Chapter 2. Embryology of the Genitourinary System

At birth, the genital and urinary systems are related only in the sense that they share certain common passages. Embryologically, however, they are intimately related. Because of the complex interrelationships of the embryonic phases of the two systems, they are discussed here as five subdivisions: the nephric system, the vesicourethral unit, the gonads, the genital duct system, and the external genitalia.

The nephric system develops progressively as three distinct entities: pronephros, mesonephros, and metanephros.

Pronephros

The pronephros is the earliest nephric stage in humans, and it corresponds to the mature structure of the most primitive vertebrate. It extends from the 4th to the 14th somites and consists of six to ten pairs of tubules. These open into a pair of primary ducts that are formed at the same level, extend caudally, and eventually reach and open into the cloaca. The pronephros is a vestigial structure that disappears completely by the 4th week of embryonic life (Figure 2–1).

Mesonephros

The mature excretory organ of the larger fish and amphibians corresponds to the embryonic mesonephros. It is the principal excretory organ during early embryonic life (4–8 weeks). It too gradually degenerates, although parts of its duct system become associated with the male reproductive organs. The mesonephric tubules develop from the intermediate mesoderm caudal to the pronephros shortly before pronephric degeneration. The mesonephric tubules differ from those of the pronephros in that they develop a cuplike outgrowth into which a knot of capillaries is pushed. This is called Bowman's capsule, and the tuft of capillaries is called a glomerulus. In their growth, the mesonephric tubules extend toward and establish a connection with the nearby primary nephric duct as it grows caudally to join the cloaca (Figure 2–1). This primary nephric duct is now called the mesonephric duct. After establishing their connection with the nephric duct, the primordial tubules elongate and become S-shaped. As the tubules elongate, a series of secondary branchings increase their surface exposure, thereby enhancing their capacity for interchanging material with the blood in adjacent capillaries. Leaving the glomerulus, the blood is carried by one or more efferent vessels that soon break up into a rich capillary plexus closely related to the mesonephric tubules. The mesonephros, which forms early in the 4th week, reaches its maximum size by the end of the 2nd month.

Metanephros

The metanephros, the final phase of development of the nephric system, originates from both the intermediate mesoderm and the mesonephric duct. Development begins in the 5- to 6-mm embryo with a budlike outgrowth from the mesonephric duct as it bends to join the cloaca. This ureteral bud grows cephalad and collects mesoderm from the nephrogenic cord of the intermediate mesoderm around its tip. This mesoderm with the meta-nephric cap moves, with the growing ureteral bud, more and more cephalad from its point of origin. During this cephalic migration, the metanephric cap becomes progressively larger, and rapid internal differentiation takes place. Meanwhile, the cephalic end of the ureteral bud expands within the growing mass of metanephrogenic tissue to form the renal pelvis (Figure 2–1). Numerous outgrowths from the renal pelvic dilatation push radially into this growing mass and form hollow ducts that branch and rebranch as they push toward the periphery. These form the primary collecting ducts of the kidney. Mesodermal cells become arranged in small vesicular masses that lie close to the blind end of the collecting ducts. Each of these vesicular masses will form a uriniferous tubule draining into the duct nearest to its point of origin.

As the kidney grows, increasing numbers of tubules are formed in its peripheral zone. These vesicular masses develop a central cavity and become S-shaped. One end of the S coalesces with the terminal portion of the collecting tubules, resulting in a continuous canal. The proximal portion of the S develops into the distal and proximal convoluted tubules and into Henle's loop; the distal end becomes the glomerulus and Bowman's capsule. At this stage, the undifferentiated mesoderm and the immature glomeruli are readily visible on microscopic examination (Figure 2–2). The glomeruli are fully developed by the 36th week or when the fetus weighs 2500 g (Osathanondh and Potter, 1964a and 1964b). The metanephros arises opposite the 28th somite (fourth lumbar segment). At term, it has ascended to the level of the first lumbar or even the twelfth thoracic vertebra. This ascent of the kidney is due not only to actual cephalic migration but also to differential growth in the caudal part of the body. During the early period of ascent (7th to 9th weeks), the kidney slides above the arterial bifurcation and rotates 90°. Its convex border is now directed laterally, not dorsally. Ascent proceeds more slowly until the kidney reaches its final position.

Certain features of these three phases of development must be emphasized: (1) The three successive units of the system develop from the intermediate mesoderm. (2) The tubules at all levels appear as independent primordia and only secondarily unite with the duct system. (3) The nephric duct is laid down as the duct of the pronephros and develops from the union of the ends of the anterior pronephric tubules. (4) This pronephric duct serves subsequently as the mesonephric duct and as such gives rise to the ureter. (5) The nephric duct reaches the cloaca by independent caudal growth. (6) The embryonic ureter is an outgrowth of the nephric duct, yet the kidney tubules differentiate from adjacent metanephric blastema.

Molecular Mechanisms of Renal and Ureteral Development

The kidney and the collecting system originate from the interaction between the mesonephric duct (Wolffian duct) and the metanephric mesenchyme (MM). The uretic bud (UB) forms as an epithelial outpouching from the mesonephric duct and invades the surrounding MM. Reciprocal induction between the UB and MM results in branching and elongation of the UB from the collecting system and in condensation and epithelial differentiation of MM around the branched tips of the UB. Branching of the UB occurs approximately 15 times during human renal development, generating approximately 300,000 and 1 million nephrons per kidney (Nyengaard and Bendtsen, 1992).

This process of reciprocal induction is dependent on the expression of specific factors. Glial cell–derived neurotrophic factor (GDNF) is the primary inducer of ureteric budding (Costantini and Shakya, 2006). GDNF interacts with several different proteins from the MM (eg, Wt-1, Pax2, Eyal, Six1, Sall 1) and from the UB itself (Pax2, Lim1, Ret) resulting in outgrowth of the UB (reviewed by Shah et al, 2004). Proper activation of the Ret/GDNF signaling pathway in the tip of UB epithelium appears to be essential in the progression of branching morphogenesis (reviewed by Michos, 2009). B-catenin and Gata-3 are important regulators of Ret expression, and correct activity of Ret is regulated by positive (Wnt-11 from MM) and negative (Sprouty1 from the UB) feedback signaling. Additional specific factors are required for (1) early branching (eg, Wnt-4 and 11, fgf 7–10); (2) late branching and maturation (bmp2, activin); and (3) branching termination and tubule maintenance (hepatocyte growth factor, transforming growth factor-alpha, epidermal growth factor receptor) (reviewed by Shah et al, 2004). BMP-7, SHH, and Wnt-11 produced from the branching ureteric bud induce the MM to differentiate. These factors induce the activation of Pax2, alpha-8-integrin, and Wnt-4 in the renal mesenchymal cells, resulting in condensation of the MM and the formation of pretubular aggregate and primitive renal vesicle (reviewed by Burrow, 2000). With the continued induction from the UB and the autocrine activity of Wnt-4, the pretubular aggregates differentiate into comma-shaped bodies. Platelet derived growth factor alpha-beta and vascular endothelial growth factor expression are required for initiating the migration of endothelial cells into the cleft of the comma-shaped bodies to form rudimentary glomerular capillary tufts (reviewed by Burrow, 2000). Wt-1 and Pod-1 may have important functions in the regulation of gene transcription necessary for the differentiation of podocytes (Ballermann, 2005).

Failure of the metanephros to ascend leads to an ectopic kidney. An ectopic kidney may be on the proper side but low (simple ectopy) or on the opposite side (crossed ectopy) with or without fusion. Failure to rotate during ascent causes a malrotated kidney.

Fusion of the paired metanephric masses leads to various anomalies—most commonly a horseshoe kidney.

The ureteral bud from the mesonephric duct may bifurcate, causing a bifid ureter at various levels depending on the time of the bud's subdivision. An accessory ureteral bud may develop from the mesonephric duct, thereby forming a duplicated ureter, usually meeting the same metanephric mass. Rarely, each bud has a separate metanephric mass, resulting in supernumerary kidneys.

If the double ureteral buds are close together on the mesonephric duct, they open near each other in the bladder. In this case, the main ureteral bud, which is the first to appear and the most caudal on the mesonephric ducts, reaches the bladder first. It then starts to move upward and laterally and is followed later by the second accessory bud as it reaches the urogenital sinus. The main ureteral bud (now more cranial on the urogenital sinus) drains the lower portion of the kidney. The two ureteral buds reverse their relationship as they move from the mesonephric duct to the urogenital sinus. This is why double ureters always cross (Weigert-Meyer law). If the two ureteral buds are widely separated on the mesonephric duct, the accessory bud appears more proximal and ends in the bladder with an ectopic orifice lower than the normal one. This ectopic orifice could still be in the bladder close to its outlet, in the urethra, or even in the genital duct system (Figure 2–3). A single ureteral bud that arises higher than normal on the mesonephric duct can also end in a similar ectopic location.

Lack of development of a ureteral bud results in a solitary kidney and a hemitrigone.

The blind end of the hindgut caudal to the point of origin of the allantois expands to form the cloaca, which is separated from the outside by a thin plate of tissue (the cloacal membrane) lying in an ectodermal depression (the proctodeum) under the root of the tail. At the 4-mm stage, starting at the cephalic portion of the cloaca where the allantois and gut meet, the cloaca progressively divides into two compartments by the caudal growth of a crescentic fold, the urorectal fold. The two limbs of the fold bulge into the lumen of the cloaca from either side, eventually meeting and fusing. The division of the cloaca into a ventral portion (urogenital sinus) and a dorsal portion (rectum) is completed during the 7th week. During the development of the urorectal septum, the cloacal membrane undergoes a reverse rotation, so that the ectodermal surface is no longer directed toward the developing anterior abdominal wall but gradually is turned to face caudally and slightly posteriorly. This change facilitates the subdivision of the cloaca and is brought about mainly by development of the infraumbilical portion of the anterior abdominal wall and regression of the tail. The mesoderm that passes around the cloacal membrane to the caudal attachment of the umbilical cord proliferates and grows, forming a surface elevation, the genital tubercle. Further growth of the infraumbilical part of the abdominal wall progressively separates the umbilical cord from the genital tubercle. The division of the cloaca is completed before the cloacal membrane ruptures, and its two parts therefore have separate openings. The ventral part is the primitive urogenital sinus, which has the shape of an elongated cylinder and is continuous cranially with the allantois; its external opening is the urogenital ostium. The dorsal part is the rectum, and its external opening is the anus.

Traditionally, it is believed that the urogenital sinus receives the mesonephric ducts. The caudal end of the mesonephric duct distal to the ureteral bud (the common excretory duct) is progressively absorbed into the urogenital sinus. By the 7th week, the mesonephric duct and the ureteral bud have independent opening sites. This introduces an island of mesodermal tissue amid the surrounding endoderm of the urogenital sinus. As development progresses, the opening of the mesonephric duct (which will become the ejaculatory duct) migrates downward and medially. The opening of the ureteral bud (which will become the ureteral orifice) migrates upward and laterally. The absorbed mesoderm of the mesonephric duct expands with this migration to occupy the area limited by the final position of these tubes (Figure 2–3). This will later be differentiated as the trigonal structure, which is the only mesodermal inclusion in the endodermal vesicourethral unit.

Recent studies suggest an alternative path of development (reviewed by McInnes and Michaud, 2009). The right and left common excretory duct appears to undergo gradual programmed cell death; the elimination of the common excretory ducts brings the distal ureters in immediate contact with the urogenital sinus epithelium. Concurrently, the ureters undergo a 180° rotation around the axis of the mesonephric duct (also known as the Wolffian duct). The distal segment of the ureters then also undergoes apoptosis. As a result, this process generates a new ureteral connection point in the urogenital sinus region that will give rise to the bladder, while the Wolffian duct remains in the region giving rise to the urethra. Further growth of the bladder and urethra moves the ureteral orifices cranially, while those to the Wolffian ducts move caudally. This pattern of development is supported by recent studies that suggest the trigone is formed mostly from bladder smooth muscle and less so from the ureters. Condensation of myoblasts in the region between the openings of the ureters and Wolffian ducts at 12 weeks of gestation gives rise to the trigone, as a single circular muscular layer and the muscles from the distal ureters cross midline to form the interureteral fold (Oswald et al, 2006).

The urogenital sinus can be divided into two main segments. The dividing line, the junction of the combined Müllerian ducts with the dorsal wall of the urogenital sinus, is an elevation called Müller's tubercle, which is the most fixed reference point in the whole structure and which is discussed in a subsequent section. The segments are as follows:

1. The ventral and pelvic portion forms the bladder, part of the urethra in males, and the whole urethra in females. This portion receives the ureter.

2. The urethral, or phallic, portion receives the mesonephric and the fused Müllerian ducts. This will be part of the urethra in males and forms the lower fifth of the vagina and the vaginal vestibule in females.

During the 3rd month, the ventral part of the urogenital sinus starts to expand and forms an epithelial sac whose apex tapers into an elongated, narrowed urachus. The pelvic portion remains narrow and tubular; it forms the whole urethra in females and the supramontanal portion of the prostatic urethra in males. The splanchnic mesoderm surrounding the ventral and pelvic portion of the urogenital sinus begins to differentiate into interlacing bands of smooth muscle fibers and an outer fibrous connective tissue coat. By the 12th week, the layers characteristic of the adult urethra and bladder are recognizable (Figure 2–4).

The part of the urogenital sinus caudal to the opening of the Müllerian duct forms the vaginal vestibule and contributes to the lower fifth of the vagina in females (Figure 2–5). In males, it forms the inframontanal part of the prostatic urethra and the membranous urethra. The penile urethra is formed by the fusion of the urethral folds on the ventral surface of the genital tubercle. In females, the urethral folds remain separate and form the labia minora. The glandular urethra in males is formed by canalization of the urethral plate. The bladder originally extends up to the umbilicus, where it is connected to the allantois that extends into the umbilical cord. The allantois usually is obliterated at the level of the umbilicus by the 15th week. The bladder then starts to descend by the 18th week. As it descends, its apex becomes stretched and narrowed, and it pulls on the already obliterated allantois, now called the urachus. By the 20th week, the bladder is well separated from the umbilicus, and the stretched urachus becomes the middle umbilical ligament.

The prostate develops as multiple solid outgrowths of the urethral epithelium both above and below the entrance of the mesonephric duct. These simple tubular outgrowths begin to develop in five distinct groups at the end of the 11th week and are complete by the 16th week (112-mm stage). They branch and rebranch, ending in a complex duct system that encounters the differentiating mesenchymal cells around this segment of the urogenital sinus. These mesenchymal cells start to develop around the tubules by the 16th week and become denser at the periphery to form the prostatic capsule. By the 22nd week, the muscular stroma is considerably developed, and it continues to increase progressively until birth.

From the five groups of epithelial buds, five lobes are eventually formed: anterior, posterior, median, and two lateral lobes. Initially, these lobes are widely separated, but later they meet, with no definite septa dividing them. Tubules of each lobe do not intermingle with each other but simply lie side by side.

The anterior lobe tubules begin to develop simultaneously with those of the other lobes. Although in the early stages, the anterior lobe tubules are large and show multiple branches; gradually, they contract and lose most of the branches. They continue to shrink so that at birth, they show no lumen and appear as small, solid embryonic epithelial outgrowths. In contrast, the tubules of the posterior lobe are fewer in number yet larger, with extensive branching. These tubules, as they grow, extend posterior to the developing median and lateral lobes and form the posterior aspect of the gland, which may be felt rectally.

Prostate development results from complex interaction between urogenital sinus epithelium and mesenchyme in the presence of androgens (reviewed by Cunha et al, 2004, and Thomson, 2008). Early in development, the androgen receptors are solely expressed in the urogenital sinus mesenchyme. Under the influence of androgen, the mesenchyme induces epithelial bud formation, regulates the growth and branching of epithelial bud, promotes differentiation of a secretory epithelium, and specifies differential expression of prostatic secretory proteins. Several members of the fibroblast growth factor (eg, FGF7 and FGF10) play essential role in prostate development, though they do not appear to be directly regulated by androgens. Other factors involved in prostatic duct branching and patterning include Hoxa10, Fut1, and Shh/Ptc. In contrast, other factors such as Activin A serve to inhibit ductal branching in order to maintain tissue homeostasis and regulated growth in the prostate.

Failure of the cloaca to subdivide is rare and results in a persistent cloaca. Incomplete subdivision is more frequent, ending with rectovesical, rectourethral, or rectovestibular fistulas (usually with imperforate anus or anal atresia).

Failure of descent or incomplete descent of the bladder leads to a urinary umbilical fistula (urachal fistula), urachal cyst, or urachal diverticulum depending on the stage and degree of maldescent.

Development of the genital primordia in an area more caudal than normal can result in formation of the corpora cavernosa just caudal to the urogenital sinus outlet, with the urethral groove on its dorsal surface. This defect results in complete or incomplete epispadias depending on its degree. A more extensive defect results in vesical exstrophy. Failure of fusion of urethral folds leads to various grades of hypospadias. This defect, because of its mechanism, never extends proximal to the bulbous urethra. This is in contrast to epispadias, which usually involves the entire urethra up to the internal meatus.

Most of the structures that make up the embryonic genital system have been taken over from other systems, and their readaptation to genital function is a secondary and relatively late phase in their development. The early differentiation of such structures is therefore independent of sexuality. Furthermore, each embryo is at first morphologically bisexual, possessing all the necessary structures for either sex. The development of one set of sex primordia and the gradual involution of the other are determined by the sex of the gonad.

The sexually undifferentiated gonad is a composite structure. Male and female potentials are represented by specific histologic elements (medulla and cortex) that have alternative roles in gonadogenesis. Normal differentiation involves the gradual predominance of one component.

The primitive sex glands make their appearance during the 5th and 6th weeks within a localized region of the thickening known as the urogenital ridge (this contains both the nephric and the genital primordia). At the 6th week, the gonad consists of a superficial germinal epithelium and an internal blastema. The blastemal mass is derived mainly from proliferative ingrowth from the superficial epithelium, which comes loose from its basement membrane.

During the 7th week, the gonad begins to assume the characteristics of a testis or ovary. Differentiation of the ovary usually occurs somewhat later than differentiation of the testis.

If the gonad develops into a testis, the gland increases in size and shortens into a more compact organ while achieving a more caudal location. Its broad attachment to the mesonephros is converted into a gonadal mesentery known as the mesorchium. The cells of the germinal epithelium grow into the underlying mesenchyme and form cordlike masses. These are radially arranged and converge toward the mesorchium, where a dense portion of the blastemal mass is also emerging as the primordium of the rete testis. A network of strands soon forms that is continuous with the testis cords. The latter also split into three to four daughter cords. These eventually become differentiated into the seminiferous tubules by which the spermatozoa are produced. The rete testis unites with the mesonephric components that will form the male genital ducts, as discussed in a subsequent section (Figure 2–6).

If the gonad develops into an ovary, it (like the testis) gains a mesentery (mesovarium) and settles in a more caudal position. The internal blastema differentiates in the 9th week into a primary cortex beneath the germinal epithelium and a loose primary medulla. A compact cellular mass bulges from the medulla into the mesovarium and establishes the primitive rete ovarii. At 3–4 months of age, the internal cell mass becomes young ova. A new definitive cortex is formed from the germinal epithelium as well as from the blastema in the form of distinct cellular cords (Pflüger's tubes), and a permanent medulla is formed. The cortex differentiates into ovarian follicles containing ova.

The molecular mechanism that regulates testis and ovary differentiation remains to be fully defined. In the presence of a Y chromosome, SRY (as known as testis determining factor [TDF]) induces the upregulation of Sox 9 in the undifferentiated gonad (reviewed by Sekido, 2010). This in turn upregulates the expression of FGF9 and increases PGD2 synthesis, both helping to maintain Sox 9 expression. Sox 9 directs the differentiation of cells into Sertoli cell by activating several downstream genes such as Amh, Cbln4, FGF9, and Ptgds. In the absence of a Y chromosome and SRY, Rspo1 is upregulated in the undifferentiated gonads (reviewed by Nef and Vassalli, 2009). Rspo1 is required for Wnt-4 expression and together they activate β-catenin, which, in turn, suppresses the formation of the testis cords by inhibiting Sox 9 and FGF9. A second pathway involving the upregulation of Foxl2 also serves to inhibit Sox 9 and FGF9 activity, contributing to the development of the ovary.

Descent of the Gonads

Testis

In addition to its early caudal migration, the testis later leaves the abdominal cavity and descends into the scrotum. By the 3rd month of fetal life, the testis is located retroperitoneally in the false pelvis. A fibromuscular band (the gubernaculum) extends from the lower pole of the testis through the developing muscular layers of the anterior abdominal wall to terminate in the subcutaneous tissue of the scrotal swelling. The gubernaculum also has several other subsidiary strands that extend to adjacent regions. Just below the lower pole of the testis, the peritoneum herniates as a diverticulum along the anterior aspect of the gubernaculum, eventually reaching the scrotal sac through the anterior abdominal muscles (the processus vaginalis). The testis remains at the abdominal end of the inguinal canal until the 7th month. It then passes through the inguinal canal behind (but invaginating) the processus vaginalis. Normally, it reaches the scrotal sac by the end of the 8th month.

Ovary

In addition to undergoing an early internal descent, the ovary becomes attached through the gubernaculum to the tissues of the genital fold and then attaches itself to the developing uterovaginal canal at its junction with the uterine (fallopian) tubes. This part of the gubernaculum between the ovary and uterus becomes the ovarian ligament; the part between the uterus and the labia majora becomes the round ligament of the uterus. These ligaments prevent extra-abdominal descent, and the ovary enters the true pelvis. It eventually lies posterior to the uterine tubes on the superior surface of the urogenital mesentery, which has descended with the ovary and now forms the broad ligament. A small processus vaginalis forms and passes toward the labial swelling, but it is usually obliterated at full term.

Lack of development of the gonads is called gonadal agenesis. Incomplete development with arrest at a certain phase is called hypogenesis. Supernumerary gonads are rare. The commonest anomaly involves descent of the gonads, especially the testis. Retention of the testis in the abdomen or arrest of its descent at any point along its natural pathway is called cryptorchidism, which may be either unilateral or bilateral. If the testis does not follow the main gubernacular structure but follows one of its subsidiary strands, it will end in an abnormal position, resulting in an ectopic testis.

Failure of union between the rete testis and mesonephros results in a testis separate from the male genital ducts (the epididymis) and azoospermia.

Alongside the indifferent gonads, there are, early in embryonic life, two different yet closely related ducts. One is primarily a nephric duct (Wolffian duct), yet it also serves as a genital duct if the embryo develops into a male. The other (Müllerian duct) is primarily a genital structure from the start.

Both ducts grow caudally to join the primitive urogenital sinus. The Wolffian duct (known as the pronephric duct at the 4-mm stage) joins the ventral part of the cloaca, which will be the urogenital sinus. This duct gives rise to the ureteral bud close to its caudal end. The ureteral bud grows cranially and meets metanephrogenic tissue. The part of each mesonephric duct caudal to the origin of the ureteric bud becomes absorbed into the wall of the primitive urogenital sinus so that the mesonephric duct and ureter open independently. This is achieved at the 15-mm stage (7th week). During this period, starting at the 10-mm stage, the Müllerian ducts start to develop. They reach the urogenital sinus relatively late—at the 30-mm stage (9th week); their partially fused blind ends producing the elevation called Müller's tubercle. Müller's tubercle is the most constant and reliable point of reference in the whole system.

If the gonad starts to develop into a testis (17-mm stage, 7th week), the Wolffian duct will start to differentiate into the male duct system, forming the epididymis, vas deferens, seminal vesicles, and ejaculatory ducts. At this time, the Müllerian duct proceeds toward its junction with the urogenital sinus and immediately starts to degenerate. Only its upper and lower ends persist, the former as the appendix testis and the latter as part of the prostatic utricle.

If the gonad starts to differentiate into an ovary (22-mm stage, 8th week), the Müllerian duct system forms the uterine (fallopian) tubes, uterus, and most of the vagina. The Wolffian ducts, aside from their contribution to the urogenital sinus, remain rudimentary.

Epididymis

Because of the proximity of the differentiating gonads and the nephric duct, some of the mesonephric tubules are retained as the efferent ductules, and their lumens become continuous with those of the rete testis. These tubules, together with the part of the mesonephric duct into which they empty, will form the epididymis. Each coiled ductule makes a conical mass known as the lobule of the epididymis. The cranial end of the mesonephric duct becomes highly convoluted, completing the formation of the epididymis. This is an example of direct inclusion of a nephric structure into the genital system. Additional mesonephric tubules, both cephalad and caudal to those that were included in the formation of the epididymis, remain as rudimentary structures, that is, the appendix of the epididymis and the paradidymis.

Vas Deferens, Seminal Vesicles, and Ejaculatory Ducts

The mesonephric duct caudal to the portion forming the epididymis forms the vas deferens. Shortly before this duct joins the urethra (urogenital sinus), a localized dilatation (ampulla) develops, and the saccular convoluted structure that will form the seminal vesicle is evaginated from its wall. The mesonephric duct between the origin of the seminal vesicle and the urethra forms the ejaculatory duct. The whole mesonephric duct now achieves its characteristic thick investment of smooth muscle, with a narrow lumen along most of its length.

Both above and below the point of entrance of the mesonephric duct into the urethra, multiple outgrowths of urethral epithelium mark the beginning of the development of the prostate. As these epithelial buds grow, they meet the developing muscular fibers around the urogenital sinus, and some of these fibers become entangled in the branching tubules of the growing prostate and become incorporated into it, forming its muscular stroma (Figure 2–4).

The Müllerian ducts, which are a paired system, are seen alongside the mesonephric duct. It is not known whether they arise directly from the mesonephric ducts or separately as an invagination of the celomic epithelium into the parenchyma lateral to the cranial extremity of the mesonephric duct, but the latter theory is favored. The Müllerian duct develops and runs lateral to the mesonephric duct. Its opening into the celomic cavity persists as the peritoneal ostium of the uterine tube (later it develops fimbriae). The other end grows caudally as a solid tip and then crosses in front of the mesonephric duct at the caudal extremity of the mesonephros. It continues its growth in a caudomedial direction until it meets and fuses with the Müllerian duct of the opposite side. The fusion is partial at first, so there is a temporary septum between the two lumens. This later disappears, leaving one cavity that will form the uterovaginal canal. The potential lumen of the vaginal canal is completely packed with cells. The solid tip of this cord pushes the epithelium of the urogenital sinus outward, where it becomes Müller's tubercle (33-mm stage, 9th week). The Müllerian ducts actually fuse at the 63-mm stage (13th week), forming the sinovaginal node, which receives a limited contribution from the urogenital sinus. (This contribution forms the lower fifth of the vagina.)

The urogenital sinus distal to Müller's tubercle, originally narrow and deep, shortens, widens, and opens to form the floor of the pudendal or vulval cleft. This results in separate openings for the vagina and urethra and also brings the vaginal orifice to its final position nearer the surface. At the same time, the vaginal segment increases appreciably in length. The vaginal vestibule is derived from the infratubercular segment of the urogenital sinus (in males, the same segment will form the inframontanal part of the prostatic urethra and the membranous urethra). The labia minora are formed from the urethral folds (in males they form the pendulous urethra). The hymen is the remnant of the Müllerian tubercle. The lower fifth of the vagina is derived from the portion of the urogenital sinus that combines with the sinovaginal node. The remainder of the vagina and the uterus are formed from the lower (fused) third of the Müllerian ducts. The uterine tubes (fallopian tubes, oviducts) are the cephalic two-thirds of the Müllerian ducts (Figure 2–6).

Nonunion of the rete testis and the efferent ductules can occur and, if bilateral, causes azoospermia and sterility. Failure of the Müllerian ducts to approximate or to fuse completely can lead to various degrees of duplication in the genital ducts. Congenital absence of one or both uterine tubes or of the uterus or vagina occurs rarely.

Arrested development of the infratubercular segment of the urogenital sinus leads to its persistence, with the urethra and vagina having a common duct to the outside (urogenital sinus).

During the 8th week, external sexual differentiation begins to occur. Not until 3 months, however, do the progressively developing external genitalia attain characteristics that can be recognized as distinctively male or female. During the indifferent stage of sexual development, three small protuberances appear on the external aspect of the cloacal membrane. In front is the genital tubercle, and on either side of the membrane are the genital swellings.

With the breakdown of the urogenital membrane (17-mm stage, 7th week), the primitive urogenital sinus achieves a separate opening on the undersurface of the genital tubercle.

The urogenital sinus opening extends on the ventral aspect of the genital tubercle as the urethral groove. The primitive urogenital orifice and the urethral groove are bounded on either side by the urethral folds. The genital tubercle becomes elongated to form the phallus. The corpora cavernosa are indicated in the 7th week as paired mesenchymal columns within the shaft of the penis. By the 10th week, the urethral folds start to fuse from the urogenital sinus orifice toward the tip of the phallus. At the 14th week, the fusion is complete and results in the formation of the penile urethra. The corpus spongiosum results from the differentiation of the mesenchymal masses around the formed penile urethra.

The glans penis becomes defined by the development of a circular coronary sulcus around the distal part of the phallus. The urethral groove and the fusing folds do not extend beyond the coronary sulcus. The glandular urethra develops as a result of canalization of an ectodermal epithelial cord that has grown through the glans. This canalization reaches and communicates with the distal end of the previously formed penile urethra. During the 3rd month, a fold of skin at the base of the glans begins growing distally and, 2 months later, surrounds the glans. This forms the prepuce. Meanwhile, the genital swellings shift caudally and are recognizable as scrotal swellings. They meet and fuse, resulting in the formation of the scrotum, with two compartments partially separated by a median septum and a median raphe, indicating their line of fusion.

Until the 8th week, the appearance of the female external genitalia closely resembles that of the male genitalia except that the urethral groove is shorter. The genital tubercle, which becomes bent caudally and lags in development, becomes the clitoris. As in males (though on a minor scale), mesenchymal columns differentiate into corpora cavernosa, and a coronary sulcus identifies the glans clitoridis. The most caudal part of the urogenital sinus shortens and widens, forming the vaginal vestibule. The urethral folds do not fuse but remain separate as the labia minora. The genital swellings meet in front of the anus, forming the posterior commissure, while the swellings as a whole enlarge and remain separated on either side of the vestibule and form the labia majora.

Absence or duplication of the penis or clitoris is very rare. More commonly, the penis remains rudimentary or the clitoris shows hypertrophy. These anomalies may be seen alone or, more frequently, in association with pseudohermaphroditism. Concealed penis and transposition of penis and scrotum are relatively rare anomalies.

Failure or incomplete fusion of the urethral folds results in hypospadias (see preceding discussion). Penile development is also anomalous in cases of epispadias and exstrophy (see preceding discussion).

General

Anomalies of the Nephric System

Anomalies of the Vesicourethral Unit

Gonadal Anomalies