During the 5th week, primordial germ cells migrate from the yolk sac along the dorsal mesentery to the mesenchyme of the posterior body wall around the level of T10.
- The arrival of the primordial germ cells in the area of the future gonads signals the mesonephros and adjacent coelomic epithelium to proliferate to form the genital ridges, just medial to the developing mesonephros
During the 6th week, the cells of the genital ridges invade the mesenchyme in the region of the future gonads, forming primitive sex cords
- The primitive sex cords will then invest the germ cells and support their development
- The genital ridge mesenchyme containing primitive sex cords divide into cortical and medullary regions in all embryos, then in the 6th week the courses for males and females differ
At this time, the new paramesonephric (Mullerian) duct forms, lateral to the mesonephric duct.
- They arise by invagination of the coelomic epithelium, from T3 to the posterior developing urogenital sinus
- The caudal tips of the paramesonephric ducts adhere to each other as they connect with the urogenital sinus between the openings of the left and right mesonephric ducts
- The cranial ends open into the coelomic cavity (the future peritoneum)
The development of male genitals is due to the influence of SRY (the sex determining region of the Y chromosome).
SRY induces cells in the medullary region of the primitive sex cords to differentiate into Sertoli cells, and the cortical cells degenerate.
Without SRY, the sex cords differentiate into ovarian follicles.
During the 7th week, the differentiating Sertoli cells organise to form testis cords
- The testis cords will eventually become the seminiferous tubules, canalizing after puberty
- Distal to the presumptive seminiferous tubules the testis cords forms a lumen and differentiate into the rete testis – which will connect to 5 – 12 residual tubules from the mesonephric ducts, representing the efferent tubules
- At this time the testis starts becoming round
- The degenerating cortical sex cords become separated from the coelomic (peritoneal) epithelium by the tunica albuginea
As the developing Sertoli cells differentiate under the influence of SRY, they begin to secrete Mullerian inhibiting substance (MIS).
- MIS causes the paramesonephric (Mullerian) ducts to rapidly regress between 8th – 10th weeks
- The remnants of the paramesonephric duct in men are the testicular appendage and the prostatic utricle
- Female embryos don’t make any MIS, so their paramesonephric ducts don’t regress
In the 9th or 10th week, SRY causes Leydig cells to differentiate from the genital ridge
- Some time between the 8th and 12th weeks, the testosterone from Leydig cells causes the mesonephric duct to transform into the vas deferens
- The most cranial part of the mesonephric duct becomes the epididymal appendage
- The mesonephric duct adjacent to the presumptive testis becomes the epididymis
Prostate embryology
Recall the seminal vesicles sprout from the distal mesonephric ducts, along with the epididymis and vas deferens.
The prostate and bulbourethral glands however develop from the urogenital sinus.
The initial event in prostate development is during weeks 10 – 12, when an outgrowth of solid epithelial cords arises from the urogenital sinus epithelium.
- This prostatic bud growth occurs in a way that the prostatic lobes develop
- As the epithelial cords canalize to form the ducts, two distinct cells types (luminal and basal cells) develop
Circulating androgens play a crucial role in prostate development:
- Cellular responses to circulating androgens are mediated by nuclear androgen receptors activated by either testosterone or dihydrotestosterone (DHT)
- The conversion of testosterone to the more potent DHT by 5 alpha reductase seems important to allow full prostatic development
- Androgen receptors are a requirement for the urogenital sinus to differentiate into the prostate
- There is reciprocal induction interaction between the urogenital sinus mesenchyme and epithelium
Recall from earlier the cloacal membrane is a bilaminar structure, with the intervening mesodermal cells / mesenchyme migrating cranially and medially.
- These migrating mesenchymal cells spread themselves around the cloacal membrane and pile themselves up to from swellings – cloacal folds, on either side of the membrane
- The folds meet anterior to cloacal membrane to form midline swelling – genital tubercle
- When the cloaca divides to anterior urogenital sinus and anorectal canal, the folds become the urogenital folds and anal folds
- A new pair of swellings, the labioscrotal folds, appear adjacent to the urogenital folds
As the genital tubercle elongates in males, a groove appears ventrally – the urethral groove – during the 6th week
- In both sexes an ectodermal epithelial tag is present at the tip of the genital tubercle
- The urethral groove is defined laterally by urethral folds, which are continuations of the urogenital folds
- Initially the urethral groove only extends part way along the elongated genital tubercle
- The distal portion of the urethral groove terminates in a solid epithelial plate – the urethral plate, which extends into glans
- The solid urethral plate canalises and thus extends the urethral groove distally towards glans
- Fusion of the urethral folds is thus the key step in penile urethra formation – a prerequisite of this is urethral fold fusion is the canalisation of the urethral plate and the formation of the urethral groove, bound by the folds on each side
The glanular urethra formation occurs by combination of fusion of urethral folds proximally and the ingrowth of ectodermal cells distally (the epithelial tag)
- Hence the navicular fossa is stratified squamous, not urothelium
Penile & urethral development
The development of the external genitalia occurs via 3 pathways, which are all interconnected:
- Androgen independent
- Androgen dependent
- Endocrine and environmental
The sexual dimorphism is present based on presence or absence of signalling via the androgen receptor.
- Recall that during 9th and 10th weeks SRY causes Leydig cell differentiation, which produces testosterone
- In the presence of fetal testicular androgens the mesonephric (Wolffian) ducts persist as the epididymis, vas deferens and seminal vesicles
- Testosterone and DHT interact with androgen receptors to drive growth of the external genitalia and prostate
- In the absence of androgen receptor stimulation, the mesonephric ducts degenerate, the prostate doesn’t develop and female external genitalia develop
The penis and corpora cavernosa largely form as a result of androgen mediated lengthening of the genital tubercle.
In the female, the absence of androgen receptor stimulation causes failure of the perineum to lengthen and the labioscrotal folds and urethral folds do not fuse across the midline.
- The genital tubercle becomes the clitoris
- The urethral folds become the labia minora
- The labioscrotal folds become the labia majora