2014 Group Project 4: Difference between revisions

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====Swyer Syndrome====
====Swyer Syndrome====


Swyer syndrome (46 XY, gonadal dysgenesis) is a type of hypogonadism disorder in which an individual from birth is phenotypically female with unambiguous genital form and normal mullerian structures. The condition is usually observed during adolescence since the gonads have no hormonal or reproductive function amenorrhea occurs and puberty is delayed (1).  It has been found that 10-20% of women with this condition have a deletion of the SRY gene in the DNA-binding site.  In other cases the SRY gene is normal however mutations may present in different determining factors.  Managing the syndrome consists of hormone replacement therapy (including estrogen and progesterone), to ensure bone mineral density is maintained and uterine size and shape is improved (2).  
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 (1).  It has been found that 10-20% of women with this condition have a deletion of the SRY gene in the DNA-binding site.  In other cases the SRY gene is normal however mutations may present in different determining factors.  Managing the syndrome consists of hormone replacement therapy (including estrogen and progesterone), to ensure bone mineral density is maintained and uterine size and shape is improved <ref><pubmed>18410658</pubmed></ref>.


====Swyer Syndrome====
====Swyer Syndrome====

Revision as of 07:26, 21 October 2014

2014 Student Projects
2014 Student Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7 | Group 8
The Group assessment for 2014 will be an online project on Fetal Development of a specific System.

This page is an undergraduate science embryology student and may contain inaccuracies in either description or acknowledgements.

Genital

System Development

(NB: having formatting issues trying to put the following information into a table, an attempt at the table is included below)

  • the initial stages of genital development are indifferent, both males and females are anatomically identical until morphological changes occur beginning at week 7
  • males and female changes are determined by the chromosomal sexual differentiation which occurs at fertilisation
  • initial stages of gonadal development begins during the fifth week of development. First change is a thickened area of mesothelium on the medial side of the mesonephros [primitive kidney]
  • this proliferation + underlying mesenchyme produces a bulge known as the GONADAL RIDGE
  • finger like epithelial chords [gonadal chords] grow into underlying mesenchyme
  • This who structure is referred to as an indifferent gonad
  • indifferent gonad consists of an external cortex and internal medulla
  • in embryos with an XX sex chromosome, the cortex of the indifferent gonad progresses to developing into an ovary
  • Conversely, embryos with an XY chromosome, the medulla of the indifferent gonad progresses into a testes
  • CHROMOSOMAL SEX DETERMINATION - the indifferent gonads differ after the seventh week by the presence the SRY gene which produces the TESTES DTEREMINING FACTOR on the short arm of the Y Chromosome. Under this influence, the gonadal chords differentiate to somniferous cords expression of Sox9 and Fgf9
  • once the gonad that develops [ovary or testes] then determines the type of sexual and genital differentiation which occurs
  • fetal testes produce testosterone, dihydrotestosterone and anti mullerian hormone
  • TESTES DEVELOPMENT -- insert picture here

- seminferous chords --> rete testes - development of dense tunica albiguinea- enlarging testes separate from the degenerating mesonephros to form the somniferous tubules, tubuli, recti and rate testis - seminferous tubules --> interstitial cells [leydig cells] which produce androgens - insert diagram showing the production of androgens (testosterone, dihydrotestosterone and antimullerian hormones (sertoli cells) )

  • DEVELOPMENT OF OVARIES

- ovary not identifiable until 10th week - gonadal chords aren't prominent in developing ovary but extend to medulla and form the rate ovary OOGENESIS DIAGRAM

  • DEVELOPMENT OF GENITAL DUCTS
  • fifth and sixth weeks - mesonephric ducts (wolfing duct) and paramesonephric ducts (mullein ducts)
Weeks M A L E F E M A L E
FERTILIZATION both male and female are same at this point- only difference is presence of XY or XX chromosome
WEEKS 1-7 GENITAL DEVELOPMENT IS UNDIFFERENTIATED. gonads derived from:
  • mesothelium lining posterior abdominal wall
  • underlying mesenchyme
  • primordial germ cells.
WEEK 5 development of indifferent gonads
  • thickened area of mesothelium develops on medial side of mesonephros [primitive kidney]
  • this + proliferation of underlying mesenchyme = gonadal ridge
  • fingerlike epithelial chords = gonadal chords
  • gonad = cortex + medulla
WEEK 8 seminiferous tubules begin to release androgens
WEEK 10 rudimental rete ovarii forms from indifferent gonads
WEEK 12
  • testosterone determining factor induces seminiferous chords from indifferent gonads --> branch to rete testis
  • tunica albiguinea develops
WEEK 16 primordial follicles begin to develop

Genital system development is an extremely interesting area of embryology as it is not until the later stages of embryogenesis (around week 4-6) that sexual differentiation occurs in the fetus, and the sexual organs actually look very similar up until this point, and the formation of the correct sex organs depend really on whether the genital ridge releases Testosterone or oestrogen

<pubmed>24240231</pubmed> <pubmed>24928207</pubmed> <pubmed>24741072</pubmed>

File:Image.jpg
The stages in sexual differentiation of the female and male reproductive system


Related video

Current Research, Models and Findings

Current Research and Findings

Male

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

Development of the male external genitalia, which occurs in the fetal period of development, is androgen dependent and involves epithelial-mesenchymal interactions. Because of these interactions, which are very similar to limb development, research into the development of genital tubercle has utilised similar methods for both processes. A minority of hypospadias cases are a result of the androgenic pathways being impaired and causing this congenital defect. The cell-cell interactions that allow for the development of the male external genitalia are mediated by a broad range of signaling molecules and growth factors such as fibroblast growth factors (FGFs), Sonic hedgehog (SHH) and bone morphogenetic proteins (BMPs). Such signaling and growth factors are downstream of androgen receptor signaling and an understanding of the mechanisms that underlie normal penile development during the fetal period, will lead to a deeper understanding of the aetiology of hypospadias.[1]


Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent. (2013)[2]

<pubmed>24030937</pubmed>

The differentiation of the gonads into male or female begins around week 6-8 and is linked to the sex-determining region of the Y chromosome. The formation and descent of the testis is determined by a number of hormones which are:

  • Anti-mullerian hormone (AMH) - produced by sertoli cells, which acts on the mullerian ducts.
  • Testosterone - produced by the fetal leydig cells, which ensures differentiation of wolffian ducts as well as the terminal phase of descent of the testis.
  • Insulin like factor 3 (INSL3) - is produced by the differentiated fetal leydig cells, which are involved in the transabdominal phase of descent.
  • Prostaglandins are also believed to be involved in the differentiation of the male genital tract and testis.

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

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

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

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

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

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


FEMALE



Female External Genitalia on Fetal Magnetic Resonance Imaging (2011)[3]

<pubmed>21584884</pubmed>

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

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

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

The results are important as they demonstrate the MRI’s potential to be used in adjunct to ultrasound in order to assist in the diagnosis of certain genital abnormalities, such as hypospadias or micropenis. This is necessary as such conditions can mimic female external genitalia and so hypospadias especially should be determined on the basis of parallel labial lines and not exclusively on the direction of the genital tubercle.[4]

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




In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development (2011)[5]

<pubmed>21584884</pubmed>

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

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

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

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




Fibrillin-3 in the Fetal Ovary: Can it Contribute to Polycystic Ovary Syndrome? (2012)[6]

<pubmed>23585338</pubmed>

Fibrillin-3 contributes to microfibril formation within the extracellular matrix of many mammals and is predominantly expressed during fetal life[7]. The ovary continuously remodels its stroma in order to accommodate the constantly growing follicles from fetal life through to adult life, resulting in a continuously changing extracellular matrix, and therefore, fibrillin-3. Recent studies have discovered a linkage between an allele of the fibrillin-3 gene and polycystic ovary syndrome (PCOS), where hyperandrogenic interactions result in an enlarged and hyperstromal ovary with follicles that fail to mature and get released.

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

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

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




Expression of miRNAs in Ovine Fetal Gonads: Potential Role in Gonadal Differentiation (2011)[8]

<pubmed>21223560</pubmed>

Genotype of sex is determined at the time of fertilisation, where a sperm carrying X or Y genetic material will fertilise an XX ova. This genotype that results then determines whether the genital ridge in the embryonic period will develop into the fetal testis (XY) or fetal ovaries (XX). The pathway involving testicular development includes a fine balance between genes that promote testis development and simultaneously genes that prevent ovarian development [9]

Some critical genes involved in the testicular and ovarian pathways include:

  • SRY gene (sex-determining region of the Y-chromosome) [10]
  • Rspol gene (R-spondin homolog)[11]
  • Wnt4 – wongless-related MMTV integration site 4)[12]
  • Beta-catenin[11]

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.[11]

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

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

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

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




Other current research and findings:

  • A recent study investigated the ability of in vitro cultures of female fetal mouse gonads to subsequently develop in vivo. It demonstrated that premeiotic germ cells in fetal gonads possessed the capability to develop into mature oocytes using this method. [13]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). [14]

Current Models

Current research uses mouse models and observes the development of their external genitalia, especially their penile development, which initially appears to be different to human development. However, more microscopic inspection shows that mice have very similar external genitalia and are therefore appropriate animal models for observing such fetal development. As a result, mutant mouse models can effectively be used in future research to observe molecular mechanisms underlying hypospadias and their aetiology. [1]

Also, when observing the morphology and cell biology of the developing testis, it is important to note that much of the research conducted on the subject involved the use of mouse models as a result of a lack of human subjects. It can be assumed that events in the human embryo correspond to the same events in the mouse embryo, however there are some differences between the time course of certain events and anatomy.[15]

External genitalia current model.jpg

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

Embryonic Period – fertilisation to end of 8th week (embryonic age) = AMBISEXUAL STAGE
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. The urogenital membrane degenerates to allow communication between the urogenital sinus and amniotic cavity.




MALE MODEL FEMALE MODEL
Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION
  1. 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).
  2. 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.
  3. 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.
  4. 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).
  5. 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.
  6. 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.[1]
Fetal Period – from 8th week of development = SEXUAL DIFFERENTIATION
Cross section of genital tubercle male.jpg
hfflffluftuftlufulfy
  • Hypospadias result from failure of formation or fusion of the urethral folds and this is the focus of current research.
  • The elongating phallus is covered externally by ectoderm that will eventually give rise to the penile epidermis.
  • Urethral epithelium has endodermal origins and the majority of the penis is derived from mesodermal cells.
  • During development, the mesoderm separates into connective tissues and dermis.
  • Dense areas of mesenchymal cells form within the shaft of the penis with the most superficial dense bodies forming the thick connective tissue capsule known as the tunica albuginae.
  • Mesenchyme surrounding the urethra forms smooth muscle of the urethral mucosa and submucosa. Erectile tissues such as the corpus spongiosum and corpus cavernosum then surround these two layers.
  • In some species, the mesenchyme of the genital tubercle also forms an os penis, comprised of bone and cartilage.
  • Genital tubercle development involves an outgrowth of somatic tissue from the body surface, similar to the development of the limb.[1]
HFYKDFUFFYLGUP
Anatomical diagram of testes.jpg
Third Row Column 2
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.[1]
  • 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.[1]
HFYKDFUFFYLGUP


Female

  • In females, the genital tubercle will eventually form the clitoris and the genital swellings remain apart and will eventually form the labia majora. The urogenital folds forming the border for the urogenital ostium will eventually form the labia minora in the female, thus forming the vestibule of the vagina. [1]

Future Research

Future research can work to decrease the incidence of hypospadias, which has more than doubled from 1973-2003.

[4] <pubmed>21584884</pubmed> <pubmed>18367374</pubmed> <pubmed>15086026</pubmed> <pubmed>14641326</pubmed> <pubmed>11684660</pubmed> <pubmed>22127979</pubmed> <pubmed>24631756</pubmed> <pubmed>23192465</pubmed>

Historic Finding

Female Genital Development

Female genital system development has been a subject of many historical literatures dating to the 17th century. Certain research articles aimed to focus on the female genital system as a whole, whereas others delved into specific areas such as the epithelium or specific organs such as the vagina. With the development of technology and research skills over the years, the understanding of the female genital system has improved substantially from the understanding of origin, the structure of the organs and even the nomenclature of the system. [16] [17]

Majority of the findings lead to a proposal of a theory of that organ or the system, with some of these theories still accepted today and others disproven. The research themes and theories found in historical literature can be divided into three groups. [16]

  1. The origin of the vagina and inner genital organs is the Mullerian duct.
  2. Part of the Wolffian ducts give rise to some or all of the vaginal epithelium.
  3. Contribution of the vagina is from the epithelium of the urogenital sinus.

Prior to the discovery of the importance of the Mullerian ducts, the origin of the vagina was considered to be the urogenital sinus. It was not until later that century, roughly in 1864 that the Mullerian ducts and their fusion pattern and foetal development was introduced. This realisation was later supported by many academics in their published work, particularly in the early 1900s (1912, 1927, 1930, and 1939). [16]

Development of Mullerian Ducts into mature female organs

According to the works of the early embryologists Thiersch, Banks, Felix, Bloomfield & Frazer, Hunter and von Lippmann, all who published within the timeframe of 1868 to 1939, concluded that the mullerian (paramesonephric) ducts, found laterally to the wolffian ducts, are the original structures of the female reproductive system. Female sexual organs (the fallopian tubes, uterus and vagina) originate from the mullerian ducts, which differentiates within the foetal developmental phase. Initially the foetus contains two mullerian ducts, however by the ninth week, fusion of the lower portion of the ducts is complete, creating the fundamental structure of the uterus and the vagina, however the these two organs are not continuous with the vagina being solid. The non-fused upper part of the ducts emerge into the fallopian tubes. It is not until the fourth and fifth month of development that the uterus becomes continuous with the vagina, with both organs developing a hollow lumen. The muscular layers of the uterus is also present by this stage. The cervix begins to form within the fifth month in between the continuous vagina and uterus. Also within the same month, the formation of the hymen occurs. The hymen is described as a pouting vertical slit and represents the remains of the mullerian eminence. [18] [19]


Male Genital Development

The Prostate

The mechanism behind prostate foetal development and modern understanding has been continuously reshaping since the 16th century. Throughout this period, various anatomical classifications have been proposed via dissection procedures, hormone responses and histological methods, attributing to the current understanding of prostate development. The rate of research into the structure and development of the prostate steeply increased in the 20th century, where each decade saw an improvement of the understanding of the development of the gland. [20] [21]

Date Description
1543 Andreas Vesalius published the first illustrations of the prostate gland.
1674 Gerard Blasius introduced the gland as a structure encircling the neck of the bladder.
1901 Pallin thoroughly investigated the prostate gland and its origin.
1912 Oswald S Lowsley constructed the first detailed drawing of the anatomy of the prostate by dissecting and researching on a 13-week old foetus, 30-week old foetus, and one at full-term. He proposed the concept of separating the gland into five lobes, and that the prostate originates from the urogenital sinus.
1920 Johnson reshaped the anatomical illustration after being unable to replicate Lowsley’s results. He preserved the use of the term ‘lobe’ in describing the prostatic divisions.
1954 Three concentric regions became the accepted categorising model of the prostate, as proposed by Franks.
1983 McNeal organised the gland into prostatic zones, rejecting the lobe and concentric regions theory.

Testicular descent

Testicular descent begins during the early foetal period, 8-10 weeks, and takes approximately 5 weeks for the testes to reach the inguinal region. The second phase of descent, when the testes reach the scrotum, is not complete until the 35th to 40th week. The mechanisms behind testicular descent has been debated for at least two centuries, beginning with anatomical dissections during the eighteenth and nineteenth centuries, then enhancing with endocrinological discoveries during the twentieth century.

The Scottish surgeon and anatomist, John Hunter, first documented the gubernaculum and the location of the male foetal testicles in the late 1700s. In his research, Hunter claimed that descent occurred during the 8th foetal month and was directed by the gubernaculum testis, a ligament attaching the foetal testis to the abdominal wall and the scrotum. He further proposed that the processus vaginalis closes subsequent to the decent of the testis. This is contrary to the findings of Albrecht von Haller who illustrated that foetal testis is intra-abdominal and the processus vaginalis is not closed.

Hunter described the gubernaculum as a vascular and fibrous foetal structure covered by the cremaster muscle, a muscle of unknown function. This led to more research focused on the cremaster muscle. In 1777, Palletta questioned the importance of the cremaster muscle because of its under developed state during the time of descent. This however did not stop Pancera, who in the following year, considered the muscle as the key factor in the process. Pancera’s conclusion was confirmed by Lobsetin in 1801.

The second phase of testicular descent to the scrotum has also seen many theories. Lobsetin suggested that this phase is complete by birth, influenced by respiration and the increased abdominal pressure that occurs at birth. The concept of increased abdominal pressure was reiterated by Robin in 1849, however he also introduced the theory that descent into the scrotum occurs due to the weight of the testes and muscles associated. Both Lobsetin and Robin’s work was refuted by Weber who highlighted the processus vaginalis, an embryonic pouch of peritoneum, as the main force of the migration.

In 1841, Curling detailed the structure of the gubernaculum and the cremaster muscle. Curling believed that during the foetal period, the cremaster muscle was important in descending the testis, however subsequent to the descent, the fibres of the muscle everted resulting in it’s new functions of elevating, supporting and compressing of the developed testis. The eversion of the muscle fibres were denied by Cleland, who in 1856 performed dissections on foetal specimens ranging from 5-6 gestational months old. In his experiment he found that the foetal gubernaculum did not directly attach the testicle to the scrotum and was only present in the inguinal wall. In terms of the testicular descent process, Cleland presented a similar theory as Weber, in terms that the cremaster was not the primary source of descent, second to the gubernaculum, that led the descent of the testes. In 1888, Lockwood published a completely unique theory claiming that the testes remained stationary and that it was in fact the surrounding structures that developed, resulting in the changing of the testicular location. Lockwood’s hypothesis was disagreed on by many anatomists and embryologists.

With the introduction of endocrinology and hormonal testing, the previous theories were tested on a cellular basis. Male androgen, controlled by the pituitary gland, was the first hormonal theory believed to influence testicular descent. It has been evidently proven that androgens are important in the descent however it is unclear if it is important in both stages. It is currently accepted that testosterone influences the gubernaculum during the second phase in which the testes reach the scrotum, however the exact method is currently debatable. The first phase theories are under high scrutiny, with theories ranging from the development of the gubernaculum and hormones such as the Mullerian inhibiting substance. [4]

References

4. Martyn P. L. Williams, John M. Huston The history of ideas about testicular descent. Pediatric Surgery International: 1991, 6(3):180-184 The history of ideas about testicular descent

<pubmed>18462432</pubmed> <pubmed>17232227</pubmed>

Abnormalities

We discuss both male and female genital abnormalities internally or externally, that may occur during fetal development. The abnormalities have been identified as disorders of sex differentiation(DSD), associated with congenital conditions in the atypical development of chromosomal, gonadal or phenotypical sex [22], [23].

The content will cover most common abnormalities and then also the rare cases. Most genital abnormalities have a high risk in affecting fertility of both sexes. Currently there are a variety of methods applied to ensure that infertility can be treated and this will be mentioned.

FEMALE

Abnormalities of the Uterus and Vagina

Abnormalities of the Uterus and vagina are cause by inadequate fusion or regression of Mullerian duct may result as the following;

  • double uterus and double vagina
  • double uterus
  • bicornate uterus
  • septated uterus
  • unicornate uterus
  • cervical atresia

Mullerian agenesis

Mullerian agenesis also known as ‘Mayer-Rokitansky-Kuster-Hauser’ syndrome, vaginal agenesis or Mullerian aplasia, is presented in the absence of the uterus or vagina or in some case even both. This is due to the unsuccessful development of the Mullerian ducts which then causes certain parts of the reproductive system to be underdeveloped. It is present in 1 of 4000-10 000 women. This condition also uses dilation therapy and following the neovaginal approach with the reconstruction of the vagina in its treatment strategies [24].

Vaginal agenesis

Vaginal agenesis is a rare condition involving the underdevelopment of the vagina. It is commonly cause by a combination of Rokitansky (Mullerian agenesis) and androgen insensitivity syndromes [25]. 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 [26].

Turners syndrome

A chromosomal disorder occurring among women due to the absence of the whole or part of the sex chromosome (X). The condition is characterized by short stature, cardiovascular malformations, amenorrhea and estrogen insufficiency [27]. It is prevalent in 1 of 2000 live births among females [28]. 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 [29].

Swyer Syndrome

Swyer syndrome (46 XY, gonadal dysgenesis) is a type of hypogonadism disorder in which an individual from birth is phenotypically female with unambiguous genital form and normal mullerian structures. The condition is usually observed during adolescence since the gonads have no hormonal or reproductive function amenorrhea occurs and puberty is delayed (1). It has been found that 10-20% of women with this condition have a deletion of the SRY gene in the DNA-binding site. In other cases the SRY gene is normal however mutations may present in different determining factors. Managing the syndrome consists of hormone replacement therapy (including estrogen and progesterone), to ensure bone mineral density is maintained and uterine size and shape is improved [30].

Swyer Syndrome

Swyer syndrome (46 XY, gonadal dysgenesis) is a type of hypogonadism disorder in which an individual from birth is phenotypically female with unambiguous genital form and normal mullerian structures. The condition is usually observed during adolescence since the gonads have no hormonal or reproductive function amenorrhea occurs and puberty is delayed [31]. It has been found that 10-20% of women with this condition have a deletion of the SRY gene in the DNA-binding site. In other cases the SRY gene is normal however mutations may present in different determining factors. Managing the syndrome consists of hormone replacement therapy (including estrogen and progesterone), to ensure bone mineral density is maintained and uterine size and shape is improved [32].

Also related include;

Polycystic Ovarian Syndrome

The Female reproductive system showing a normal ovary compared to one that is affected by Polycystic Ovarian Syndrome

A metabolic endocrine disorder with an immense variety of phenotypes presented. The disorder has an imbalance in female sex hormones and a resistance to insulin. Most importantly it affects the female reproductive system, with issues associated with infertility and menstrual irregularities. The treatments implemented depend on the clinical manifestations each patient develops. Insulin-sensitizing agents are among the treatments used these include Metformin, Rosiglitazone and Piglitazone all have shown to be effective [33].

MALE

Cryptorchidism

The sites where Cryptorchidism may occur

Involves the absence of both or single testis to descend into the scrotum, the testes can be ectopic, incompletely descended, absent or atrophic. It is possible that sometimes the cryptrodism may be spontaneously corrected by 3 months of age. The abnormality can occur as a result of a number of factors including maternal, genetic or environmental [34]. 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 [35].

Treatment includes human chorionic gonadotropin or gonadotroping-releasing hormones, these are not the most beneficial or advised approach. Surgical repair is intended to apply the safest and least invasive methods, focusing on repositioning the undescended testicle/s to their normal position in the scrotum. Such surgeries are recommended in early life and have proved to be most effective, with 75%+ success. The therapy used to relocate the testis into the scrotum is known as ‘Orchiopexy’, others include one-stage Fowler Stephens and two-stage FS Orchidopecy. However there are concerns with long-term effects which include infertility and testicular cancer later in life as a result of the procedure [36].

Hypospadias

In males the most common congenital malformation of the external genitalia is hypospadias, it’s also the second most common developmental disorder. It occurs due to the midline fusion of the male urethra, as a result the urethral meatus is misplaced. There are several sites where this abnormality may occur: granular, penile, penoscrotal, scrotal and perineal. [37] Its believed that genetic factors contribute to the presence of the disorder, however endocrine and environmental factors are also of significance. [38] Treatment The surgical methods currently used to treat distal hypospadias, include tabularized incised plate and meatal advancement and glansplasty intergrated repair. For proximal forms two staged procedures are employed. [39]

Klinefelter

Klinefelter is a genetic disorder caused by the addition of an X chromosome among males (47, XXY, XXY,XXXXY, XXYY), due to the inability of the extra chromosomes to detach throughout meiosis. It is believed to have an origin from either parent. The abnormality has a wide range of phenotypic variations, that typically include infertility, small testes, gynecomastia and hypergonadotropic hypogonadism [40]. An early diagnosis is important in order for treatment to be commenced right away. The treatment implemented involves Testosterone replacement therapy, which assists in easing some of the features, although infertility is still an issue. The fertility options consist of IVF, where males undergo testicular sperm extraction, cryopreservation of sperm containing semen or testicular tissue during adolescence [41].

Peyronie’s Disease

The acquired disease occurs due to fibrotic plaque formations in the tunica albuginea of the penis. This leads to sexual dysfunction, a loss in penile flexibility, shortening and penile malformations [42]. 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 [43]. 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 [44].

BOTH

Congenital adrenal hyperplasia

The condition is caused by a deficiency in 21-Hydroxylase, a genetic disorder of steroidogenesis. Occurs due to mutations in genes that encode enzymes that take part in adrenal steroid synthesis therefore there is a loss of function [45]. 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 [46]. 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 [47]. Among males symptoms aren’t present at birth a side from possible penile enlargement and slight hyperpigmentation [48]. Generally male patients also require the administration of glucocorticoid and mineralocorticoid therapies [49].

Hydrocele

Hydrocele occurs when the space between parietal and visceral layers of tunica vaginalis accumulates an abnormal amount of serous fluid. Normally caused by an imbalance in the processes of production and reabsorption of fluid or varicocelectomy. To manage the condition treatments focus on ensuring draining any excess fluid and inhibiting reaccumulation. Techniques used involve sclerotherapy and hydrocelectomy [50]. 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 [51].


Also related include;

Kallmann syndrome

Kallmann’s syndrome is a heterogenous disease expressed during puberty due to a combination of hypogonadotropic hypogonadism and anosmia. The genetic disease is responsible for infertility and the inability to smell. Seems to have affects on 1 in 10 000 males and 1 in 50 000 females [52]. 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 [53]. In females treatment focuses on maintaining and inducing secondary sex characteristics [54].

Hypogonadotropic hypogonadism

The condition results in a failure to secrete gonadotropin such as luteinizing (LH) and follicular stimulating hormones (FSH), which then reduce the gonadotropin levels [55] . 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 [56].

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