Embryology for the Urologist

3
Embryology for the Urologist


Allan Johnston1, Maike F. Eylert2, Tarik Amer1, and Omar M. Aboumarzouk1, 3


1 Glasgow Urological Research Unit, Department of Urology, Queen Elizabeth University Hospital, Glasgow, UK


2 Department of Urology, University Hospital of Wales, Cardiff, UK


3 University of Glasgow, School of Medicine, Dentistry & Nursing, Glasgow, UK



Abstract


The urogenital tract is largely derived from the mesoderm. Initial kidney structures appear in the fourth week of embryogenesis, but definitive kidney development occurs from the 5th‐10th week. The bladder and urethra start to form at the same time as the definitive kidney. Sexual development is indifferent until the sixth week of gestation, with the sex‐determining region Y (SRY) gene being the primary driver for male foetal development. This is largely through further action of anti‐müllerian hormone (AMH) and testosterone. The mesonephric ducts become the male genital duct system, and the paramesonephric ducts become the female genital duct system. Testicular descent is initially dependent on AMH and insulin‐like hormone 3, and later testosterone. Dihydrotestosterone drives male external genital development. The overall sequence of urogenital development is well established and can explain the majority of congenital malformations that may present to the urologist. Additional details will only be of interest to the subspecialist and the researcher


Keywordsanti‐müllerian hormone (AMH); development; dihydrotestosterone; embryology; genital tubercle; gonadal ridges; gubernaculum; insulin‐like hormone 3; labioscrotal folds; mesonephric duct; mesonephros; metanephros; paramesonephric duct; pronephros; SRY gene; testicular descent; testosterone; trigone; ureteric bud; urethral plate; urogenital sinus;


3.1 Historical Consideration


Embryology stems from the Greek words of ‘embry’, meaning the ‘unborn’, and –‘ology’, which is the subject of study or a branch of knowledge. [1, 2]


The Greeks were the first to describe their thoughts on the origins of man in the womb. More notably, Aristotle postulated that the foetus was formed in the uterus from a coagulum of blood (menstrual blood), and the foetus itself was fully developed in miniaturised form in the sperm. This chain of thought was carried on for centuries through Europe, even as late as the seventeenth century, when Marcello Malphigi (1672) described poultry eggs as containing a miniature chick and extrapolated that humans were fully formed in the sperm.


In 1694, 21 years after the invention of the microscope by Antonie van Leeuwenhoek, did Nicolaas Harsoeker postulate that humans were formed from the joining of the spermatozoon and ovum, further described by Lazzaro Spallanzani in 1775.


Interestingly, a revelation to the Prophet Mohamed (peace be upon him) in the seventh century detailed descriptions for embryological development, including the formation of the embryo from both the male and female ‘drops’ (i.e. sperm and ovum). Multiple Quranic verses were revealed detailing the formation of the embryo to the fully developed foetus. However, it was not until the nineteenth and twentieth centuries when these revelations were confirmed as fact and held as a true representation of embryo‐foetal development.


From the experimental works of Karl Ernst von Baer, Charles Darwin, and Ernest Haeckel, to the chemical and mechanical discoveries of embryology by Otto Warburg, paving the way for Ross Harrison, Frank R. Lillie, and Hans Spemann to describe the more detailed mechanisms of embryonic development throughout the early twentieth century. It was late in the twentieth century, with the advent of more sophisticated instruments such as the electron microscope and spectrophotometer, that embryology in its modern form took place. More notably the work of Keith Moore described the embryological and foetal development to the finest detail, giving rise to the established current knowledge of embryology.


3.2 Introduction


A description of each urological organ will be described individually; hence, overlap and repetition will inevitably exist to allow a detailed understanding of the development of each organ. Three basic cell layers comprise the embryonic disc which becomes the embryo: the ectoderm (originates from the amniotic surface), the mesoderm (originates form inpouring cells from the ectoderm), and the endoderm (yolk sac). The majority of the urogenital tract is derived from the mesoderm. Organ development in general occurs between the 3rd and 10th week of gestation (Table 3.1).


Table 3.1 Table of developmental timings.

























































































Structure Development starts Disappears Comments, ultimate structures
Pronephros 4th week 4th week No functional relevance
Mesonephros 4th week 8th week No permanent function
Mesonephric duct (male) 4th week Central zone of the prostate, ejaculatory ducts, vas deferens, seminal vesicles, epididymis, and efferent ductules
Mesonephric duct (female) 4th week 8th week Remnants: epoophoron, paroophoron, Gartner cyst
Metanephros 5th week Permanent kidney including glomeruli, convoluted tubules, loop of Henle. Urine production from 10th week.
Ureteric bud 5th week Collecting ducts, minor calyces, major calyces, renal pelvis, ureter
Urogenital sinus 5th week Bladder, posterior urethra (male) or entire urethra (female), anterior urethra (male) up to the edge of the glans penis
Gonadal ridges Germ cells migrate in 6th week Testes or ovaries
Paramesonephric duct (male) 6th week 8th week Remnants: appendix testes, utricle
Paramesonephric duct (female) 6th week Fallopian tubes, uterus, and the upper two‐thirds of the vagina
Genital tubercle enlargement (male) 6th week Penis. Urethral plate closes to form tubular urethra 12th week
Urethral endoderm and surrounding mesoderm (male) 13th week Prostate
Ingrowth of ectoderm from the tip of the glans penis (male) 15th week Fossa navicularis and urethral meatus
Testicular descent (abdominal) 8–15th week AMH and insulin‐like hormone 3 dependent
Testicular descent (inguinal) 24–28th week Testosterone dependent
Testicular descent (scrotal) 28–33rd week Testosterone dependent

AMH, anti‐müllerian hormone.


3.3 Embryology of the Kidneys and Ureters


The basic unit of the kidney is the renal pyramid, which is arranged like a bunch of flowers in a vase (Figure 3.1). The flowers are the glomeruli; the stalks are the collecting tubules; and the vase is the calix. The design of the normal pyramid is important in preventing reflux of urine up into the renal parenchyma.

Image described by caption and surrounding text.

Figure 3.1 The basic unit of the kidney is the pyramid, with a flower bunched arrangement in a vase.


There are three paired kidney systems during foetal development (Figure 3.2), with only the third system being of functional importance. First, the pronephros forms and rapidly regresses in the cervical region of the intermediate mesoderm during the fourth week. The pronephros in humans is both rudimentary and segmented.

Image described by caption.

Figure 3.2 Locations of pronephros (fourth week), mesonephros (fourth to eighth weeks), and metanephros (from fifth week) in the embryo.


Later in the fourth week, the unsegmented mesonephros forms from the intermediate mesoderm in the upper thoracic to upper lumbar segments. These appear as a pair of sausage‐shaped swellings on the posterior abdominal wall on either side of the mesentery – the genitourinary ridges. A faint groove demarcates each ridge into a medial gonadal and lateral nephrogenic part (Figures 3.3 and 3.4). These swellings lengthen and acquire primitive nephron‐like structures, which is a collection of capillaries that form a glomerulus at the medial extremity, and Bowman’s capsule, which forms around the glomerulus, forming the renal corpuscle. These simple excretory units may function briefly before regressing in the eighth week. The mesonephros functions for a short time during early foetal life by producing urine from the sixth through to the eighth weeks of development.

Image described by caption.

Figure 3.3 The mesonephros runs along the length of the foetus on the lateral side of the genitourinary ridge.

Diagram of a four‐week-old human embryo with lines indicating the heart, lung, mesonephros, and gonadal ridge labeled.

Figure 3.4 The mesonephros can be identified in the four‐week‐old human embryo.


On the lateral aspect and adjacent to the mesonephros, the mesonephric ducts advance distally to drain into the cloaca (this is the primitive hindgut which goes on to form the bladder and rectum) at the caudal end of the embryo. Whilst the caudal aspects of the tubules are differentiating, the cranial tubules and the glomeruli degenerate, with the majority of the mesonephros absent by the end of the second month of gestation. The mesonephric system disappears completely in the female around the eighth week. In the male, the mesonephric ducts (also known as the wolffian ducts) persist, giving rise to the efferent ductules of the testes, the epididymis, vasa, seminal vesicles, and appendix epididymis.


Third, the metanephros (the permanent kidneys) develops from the fifth week from metanephric mesoderm in the most caudal region of the nephrogenic ridge, the lateral aspect of the genitourinary ridge. As the tail end of the foetus curls up, the hindgut is curled with it and so are the nephrogenic ridges with their wolffian ducts, which twist upwards and inwards. Branches from the most caudal part of the wolffian (mesonephric) ducts enter the metanephros. These branches, or outgrowths, are called the ‘ureteric buds’ (Figure 3.5). In contrast to the first two systems, excretory units only form by a process called ‘reciprocal induction’ between the ureteric bud and metanephric tissue caps.

Image described by caption.

Figure 3.5 (a) The caudal part of the mesonephros becomes the metanephros. It receives its own branch from the mesonephric (wolffian) duct, the ureteric bud. (b) As the foetus curls up, the wolffian duct and the ureteric bud are bent around.


The collecting ducts develop from the ureteric bud (fifth week, Figure 3.6). The ureteric bud subdivides and induces formation of the glomeruli in the mesenchyme of the metanephros. The branches of the bud then grow peripherally into the cortex, dilating and splitting repeatedly until about 15 generations of ducts have formed (Figure 3.7). The first four or five generations of the dividing ureteric branches become dilated and incorporated in the eventual renal pelvis (Figure 3.8). The next four or five generations form the major calices and collecting tubules (Figure 3.8) [3]. The successive generations elongate and converge on the minor calyx (seventh week), thereby forming the renal pyramid in the flower–vase configuration described previously. Subsequent generations elongate and converge to form renal pyramids, and ultimately, they form around one million collecting ducts per kidney (until the fifth month).

Diagram displaying the ureteric bud developing as an outgrowth of the mesonephric duct close to the urogenital sinus (fifth week). Allantois, foetal hindgut, urogenital sinus, mesonephros, etc. are labeled.

Figure 3.6 The ureteric bud develops as an outgrowth of the mesonephric duct close to the urogenital sinus (fifth week).

Image described by caption.

Figure 3.7 The ureteric bud splits repeatedly until about 15 generations of ducts have formed. The first generation becomes the renal pelvis, the second the major calyces, the third to fifth minor calyces, and the remainder become renal pyramids and collecting ducts.

Image described by caption and surrounding text.

Figure 3.8 As the ureteric bud approaches the metanephros, it branches repeatedly. The branches induce the formation of glomeruli. The first four or five generations of branches become incorporated into the renal pelvis.


The metanephric tissue caps covering each collecting tubule form renal vesicles which develop into nephrons. Capillaries grow into the opposite end of the nephron giving rise to glomeruli (Figure 3.9). From about the 10th week, urine is produced by the metanephros; however, nephrons continue to form until birth. After birth, no further nephrons will form (approximately 700 000 per kidney), but existing ones will continue to grow. This growth is responsible for the change from lobulated kidneys at birth to kidneys with a smooth outline.

Image described by caption and surrounding text.

Figure 3.9 The metanephric tissue caps covering each collecting tubule form renal vesicles which develop into nephrons. Capillaries grow into the opposite end of the nephron, giving rise to glomeruli.


The metanephros ascends during weeks 6–10 as a result of the elongation of the sacral and lumbar regions of the embryo as well as loss of the initial curvature of the embryo. The arterial supply originates from the aorta, and serial arteries are formed and regress during renal ascent. Some vessels may remain as accessory renal arteries.


During the fourth to sixth weeks of gestation, while the caudal end of the foetus curls up and bends the hindgut into a U configuration, the mesoderm grows down into the gap between the future rectum and bladder, thus forming the urorectal septum (Figure 3.10). This septum separates the cloaca into a primary urogenital sinus (ventrally) and rectum (dorsally). The wolffian ducts lie in this wedge‐shaped septum, and grow down with it. They also become bent into a loop and take the ureteric buds with them (Figure 3.10) [4]. Part of this septum is incorporated into the bladder to form the trigone, and because of the incorporated loop of the wolffian duct, the ureteric duct comes to open into the bladder cephalad to the duct. In males, the wolffian duct becomes the vas deferens and seminal vesicles, whilst in the females these ducts regress in the absence of testosterone [4]. At this stage, the tail end of the foetus is roughly 1‐cm long and the space between the tail and the umbilical cord is filled by the cloacal membrane. On either side of this membrane are the two small genital tubercles (Figure 3.11). This membrane is formed by tightly packed ectoderm and endoderm cells with no intervening mesoderm. As this membrane dissolves, the two genital tubercles fuse to form the united phallic tubercle (Figure 3.11).

Diagram displaying the urorectal septum between the future bladder and rectum. Lines indicate mesonephros, wolffian duct, ureter, cloacal membrane, bladder, rectum, and urorectal septum.

Figure 3.10 The urorectal septum grows down between the future bladder and rectum.

Diagrams displaying the umbilical cord, genital tubercle, cloacal membrane, urorectal septum, and tail (top) and the bladder, phallus, urorectal septum, tail, and rectum (bottom).

Figure 3.11 The cloacal membrane disappears and the phallic tubercles meet in the midline.


While all this is taking place, the mesonephros is withering away, but as it regresses, the wolffian duct generates a second duct, parallel and lateral to it, the müllerian duct (Figure 3.12). As the urogenital ridge twists round, so the müllerian ducts approach each other, meet in the midline in front of the wolffian ducts, and burrow down in the urorectal septum (Figure 3.12). The urorectal septum is partially absorbed into the trigone, and the müllerian ducts open into the urethra medial to, and in front of, the wolffian ducts.

Image described by caption.

Figure 3.12 (a) A second (müllerian) duct forms on the lateral side of the mesonephros. (b) The müllerian duct roll towards each other, meet in the midline in front of the wolffian ducts, and burrow down into the urorectal septum to form the uterus and fallopian tubes in the female.


The subsequent fate of the wolffian and müllerian ducts is determined by the X and Y chromosomes. Until the fourth week, the urogenital ridge is neuter. At four weeks it is invaded by gonadal cells, which migrate by amoeboid movements from the yolk sac across the coelom and burrow into the gonadal ridge (Figure 3.13). By the sixth week, it is estimated that there are about 60 000 gonadal cells in each gonadal ridge. The male ones are active at once; the female gonadocytes stay dormant for another two weeks.

Illustration of the migration of the germ cells from the yolk sac to the genital ridge. Lines indicate the genital ridge, germ cells, coelom, and yolk sac.

Figure 3.13 Migration of the germ cells from the yolk sac to the genital ridge.


3.3.1 Relevant Congenital Malformations


Partial or complete ureteric duplication results from early splitting of the ureteric bud. In a complete duplex system, the Weigert‐Meyer rule states that the ureter draining the lower moiety tends to reflux as a result of a shorter submucosal tunnel positioned laterally and superior; the upper pole tends to obstruct, be ectopic, or form ureteroceles and is positioned medially and inferiorly (Figure 3.14). An ectopic ureter may drain into the bladder, bladder neck, or prostatic urethra in males, or into the vagina, uterus, or ovary in females (Figure 3.15). The pathophysiology of duplex kidney is explained by the insertion of the ureter into the bladder, whilst the lower pole tends to reflux due to a shorter submucosal tunnel, and the upper pole tends to obstruct, be ectopic, or form ureteroceles.

Diagram of the complete duplex system with lines indicating the upper moiety, lower moiety, normal ureter of lower moiety, ectopic ureter of lower moiety, prostate, bladder neck, normal ureteric orifices, etc.

Figure 3.14 Complete duplex system on the left. The Wiegert‐Meyer rule states that the ureter from the upper moiety will enter inferomedial to the lower moiety ureter.

Diagram displaying the ureter from upper half-kidney draining into ectopic orifice. Lines indicate the external sphincter and ectopic ureter.

Figure 3.15 The ureter from the upper half‐kidney may open into the vagina below the sphincter and cause incontinence.


Failure of renal ascent gives rise to a pelvic kidney (Figure 3.16). Midline fusion of both kidneys during their ascent gives rise to a horseshoe kidney, with further ascent limited by the root of the inferior mesenteric artery. The midpoint joining both kidneys is known as the isthmus (Figure 3.17). Crossed fused renal ectopia results from both kidneys ascending on the same side of the body and fusing in the process (Figure 3.18).

Illustration of the pelvic kidney.

Figure 3.16 If the kidney remains in the pelvis, it stays ‘rotated’.

Diagram displaying the horseshoe kidney and superior mesenteric artery.

Figure 3.17 If the lower end of the metanephros fuse together, they remain ‘rotated’, and their course up the abdomen is held by the superior or, rarely, the inferior mesenteric arteries.

Image described by caption and surrounding text.

Figure 3.18 Crossed renal ectopia.


Renal agenesis results from failed reciprocal induction, intrinsic defects within the mesenchyme, or involution of a multicystic dysplastic kidney. Multicystic dysplastic kidney may be the result of faulty ureteric bud development. Renal dysplasia results from defects in reciprocal induction or from obstruction during the foetal period.


3.4 Embryology of the Bladder


The foetal hindgut is curled, following the outline of the tail end of the embryo, in the shape of a hook (Figure 3.19). The caudal most part of the hindgut remains in communication with the allantois and will form the bladder. As stated, the urorectal septum descends at four to six weeks to separate the cloaca into the urogenital sinus anteriorly and the anal canal posteriorly. The cloacal membrane dissolves to open both canals (Figures 3.20 and 3.21).

Image described by caption and surrounding text.

Figure 3.19 The foetal hindgut bends round and the urogenital septum descends to separate the bladder from the rectum; the patent urachus keeps the future cladder in continuity with the allantois.

Illustration of a fetus and an inset displaying a leftward arrow in the urorectal septum. Allantois, urogenital sinus, cloacal membrane (dissolving), anal canal, and urorectal septum are indicated by lines.

Figure 3.20 The urorectal septum descends at four to six weeks to separate the cloaca into the urogenital sinus anteriorly and the anal canal posteriorly. The cloacal membrane dissolves to open both canals.

Left: Diagram displaying allantois, urogenital sinus, wolffian mesonephric duct, metanephros, ureteric bud, genital tubercle, etc. Right: Diagram displaying urachus, bladder, ureter, rectum, and urorectal septum.

Figure 3.21 As the urogenital septum reaches the perineum, the cloacal membrane dissolves to reveal two openings, the urethra and the rectum.


As the allantois shrinks it becomes a solid cord – the urachus – linking the apex of the bladder to the umbilicus. In clinical terms, the urachus becomes the median umbilical ligament upon closing. If it remains patent, the patient will have a congenital umbilical fistula. The urogenital sinus itself will give rise to the bladder, the posterior urethra (male) or entire urethra (female), and the anterior urethra (male) up to the edge of the glans penis. These are all endodermal (originates from yolk sac) in origin.


The male anterior urethra is not initially tubular, but rather a flattened urethral plate, which is pulled forwards with the growing phallus (Figure 3.22). It then folds in sideways and closes along the midline at around 12 weeks (Figure 3.23 and 3.24). The terminal part of the male urethra (fossa navicularis and external urethral meatus) is formed by ingrowth of ectoderm (derived from amniotic sac) from the tip of the glans penis (15 weeks).

Diagram of the male anterior urethra displaying a flattened urethral plate, phallus, urogenital sinus, and hindgut.

Figure 3.22 The male anterior urethra is not initially tubular, but rather a flattened urethral plate, which is pulled forwards with the growing phallus.

Image described by caption.

Figure 3.23 The male anterior urethra folds in sideways and closes along the midline at around 12 weeks. The genital and labioscrotal folds move caudally and fuse to form the scrotum with the midline scrotal septum.

Image described by caption.

Figure 3.24 The skin rolls in on either side to form the urethra.


The lower ends of the mesonephric ducts (due to become the vasa efferentia) and the lower ends of the ureters become incorporated into the posterior wall of the bladder, and thus form the trigone (Figures 3.25 and 3.26). Descent of the testes then causes the vas deferens on either side to swing anteriorly over the ureter (‘water under the bridge’).

Image described by caption.

Figure 3.25 The lower ends of the mesonephric ducts (due to become the vasa efferentia) and the lower ends of the ureters become incorporated into the posterior wall of the bladder, and thus form the trigone. Descent of the testes then causes the vas deferens on either side to swing anteriorly over the ureter.

Diagram displaying the wolffian duct, rectum, and bladder.

Figure 3.26 The urogenital septum brings down the wolffian ducts, which will become the ureters.


3.4.1 Relevant Congenital Malformations


Failure of fusion of the urethral folds results in hypospadias. Epispadias results if the genital tubercle (see discussion in this chapter) forms in the urorectal septum with part of the membrane cranial to the genital tubercle. Exstrophy of the bladder (which always includes epispadias) is caused by failure of the abdominal wall to form.


3.5 Embryology of the Indifferent Genital System


The gonads begin their development from the urogenital ridge, located behind the coelom. They divide longitudinally, in the third week, to form the gonadal or genital ridge on the medial side and the embryonic mesonephros on the lateral side, which later becomes the urinary tract. Paramesonephric ducts (müllerian ducts) develop from these genital ridges.


Between weeks five and six of embryonic development, the germ cells arising from the yolk sac integrate into the gonadal ridge after travelling by amoeboid movement through the umbilical cord and the coelom (Figures 3.273.28). Upon the arrival of germ cells, primitive sex cords form in the still indifferent gonad. Failure of gonadal development occurs if the germ cells do not reach the gonadal ridges because they trigger the development of the gonad into ovary or testis [5].

Diagram displaying the phallus and arrow in the labioscrotal fold.

Figure 3.27 Cloacal folds form in the third week and will become genital folds. The genital tubercle forms at the same time. Indifferent labioscrotal folds form lateral to the genital folds.

Image described by caption.

Figure 3.28 The germ cells pass from the yolk sac across the coelom to the gonadal ridge.


In the human embryo, the gonads remain undifferentiated until about week seven of development. Depending on the XY genetic constitution they then differentiate into the testes or the ovaries [6].


3.6 Embryology of the Male Genital System


Once in the gonadal ridge, the presence of the sex‐determining region Y (SRY) gene located on the short arm of the Y chromosome leads to testicular development and male phenotyping. Down streaming from SRY produces steroidogenesis factor (SF1) and SOX9 that stimulate testicular cellular differentiation. This induces the first step of the organogenesis of the testes, the formation of gonadocytes, and proliferation of Leydig cells and sustentacular cells of Sertoli (Figures 3.29 and 3.30) [7]. This development not only relies on the presence of the SRY gene, but also the lack of the DAX1 gene (which can down regulate the SRY gene action) and WNT4 gene, which is responsible for female gonadal development.

3 Circles with Leydig cells in between and gonadocytes and sertoli cells (secrete müllerian duct inhibiting factor) in 1 of the circles.

Figure 3.29 Sertoli cells secrete müllerian duct inhibiting factor. About a week later, Leydig cells secrete testosterone, which is activated to dihydrotestosterone, and causes descent of the testicles and formation of the penis and urethra.

Flow diagram from foetal pituitary to Leydig and sertoli cells to differentiation of genital tubercle and urogenital sinus, differentiation of wolffian ducts, testicular descent, and regression of müllerian ducts.

Figure 3.30 Male hormone dependence.


These cells then proliferate with the aid of SRY gene proteins and form the primary sex cords. These further proliferate and extend into the medulla of the gonad to form the testis or medullary cords. Once here, the cords branch with their deep ends anastomosing to form the tubules of the rete testis. The gonadal cords further develop to give rise to the testicular cords which differentiate to become the seminiferous tubules. The tubuli recti are formed from the narrowing of the deeper portion of the semiferous tubules, and it converges into the tubuli recti. The tubules’ connections with the germinal epithelium are discontinued with the formation of a dense network of fibrous connective tissue known as the ‘tunica albuginea’ [5].


Male genital development depends on the SRY gene, anti‐müllerian hormone (AMH; also called müllerian inhibitory substance [MIS]), insulin‐like hormone 3, testosterone, and dihydrotestosterone (DHT).


The gene does two things consecutively:



  1. It makes the gonadocytes differentiate into Sertoli cells which secrete another simple polypeptide, the müllerian duct‐inhibiting factor. This has a dramatic effect: the entire müllerian duct system disappears within a single day, leaving behind only the tiny vestige of the utriculus masculinis in the verumontanum (Figure 3.31). MIS also inhibits the formation of the uterus and fallopian tubes (the müllerian structures) [79].
  2. Approximately one week later (approximately week eight), the SRY gene enables the differentiation of the germ cells located between the testicular cords into Leydig cells derived from the mesenchyme of the gonadal ridge. These contain 17‐ketosteroid reductase which is involved in the synthesis of testosterone, which is activated by the enzyme 5‐alpha reductase to 5‐alpha DHT. This active substance reacts with a cytosol receptor in the phallic tubercles and wolffian ducts to secrete growth factor. This results in the two changes necessary to convert the neuter foetus into the male. The cytosol receptor factor is a product of one of the genes in the X chromosome.
3 Illustrations of the Wolffian duct, müllerian duct, ureteric bud, and male gonads, with müllerian duct‐inhibiting factor causing the müllerian ducts to disappear except for the utriculus masculinus in the verumontanum.

Figure 3.31 The müllerian duct‐inhibiting factor from Sertoli cells cause the müllerian ducts to disappear except for the pit in the verumontanum.


In the presence of testis determining factor (SRY protein), medullary cords of the testis, and the rete testis form (Figure 3.32). Formation of the tunica albuginea follows. Sertoli cells (from epithelium) and Leydig cells (from mesenchyme) form dependent on the SRY protein. SRY protein stimulates AMH production by Sertoli cells (seventh week), which in turn causes Leydig cells to produce testosterone and insulin‐like hormone 3 (ninth week). The testis cord continues to remain solid until the onset of puberty, when it acquires a lumen to form the seminiferous tubules, which connects with the rete testis and enters the ductuli efferentes, which are remnants of the mesonephric system. The ductus deferens is formed when rete testis is joined to the wolffian duct with the aid of the ductuli efferentes [5].

Diagram of a fetus with lines indicating the vitelline duct, germ cells, mesonephros, gonadal ridge, and hindgut.

Figure 3.32 Upon arrival of germ cells, primitive sex cords form in the then‐indifferent gonad. In the presence of testis determining factor (SRY protein), medullary cords of the testis and the rete testis form.


AMH causes involution of the paramesonephric ducts. Only small remnants from the paramesonephric ducts persist (i.e. appendix testes, utricle). Testosterone influences development of the mesonephric ducts and male external genitalia. Mesonephric ducts differentiate into the central zone of the prostate, ejaculatory ducts, vas deferens, seminal vesicles, epididymis, and efferent ductules (Figures 3.33 and 3.34)

4 Illustrations of the stages of a growing phallus and urethra rolling in from either side (left–right) caused by testosterone from the Leydig cells.

Figure 3.33 (a–d) Testosterone from the Leydig cells cause the phallus to grow and the urethra to roll in from either side.

Diagram displaying [Müllerian] appendix testis, appendix epididymis, vas deferens, seminal vesicle, and utriculus masculinus in male.

Figure 3.34 In males, the wolffian duct becomes the vas deferens, epididymis, and seminal vesicles.


3.6.1 The Descent of the Testis


Testicular descent happens in two phases, guided by the action on the gubernaculum (Figure 3.35).



  1. Passive phase: Dependent on AMH/MIS and insulin‐like hormone 3 guiding abdominal descent to the inguinal ring (8–15th week)
  2. Active phase: Dependent on testosterone through the inguinal canal (24–28th week), and to the base of the scrotum (28th‐33rd week).
Image described by caption.

Figure 3.35 Testicular descent happens in two phases: (1) dependent on AMH and insulin‐like hormone 3 during abdominal descent to the inguinal ring (8–15th week) and (2) dependent on testosterone through the inguinal canal (24–28th week),and to the base of the scrotum (28–33rd week). Both phases are guided by the gubernaculum. During their descent, the testes acquire a layer of peritoneum, which becomes the tunica vaginalis.


During their descent, the testes acquire a layer of peritoneum, which becomes the tunica vaginalis.


During development the testis begins its journey in the lumbar area of the retroperitoneum. It transfers from here to the scrotum near the end of the third month of pregnancy. This is mediated by testosterone and the gubernaculum (Figure 3.36), a lump of jelly, which forms an expanding track, which leads to and inserts into the genital swelling, the future scrotum [10]. Ectopic testes are formed when the gubernaculum leads them in the wrong direction, such as towards the penis or the thigh, and incomplete descent occurs if the gubernaculum fails to form a path to the scrotum (Figure 3.37) [1113].

3 Illustrations of normal migration of the testicle (left–right), with lines indicating the peritoneum, gubernaculum, and processus vaginalis.

Figure 3.36 Normal migration of the testicle.

Diagram of the testis with lines indicating the efferent ductile, epididymis, vas deferens, vas deferens, ejaculatory duct, and central zone of the prostate.

Figure 3.37 The maldescended testis may be off its normal course of descent (ectopic) or on the normal course (incomplete) descent.


3.6.2 Relevant Congenital Malformations


As the testis descends, it is accompanied by the processus vaginalis. The lumen of the processus vaginalis is normally obliterated within a few weeks of birth; however, if it persists, it gives rise to defects such as a congenital hernia, hydrocele, an encysted hydrocele of the cord, or an abdominoscrotal hydrocele (Figures 3.38 and 3.39) [14].

Illustrations of congenital hydrocele (top left), encysted hydrocele of the cord (top right), hernia magna (bottom left), and intra-abdominal hydrocele (bottom right).

Figure 3.38 Varieties of hydrocele and hernia.

Image described by caption.

Figure 3.39 Various types of hernia and hydrocele. (a) Common hydrocele, (b) encysted hydrocele, (c) ‘double’ hydrocele, (d) hernia and hydrocele, (e) ‘hernia magna’, and (f) abdominoscrotal hydrocele.


Maldescent of a testis results in an undescended testis. Malposition of the gubernaculum or an abnormally long gubernaculum result in an ectopic testis. Failure of, incomplete, or inappropriate development of the genital system leads to disorders of sexual differentiation.


In males, the müllerian duct lingers as two tiny vestiges, the utriculus masculinis in the verumontanum and the appendix testis, neighbouring the appendix epididymis which is a vestige of the wolffian duct (Figures 3.31 and 3.34 ) [5]. If there is a congenital deficiency of MIS, phenotypical males are born with fallopian tubes and a uterus, usually found by chance at laparoscopic orchidopexy or hernia repair, and occasionally, associated with testicular tumours [7].


3.7 Embryology of the Prostate


As described previously, the male foetus develops in the presence of a Y chromosome, which encodes the SRY protein, thus enabling testicular differentiation and the production of androgens such as testosterone. In addition to the actions of SRY protein and androgens, a third factor is required for male development, AMH, also known as MIS [15]. This causes the müllerian (paramesonephric) duct to degenerate, forming the prostatic utricle (or utriculus masculinis). Blandy originally described this as, ‘a volcanic crater on the summit of the verumontanum’.


The prostate forms in the mesenchyme of the urogenital septum. The cloacal membrane, a thin film which covers the convexity of the hindgut, regresses to leave gaps in front of and behind the urogenital septum, and in so doing, forming the urethra and anus. Running down in this septum are the müllerian and wolffian ducts and the ureteric buds (Figure 3.40).

Diagram displaying the testis, wolffian duct, metanephros, ureter, rectum, bladder, urorectal septum, and tail.

Figure 3.40 The prostate begins to form in the mesenchyme of the urogenital septum in the vicinity of the opening of the wolffian ducts.


At approximately week eight, the Leydig cells of the foetal testis secrete testosterone [16, 17], and as a consequence, the human prostate begins its development at about the 10th week of gestation. The initial outgrowths of the epithelial ‘prostatic’ buds from the urethra into the urogenital sinus (UGS) occur in response to the binding of 5α‐dihydrotestosterone to androgen receptors localised in the surrounding mesenchymal tissue [1821]. There are five pairs of buds. The top pairs are derived from mesoderm (i.e. wolffian structures) and form the transitional, periurethral, and central zones of the prostate, whereas, the bottom pairs are derived from endoderm and form the peripheral zone.


These prostatic buds begin as solid cords of epithelial cells that elongate and undergo extensive branching morphogenesis during the latter stages of foetal growth to develop primitive lumens [22]. During weeks 13–15, serum testosterone elevates and remains high until week 25, which in turn induces epithelial differentiation. At this point, the three important epithelial populations, other than the stem cells, are distinct: luminal, basal, and neuroendocrine cells [22]. The stromal component compromises of fibroblasts, smooth muscles, and myofibroblasts. At week 25, the testosterone level diminishes, and the gland remains in a quiescent state until puberty. The central zone is primarily sensitive to testosterone, whereas the peripheral and transitional/periurethral are sensitive to DHT.


Summary: DHT prompts development of the prostate from urethral endoderm and surrounding mesoderm (13–16th weeks), giving rise to the transitional zone and peripheral zone. The central zone is formed from the mesonephric duct.


3.8 Embryology of the Penis and Urethra


Two crucial events occur in the male embryo, between the fifth and seventh week:



  • the disappearance of the müllerian ducts
  • the transformation of the phallic tubercles

Both events are orchestrated by the two sex chromosomes. On the Y chromosome, the SRY gene controls germ cell differentiation into Sertoli cells (whose müllerian inhibiting factor causes the müllerian ducts to disappear). By the eighth week of gestation, the mesenchymal cells of the genital ridge differentiate into Leydig cells which secrete testosterone, which enters the wolffian ducts and the phallic and genital tubercles. These tissues contain 5‐alpha reductase, an enzyme which activates testosterone to a more potent form, DHT. DHT binds to a cytosol receptor protein and sets off the changes in growth, which allow the wolffian ducts to develop into the vasa efferentia, seminal vesicles, and epididymis. The phallic and genital tubercles become the penis, scrotum, and urethra (Figure 3.41). A gene on the X chromosome codes the cytosol receptor protein. Each step on this ladder of events is carried out by a certain enzyme coded by a single gene. In the absence of this organised testicular development, the differentiated gonads will develop into ovaries by the 13th and 14th weeks of gestation [23]. Each step may go wrong and result in one of the variations of intersex.

Image described by caption and surrounding text.

Figure 3.41 The Y chromosome produces the HY gene, which turns germ cells either into Sertoli cells, which secrete the müllerian duct‐inhibiting factor, or Leydig cells. The Leydig cells secrete testosterone, which is hydrogenated to dihydrotestosterone, and binds to receptors in the wolffian ducts and phallic tubercles.


By week seven, the cloacal membrane dissolves, and the primitive bladder opens on the ventral aspect of the genital tubercle (Figure 3.42). This elongates to form the penis under which a groove is folded in from either side to form the urethra (Figure 3.43). Rods of mesenchyme in each fold differentiate into the corpora cavernosa and corpus spongiosum. At the tip of the penis, a groove demarcates the glans through which a solid cord extends and then becomes canalised as, the terminal urethra (Figure 3.44). Skin grows forwards from the coronal sulcus to enclose the glans in the prepuce and then becomes adherent.

Diagram of the cloacal membrane with lines indicating the umbilical cord, phallic tubercle, urogenital sinus, genital tubercles, urogenital septum, and rectum.

Figure 3.42 When the cloacal membrane dissolves, the bladder opens behind the genital tubercle.

Diagram of a fetus displaying the formed penis, with lines indicating the genital tubercle, genital fold, and labioscrotal fold.

Figure 3.43 Under the influence of dihydrotestosterone, the genital tubercle elongates, and a groove folds in on either side to form the urethra, up to the groove behind the solid glans penis.

3 Illustrations of the tip of the penis with a cord extending through the solid glans and becomes canalized, forming the terminal urethra. Upward arrows at the middle illustration depict the skin growing from coronal sulcus.

Figure 3.44 A cord extends through the solid glans and then becomes canalised to form the terminal urethra. Skin grows forwards from the coronal sulcus to enclose and adhere to the glans.


The scrotum is formed by the meeting together in the midline of the two genital tubercles over the urethra (Figure 3.45).

Image described by caption and surrounding text.

Figure 3.45 The scrotum is formed by the in‐rolling of the two genital tubercles over the urethra.


All these processes must be complete within a critical window of time. If the genital folds and penis are not completed by the 12th week they never will be. However much androgen is given later on, all it can do is slightly enlarge the penis [24, 25].


Summary: Under the influence of DHT (formed from testosterone by the action of 5‐α‐reductase), the penis, scrotum, and prostate form. DHT causes elongation of the genital tubercle after six weeks to form the phallus with the urethral plate. The genital and labioscrotal folds on either side move caudally and fuse along the midline, which carries the urethra to the tip of the formed penis and forms the scrotum with the midline scrotal septum. DHT sets off the train of events leading to the growth and fusion of the phallus, in‐rolling of the urethral tube, formation of the scrotal sac, and the downward migration of the testes [7, 8]. The wolffian ducts are dependent on testosterone to develop and form the epididymis, vas deferens, and seminal vesicles.


3.9 Neuter State


Without a Y chromosome or its SRY genes, the foetus stays neuter. The neuter state seems at first glance to be female: There is no phallus; the müllerian ducts persist; and the wolffian ducts fail to turn into the vas deferens.


3.10 Embryology of the Female Genital System


The paramesonephric ducts form the basis of the female genital system. In the absence of the SRY gene, default development is down the female pathway. The mesonephric ducts regress and only leave a few remnants, including Gartner’s cysts, paroophoron, and epoophoron. The paramesonephric ducts develop into fallopian tubes, uterus, and the upper two‐thirds of the vagina (Figure 3.46).

Image described by caption and surrounding text.

Figure 3.46 Derivatives of the paramesonephric duct in females: fallopian tubes, uterus, and the upper two‐thirds of the vagina.


With regards to external genitalia, the genital tubercle develops into the clitoris, the urogenital sinus forms the introitus and vestibule of the vagina (distal one‐third), the genital folds become the labia minora, and the labioscrotal folds become the labia majora (Figure 3.47).

Image described by caption and surrounding text.

Figure 3.47 Female external genital development: the genital tubercle develops into the clitoris, the genital folds become the labia minora, and the labioscrotal folds become the labia majora.


3.11 Embryology of the Adrenal Gland


There are two distinct components of the adrenal gland: cortex and medulla. The cortex is derived from the mesoderm. At about the fifth to sixth weeks of life, the foetal cortex develops arising from the genitourinary ridge, subsequently surrounded by a second wave of mesothelial cells, which will eventually form the definitive cortex near the developing gonads and kidneys; tiny rests of adrenal cortical tissue are common in the renal cortex, retroperitoneum, and testis as well as the broad ligament near the ovary (Figures 3.48 and 3.49). After birth, the foetal cortex regresses except for its outermost layer, which differentiates into the reticular zone. The adrenal cortex shares many of the enzymes of gonads – notably those for the synthesis of steroids – so that some inborn errors of metabolism affect them both.

Diagram with arrows depicting migration of neuroblasts (week 7) and fetal cortex arising from genitourinary ridge (week 5). Neural tube, adrenal cortex, adrenal medulla, and genitourinary ridge are labeled.

Figure 3.48 Migration of neuroectodermal cells from neural crest.

Image described by caption.

Figure 3.49 The cortex arises in the mesoderm of the ‘intermediate cell mass’, which later forms the genitourinary ridge. Neuroectodermal cells migrate into it from the neural crest to form the medulla.


In the seventh week of foetal life, neuroblasts from the sympathetic system of the neural crest (ectodermal cells) invade the medial aspect of the developing adrenal cortex to form the medulla. After a week, they differentiate into sympathicoblasts and pheochromocytes containing the intracellular catecholamines, adrenaline, and noradrenaline.


Cells derived from the neural crest migrate on each side of the aorta to form the sympathetic chains. It is from these paraganglia cells that extra‐adrenal neuro‐ectodermal tumours (paragangliomas) arise.


In foetal life, the adrenals are larger than the kidneys and are still about one‐third of their size at birth.

Aug 6, 2020 | Posted by in UROLOGY | Comments Off on Embryology for the Urologist

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