br />
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>. <br />
<br />
====Vaginal agenesis====<br />
<br />
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>. <br />
<br />
====Turners syndrome====<br />
<br />
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>.<br />
<br />
====Swyer Syndrome====<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| '''Polycystic Ovarian Syndrome'''<br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
===<font color=lightskyblue>Cryptorchidism</font>===<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
===<font color=lightskyblue>Hypospadias</font>===<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
===<font color=lightskyblue>Klinefelter</font>===<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
===<font color=lightskyblue>Peyronie's Disease</font>===<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=lightskyblue>Also related include;</font><br />
|- <br />
| <font color=dodgerblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=slateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=slateblue>True Hermaphroditism</font>==== <br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| <font color=slateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=darkorchid>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1575022014 Group Project 92014-10-23T12:59:46Z<p>Z3415716: /* Testicular descent */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
==Historic Finding==<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
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><br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>. <br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Lower foetal abdominal area at 6 months, highlighting the location of the testis and the large gubernaculum attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divided the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
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. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout their life. <br />
<br />
===FEMALE===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia<br />
<br />
====Mullerian agenesis====<br />
<br />
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>. <br />
<br />
====Vaginal agenesis====<br />
<br />
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>. <br />
<br />
====Turners syndrome====<br />
<br />
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>.<br />
<br />
====Swyer Syndrome====<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| '''Polycystic Ovarian Syndrome'''<br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
===<font color=lightskyblue>Cryptorchidism</font>===<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
===<font color=lightskyblue>Hypospadias</font>===<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
===<font color=lightskyblue>Klinefelter</font>===<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
===<font color=lightskyblue>Peyronie's Disease</font>===<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=lightskyblue>Also related include;</font><br />
|- <br />
| <font color=dodgerblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=slateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=slateblue>True Hermaphroditism</font>==== <br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| <font color=slateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=darkorchid>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1574962014 Group Project 92014-10-23T12:51:34Z<p>Z3415716: /* Testicular descent */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
==Historic Finding==<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
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><br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>. <br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
[[File:Keith1902 fig103.jpg|400px|right|thumb|Representation of the lower foetal abdominal area at 6 months, highlighting the location of the testis prior to descent and the large gubernaculum, in comparison to the testis, attaching the gonads to the scrotum in preparation for testicular descent]]<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divided the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
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. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout their life. <br />
<br />
===FEMALE===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia<br />
<br />
====Mullerian agenesis====<br />
<br />
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>. <br />
<br />
====Vaginal agenesis====<br />
<br />
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>. <br />
<br />
====Turners syndrome====<br />
<br />
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>.<br />
<br />
====Swyer Syndrome====<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| '''Polycystic Ovarian Syndrome'''<br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
===<font color=lightskyblue>Cryptorchidism</font>===<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
===<font color=lightskyblue>Hypospadias</font>===<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
===<font color=lightskyblue>Klinefelter</font>===<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
===<font color=lightskyblue>Peyronie's Disease</font>===<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=lightskyblue>Also related include;</font><br />
|- <br />
| <font color=dodgerblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=slateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=slateblue>True Hermaphroditism</font>==== <br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| <font color=slateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=darkorchid>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Mullerian_ducts_development.jpeg&diff=157436File:Mullerian ducts development.jpeg2014-10-23T12:29:16Z<p>Z3415716: </p>
<hr />
<div>This is a diagram illustrating the origin of the female genital organs from the Mullerian ducts, in accordance with the anatomists of the 17th and 18th century. The Mullerian ducts (A) are separated into an upper and lower part, both developing into the mature internal female organs (B). The lower part is the origin of the vagina and uterus, whereas the upper part is the origin of the uterine tube.<br />
This drawing is an adaption from <ref><pubmed>13230915</pubmed></ref><br />
<br />
===Reference===<br />
<references/><br />
<br />
===Copyright===<br />
<br />
Beginning six months after publication, I z3415716 grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode<br />
<br />
{{Template:Student Image}}</div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1573822014 Group Project 92014-10-23T11:52:32Z<p>Z3415716: /* Male Genital Development */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
==Historic Finding==<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
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><br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>. <br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>. 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 <ref name=Martyn1991>Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184</ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divided the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
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. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout their life. <br />
<br />
===FEMALE===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia<br />
<br />
====Mullerian agenesis====<br />
<br />
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>. <br />
<br />
====Vaginal agenesis====<br />
<br />
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>. <br />
<br />
====Turners syndrome====<br />
<br />
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>.<br />
<br />
====Swyer Syndrome====<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| '''Polycystic Ovarian Syndrome'''<br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
===<font color=lightskyblue>Cryptorchidism</font>===<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
===<font color=lightskyblue>Hypospadias</font>===<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
===<font color=lightskyblue>Klinefelter</font>===<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
===<font color=lightskyblue>Peyronie's Disease</font>===<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=lightskyblue>Also related include;</font><br />
|- <br />
| <font color=dodgerblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=slateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=slateblue>True Hermaphroditism</font>==== <br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| <font color=slateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=darkorchid>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1573642014 Group Project 92014-10-23T11:46:32Z<p>Z3415716: /* Female Genital Development */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
==Historic Finding==<br />
===<font color=deeppink>Female Genital Development</font>===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
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><br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>. <br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref>. 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 <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divided the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
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. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout their life. <br />
<br />
===FEMALE===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia<br />
<br />
====Mullerian agenesis====<br />
<br />
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>. <br />
<br />
====Vaginal agenesis====<br />
<br />
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>. <br />
<br />
====Turners syndrome====<br />
<br />
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>.<br />
<br />
====Swyer Syndrome====<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| '''Polycystic Ovarian Syndrome'''<br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
===<font color=lightskyblue>Cryptorchidism</font>===<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
===<font color=lightskyblue>Hypospadias</font>===<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
===<font color=lightskyblue>Klinefelter</font>===<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
===<font color=lightskyblue>Peyronie's Disease</font>===<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=lightskyblue>Also related include;</font><br />
|- <br />
| <font color=dodgerblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=slateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=slateblue>True Hermaphroditism</font>==== <br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| <font color=slateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=darkorchid>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1573492014 Group Project 92014-10-23T11:42:48Z<p>Z3415716: /* Male Genital Development */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
==Historic Finding==<br />
===Female Genital Development===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
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><br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>. <br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
===<font color=dodgerblue>Male Genital Development</font>===<br />
<br />
====The Prostate====<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
====Testicular descent====<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref>. 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 <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
====The prepuce====<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divided the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
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. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout their life. <br />
<br />
===FEMALE===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia<br />
<br />
====Mullerian agenesis====<br />
<br />
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>. <br />
<br />
====Vaginal agenesis====<br />
<br />
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>. <br />
<br />
====Turners syndrome====<br />
<br />
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>.<br />
<br />
====Swyer Syndrome====<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| '''Polycystic Ovarian Syndrome'''<br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
===<font color=lightskyblue>Cryptorchidism</font>===<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
===<font color=lightskyblue>Hypospadias</font>===<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
===<font color=lightskyblue>Klinefelter</font>===<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
===<font color=lightskyblue>Peyronie's Disease</font>===<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=lightskyblue>Also related include;</font><br />
|- <br />
| <font color=dodgerblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=slateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=slateblue>True Hermaphroditism</font>==== <br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| <font color=slateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=darkorchid>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1573372014 Group Project 92014-10-23T11:38:02Z<p>Z3415716: /* Female Genital Development */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
==Historic Finding==<br />
===Female Genital Development===<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
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><br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
====The hymen====<br />
<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>. <br />
<br />
====The clitoris====<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
==Male Genital Development==<br />
===The Prostate===<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
===Testicular descent===<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref>. 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 <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
===The prepuce===<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divided the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
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. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout their life. <br />
<br />
===FEMALE===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia<br />
<br />
====Mullerian agenesis====<br />
<br />
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>. <br />
<br />
====Vaginal agenesis====<br />
<br />
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>. <br />
<br />
====Turners syndrome====<br />
<br />
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>.<br />
<br />
====Swyer Syndrome====<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| '''Polycystic Ovarian Syndrome'''<br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
===<font color=lightskyblue>Cryptorchidism</font>===<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
===<font color=lightskyblue>Hypospadias</font>===<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
===<font color=lightskyblue>Klinefelter</font>===<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
===<font color=lightskyblue>Peyronie's Disease</font>===<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=lightskyblue>Also related include;</font><br />
|- <br />
| <font color=dodgerblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
|}<br />
<br />
===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=slateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=slateblue>True Hermaphroditism</font>==== <br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| <font color=slateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=darkorchid>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
<br />
==References==<br />
<br />
<references/></div>Z3415716https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_9&diff=1573162014 Group Project 92014-10-23T11:33:40Z<p>Z3415716: /* Female Genital Development */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Genital=<br />
<br />
==Historic Finding==<br />
==Female Genital Development==<br />
<br />
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><br />
<br />
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 while others disproven. The research themes and theories found in historical literature can be divided into three groups. <ref name=PMID13475148><pubmed>13475148</pubmed></ref><br />
<br />
# Those who researched the origin of the vagina and inner genital organs, concluding the origin to be the Mullerian duct.<br />
# Those who focused on the vaginal epithelium, indicating that it arises from part of the Wolffian ducts.<br />
# Those who emphasised the importance of the epithelium of the urogenital sinus in contributing to the vagina.<br />
<br />
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><br />
<br />
[[File:Mullerian ducts development.jpeg|300px|right|thumb|Development of Mullerian Ducts into mature female organs]]<br />
<br />
According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the time frame of 1868 to 1939, concluded that the Mullerian (paramesonephric) ducts, found laterally to the Wolffian ducts, are the original structures of the female reproductive organs (the fallopian tubes, uterus and vagina). 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, and the non-fused upper part of the ducts emerge into the fallopian tubes. At the time it was also already know that it was 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. <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID13230915><pubmed>13230915</pubmed></ref><br />
<br />
===The hymen===<br />
<br />
[[File:Keibel's model of urogenital organs.jpg|400px|right|thumb|Model depicting the development of the urogenital organs in an eight week old foetus, illustrated by Franz Keibel in 1896.]]<br />
<br />
Throughout history the categorisation of the hymen has been debated, with academics either considering this feature as part of or separate to the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. Studies carried out in the 19th century concluded that a hymen was always present in a foetus at full term, even in those with genital disorders such as atresia vaginae, absence or incomplete development of the vagina <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The origin of the hymen has been proposed since the 1800s, with model illustrations from anatomists and embryologists such as Franz Keibel <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. The origin is said to be from the junction of the lower part of the Mullerian duct and the superior portion of the urogenital sinus, an area referred to as the Mullerian eminence <ref name=PMID13475148><pubmed>13475148</pubmed></ref>. The developed hymen has been mentioned in numerous historical published articles, describing the membranous structure as a protruding vertical slit, circular or oblong, and composed of connective tissue and vaginal epithelium <ref name=PMID13475148><pubmed>13475148</pubmed></ref> <ref name=PMID17232227><pubmed>17232227</pubmed></ref> <ref name=PMID17232036><pubmed>17232036</pubmed></ref>. <br />
<br />
===The clitoris===<br />
<br />
The clitoris, a female organ found anterior to the urethral opening, at the junction of the labia minora, is the most sensitive sexual organ of a female as has been researched for many centuries. In 1896 Berry Hart examined the foetal development of the gland, describing the gland clitorides in the early foetus as bulbous and entire. He proposed that the cells of this gland are epithelial in nature and that a horse-shoe like structure is found surrounding the gland, the prepuce. The prepuce and the clitoris is said to separate at the third month of development when the epithelial cells begin desquamating <ref name=PMID17232227><pubmed>17232227</pubmed></ref>. <br />
<br />
The nerve supplying the clitoris, dorsalis clitoridis or dorsal nerve of clitoris, was studied by Yamada in 1950. The nerve was described as containing thick sensory fibres <ref name=PMID14884176><pubmed>14884176</pubmed></ref>. Pacinian corpuscles were also found along the nerve and in the clitoris, however they were simply branched or unbranched. Furthermore, it was discovered that degeneration of the nerve fibre occurs during the foetal period as the intraepithelial nerve fibres in the 10th month foetus was poorer in comparison to the 7th month foetus. <ref name=PMID14884176><pubmed>14884176</pubmed></ref><br />
<br />
==Male Genital Development==<br />
===The Prostate===<br />
<br />
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><br />
<br />
{| <br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| 1543 ||bgcolor="FCFCFC"| Andreas Vesalius published the first illustrations of the prostate gland.<br />
|-<br />
|bgcolor="F5FAFF"| 1674 ||bgcolor="F5FAFF"| Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.<br />
|-<br />
|bgcolor="FCFCFC"| 1901 ||bgcolor="FCFCFC"| Pallin thoroughly investigated the prostate gland and its origin.<br />
|-<br />
|bgcolor="F5FAFF"| 1912 ||bgcolor="F5FAFF"| 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.<br />
|-<br />
|bgcolor="FCFCFC"| 1920 ||bgcolor="FCFCFC"| 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1954 ||bgcolor="F5FAFF"| Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.<br />
|-<br />
|bgcolor="FCFCFC"| 1983 ||bgcolor="FCFCFC"| McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.<br />
|}<br />
<br />
===Testicular descent===<br />
<br />
Testicular descent, which beings during the early foetal period, has been an area of research from the 1700s, when anatomists such as John Hunter began to notice the origin and development of the testicles and their location <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref> <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections on both human and animal foetuses during the eighteenth and nineteenth centuries <ref name=PMID4380018><pubmed>4380018</pubmed></ref> <ref name=PMID4379058><pubmed>4379058</pubmed></ref>, then enhancing with endocrinological discoveries during the twentieth century <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID17104926><pubmed>17104926</pubmed></ref>.<br />
<br />
Many theories were proposed and revoked since the discovery of testicular descent. One of the earliest debate was between John Hunter and Albretch von Haller, who concluded that the foetal testis is intra-abdominal and the processus vaginalis remains opened, contrary to the results published by Hunter <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
Hunter’s description of the gubernaculum as a vascular and fibrous foetal structure and the covering cremaster muscle led to further research and numerous theories <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref> <ref name=PMID14172018><pubmed>14172018</pubmed></ref>. Over the years academics mainly disputed the importance of the gubernaculum and the cremaster muscle in both the first and second phase of testicular descent <ref name=PMID14172018><pubmed>14172018</pubmed></ref>.<br />
<br />
With the introduction of endocrinology and hormonal testing, the previous historical theories were tested on a cellular basis <ref name=PMID17104926><pubmed>17104926</pubmed></ref>. It has been evidently proven, mainly utilising animal populations, that androgens are important in the descent <ref name=PMID6652187><pubmed>6652187</pubmed></ref>, however it is unclear if it is important in both stages <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref>. 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 <ref name=Martyn1991><Martyn P. L. Williams, John M. Huston '''The history of ideas about testicular descent'''. Pediatric Surgery International: 1991, 6(3):180-184></ref>.<br />
<br />
{|<br />
|-<br />
|bgcolor="lightskyblue"| '''Date''' ||bgcolor="lightskyblue"| '''Description'''<br />
|-<br />
|bgcolor="FCFCFC"| Late 1700s ||bgcolor="FCFCFC"| Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles. <br />
|-<br />
|bgcolor="F5FAFF"| 1770 ||bgcolor="F5FAFF"| Palleta emphasised that the cremaster muscle was under developed during the time of descent and thus is not an important factor in the process.<br />
|-<br />
|bgcolor="FCFCFC"| 1771 ||bgcolor="FCFCFC"| Pancera considered the cremaster muscle as the key factor in testicular descent.<br />
|-<br />
|bgcolor="F5FAFF"| 1801 ||bgcolor="F5FAFF"| Lobsetin confirmed the findings of Pancera, further highlighting the cremaster muscle. Also suggested that the second phase of testicular descent is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth.<br />
|-<br />
|bgcolor="FCFCFC"| 1841 ||bgcolor="FCFCFC"| Curling published his work on the structure of the gubernaculum and the cremaster muscle, concluding that that muscle was important in descending the testis, and 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.<br />
|-<br />
|bgcolor="F5FAFF"| 1847 ||bgcolor="F5FAFF"| Weber highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.<br />
|-<br />
|bgcolor="FCFCFC"| 1849 ||bgcolor="FCFCFC"| The theory that descent into the scrotum occurs due to the weight of the testes and muscle associated is introduced.<br />
|-<br />
|bgcolor="F5FAFF"| 1856 ||bgcolor="F5FAFF"| Cleland performed dissections on foetal specimens finding that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. He presented the theory that the cremaster was not the primary source of descent, second to the gubernaculum.<br />
|-<br />
|bgcolor="FCFCFC"| 1888 ||bgcolor="FCFCFC"| Lockwood proposed 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.<br />
|-<br />
|bgcolor="F5FAFF"| Early 20th Century ||bgcolor="F5FAFF"| Introduction of endocrinology and hormonal testing leading to the theory that the male androgen, controlled by the pituitary gland, influence testicular descent.<br />
|}<br />
<br />
===The prepuce===<br />
<br />
The development of the prepuce is another genital process that takes place during the foetal phase. It was through medical cases, such as diphtheria <ref name=PMID19971144><pubmed>19971144</pubmed></ref>, presence of adhesions <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, and the most common, congenital phimosis <ref name=PMID20764862><pubmed>20764862</pubmed></ref>, that this penile feature become of interest in medical literature.<br />
<br />
Studies from the late 19th century to early 20th century began to focus on the prepuce and discovered the stages of growth and differentiation <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. Conflicting results were obtained throughout this period, with some experiments concluding that this epithelial superficial layer was present and with foetal development, it began degeneration and separation from the enlarging glans, whereas others forwarded the theory that it was the prepuce that eventually grew over a previously exposed penile glans, a theory that was more widely supported <ref name=PMID17104576><pubmed>17104576</pubmed></ref>.<br />
<br />
The initial tests carried on the development of the prepuce were able to divided the progress into stages <ref name=PMID20764862><pubmed>20764862</pubmed></ref> <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The stages were ultimately based on the gestational age of the foetus, however this was expressed in terms of the caudal-rostral length of the foetus <ref name=PMID17104576><pubmed>17104576</pubmed></ref>. The construction of stages became accepted as various academics, without collaboration, obtained similar results, organised in a similar method <ref name=PMID20764862><pubmed>20764862</pubmed></ref>. <br />
<br />
This step-theory explained that each stage correlated to further growth of the prepuce until the glans was completely covered. It also described its origin and highlighted the desquamating and degenerating process of the ectodermal tissue, resulting in the prepuce not being entirely attached to the glans and allowing retraction <ref name=PMID17104576><pubmed>17104576</pubmed></ref>, a process absent in males with adherent prepuce <ref name=PMID20764862><pubmed>20764862</pubmed></ref>.<br />
<br />
==Abnormalities==<br />
<br />
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. <br />
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. All abnormalities may have a specific approach to deal with each case, however management strategies are combined with the addition of psychological treatment. It is implemented to allow parents and patients to deal with any distress or issues that these disorders may cause throughout their life. <br />
<br />
===FEMALE===<br />
<br />
[[File:Uterus and Vagina Abnormalities.jpg|400px|right|border|thumb|Abnormalities of the Uterus and Vagina]]<br />
Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;<br />
<br />
*double uterus and double vagina<br />
*double uterus<br />
*bicornate uterus<br />
*septated uterus<br />
*unicornate uterus<br />
*cervical atresia<br />
<br />
====Mullerian agenesis====<br />
<br />
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>. <br />
<br />
====Vaginal agenesis====<br />
<br />
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>. <br />
<br />
====Turners syndrome====<br />
<br />
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>.<br />
<br />
====Swyer Syndrome====<br />
[[File:WomenwithSwyerSyndrome.png|300px|thumb|border|right|Comparison of measures among women with Swyer Syndrome and women without it. The measures are uterine cross sectional areas (UXA).]]<br />
<br />
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. <br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| '''Polycystic Ovarian Syndrome'''<br />
[[File:PolycysticOvarianSyndrome.jpg|300px|right|thumb|The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome]]<br />
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. <br />
Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. <br />
The treatments implemented depend on the clinical manifestations each patient develops. <br />
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>.<br />
|}<br />
<br />
<br />
===<font color=dodgerblue>MALE</font>===<br />
<br />
===<font color=lightskyblue>Cryptorchidism</font>===<br />
<br />
[[File:Cryptorchidism.jpg|350px|right|thumb|The sites where Cryptorchidism may occur]]<br />
<br />
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>. <br />
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. <br />
Following is the inguinoscrotal stage that requires testicular androgens <ref><pubmed>18032558</pubmed></ref>.<br />
<br />
Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. <br />
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>.<br />
<br />
===<font color=lightskyblue>Hypospadias</font>===<br />
<br />
[[File:Hypospadia classifications.jpg|350px|right|thumb|Different locations of the Meatus in Hypospadia]]<br />
<br />
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. <br />
<ref><pubmed>24936573</pubmed></ref><br />
Treatment <br />
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><br />
<br />
===<font color=lightskyblue>Klinefelter</font>===<br />
[[File:Klinefelter.jpg|300px|right|thumb|Characteristics presented among men with Klinefelter Syndrome.]]<br />
<br />
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. <br />
The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. <br />
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>.<br />
<br />
===<font color=lightskyblue>Peyronie's Disease</font>===<br />
<br />
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>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <font color=lightskyblue>Also related include;</font><br />
|- <br />
| <font color=dodgerblue>''Chordee'''</font><br />
Chordee is an abnormality in the development of the penis, it may occur in conjunction with hypospadias. The disorder results in the curvature of the penis and erectile dysfunction <br />
<ref>http://www.webmd.com/men/guide/chordee-repair-treatment</ref>. The causes are evident among males with hypospadias, however in cases where hypospadia is absent the causes are not known and haven’t thus far been identified. The condition occurs in about 4-10% of males. There are a variety of methods used to treat the curvatur these include; skin bridge and frenular release, skin release transfer, pitation technique, dermal grafts, corporal rotation and penile disassembly and finally penile torsion. Any surgical techniques are recommended at the first year of life. Through the treatment surgeons focus on ensuring the urethral plate and neurovascular structures are preserved <ref><pubmed>21805016</pubmed></ref>.<br />
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===<font color=blueviolet>BOTH</font>===<br />
<br />
====<font color=slateblue>Congenital adrenal hyperplasia</font>====<br />
<br />
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>.<br />
<br />
====<font color=mediumslateblue>Hydrocele</font>====<br />
<br />
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>.<br />
<br />
====<font color=slateblue>True Hermaphroditism</font>==== <br />
True hermaphroditism also known as ovo-testicular disorder of sexual differentiation or ‘true gonadal intersex’, is a rare intersex abnormality in which an individual has both male and female genitalia. The gonads are asymmetrical with ovarian and testicular differentiation combines as ovo-testis or separately on either side <ref><pubmed>3418019</pubmed></ref>. The individual may have XX, XY or both chromosome types. Treatment involves reconstructive surgery upon each individual case having to choose a gender, this decision has short and long-term consequences. Each case is determined differently as there are many factors to consider when choosing the gender identity. This comprises a long process providing parents with support and guidance in making their decision <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001669.htm</ref>.<br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Also related include;<br />
|- <br />
| <font color=slateblue>Kallmann syndrome</font><br />
<br />
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>.<br />
<br />
====<font color=darkorchid>Hypogonadotropic hypogonadism</font>====<br />
<br />
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>.<br />
|}<br />
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==References==<br />
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<references/></div>Z3415716