2014 Group Project 4

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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

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File:Image.jpg

The stages in sexual differentiation of the female and male reproductive system

Related video

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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.

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

<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.