The urinary and reproductive systems in both males and females are embryologically and anatomically interrelated in that both develop from a urogenital ridge of intermediate mesoderm located along the posterior body wall in the developing abdominal cavity and both open into an endoderm-lined cloaca at the caudal end of the embryo (Table 1.1, Fig. 1.3). During the 4th week of development, excretory tubules of the mesonephros arise within the lateral, or mesonephric, portion of the urogenital ridge along the body axis extending from the thoracic to upper lumbar body segments [2]. The excretory tubules elongate into S-shaped loops encapsulating a rudimentary glomerular capillary tuft located along their medial portion. The lateral end of each excretory tubule attaches to a collecting duct running longitudinally known as the mesonephric or Wolffian duct, which opens into a portion of the cloaca that will invaginate to form the urogenital sinus. As the name implies, the urogenital sinus contributes to the lower urinary tract, namely, the bladder and urethra, as well as a portion of the reproductive tracts in both the male (prostate and prostatic urethra) and female (vagina and vestibule). Initially, the segmental nephrons of the mesonephros provide functional urine output but then regress as the definitive, metanephric kidneys arise from the caudal intermediate mesoderm. The longitudinal mesonephric duct on each side persists and becomes part of a paired set of genital ducts that contribute significantly to the male reproductive tract. As described below, the mesonephric ducts largely regress in the female and normally only contribute to rudimentary structures.

During the 6th week, primordial germ cells appear within the medial, or genital, portion of the urogenital ridge. These germ cells initially arise in the embryo’s epiblast, migrate through the primitive streak during gastrulation in the 3rd week, and come to rest in the wall of the yolk sac near the forming allantois. Soon after gastrulation, the germ cells migrate back into the embryo along the dorsal mesentery of the hindgut and invade the medial edge of the urogenital ridge. In response to the germ cells, the overlying coelomic epithelium of the genital ridge proliferates and invades the mesenchymal tissue to form a series of irregularly shaped, primitive sex cords that remain connected to the surface epithelium and become closely associated with the germ cells. The surrounding mesenchymal cells, in turn, will develop into sex-specific interstitial cells of the gonads that contribute to the differentiation of the male or female phenotype.

During this same period, a second set of genital ducts, the paramesonephric (Müllerian) ducts, arise as the epithelium along the lateral edge of the genital ridge adjacent to the mesonephric ducts invaginates to form a longitudinal tube. At their cranial end, the paramesonephric ducts are lateral to the mesonephric ducts and end in a funnel-shaped opening into the abdominal cavity at about the same level as the superior aspect of the indifferent gonad. Caudally, the paramesonephric ducts continue lateral to the mesonephric ducts and then cross under (ventral to) the mesonephric ducts to course medially and partially fuse in the midline to form the uterine canal. The uterine canal projects caudally until it meets the wall of the urogenital sinus, where it causes a small swelling known as the paramesonephric, or Müllerian, tubercle to form [3].

At this point, the gonads of males and females are indistinguishable. The ductal systems are distinguishable by location only, but not histologically. However, from the 7th week on, the male and female systems diverge greatly as the process of sexual differentiation ensues. In the male, the sex-determining region of the Y-chromosome gene (SRY) acts in conjunction with SOX9 to upregulate the expression of steroidogenic factor 1 (SF1) [4]. SF1 stimulates the differentiation of the epithelial sex cord cells into Sertoli cells, which then secrete anti-Müllerian hormone (AMH, also known as Müllerian inhibiting substance, or MIS) [5]. AMH is a transforming growth factor-beta (TGF-β) family member which induces apoptosis and regression of the paramesonephric ducts. The Sertoli cells also express CYP26, which degrades local retinoic acid, thus inducing meiotic arrest in the germ cells. In this milieu, the germ cells are directed to become spermatogonia [6]. SF1 also directs the differentiation of the interstitial cells of the male gonad into Leydig cells that secrete testosterone, which promotes growth and differentiation of the mesonephric ducts into the efferent ductules, epididymis, vas deferens, and seminal vesicles [7]. Testosterone is further converted by 5-α reductase into dihydrotestosterone, which stimulates growth and differentiation of the prostate and external genitalia.

In the female, SRY expression is absent, and instead the dominant genetic program is directed by WNT4, which initiates differentiation of the female phenotype [8]. Under this program, the surface epithelium of the female gonad proliferates rapidly to give rise to a secondary generation of sex cords known as cortical cords which will then become follicular cells rather than Sertoli cells. As there are no Sertoli cells, AMH is absent and the paramesonephric ducts persist. Moreover, retinoic acid signaling within the gonad induces progression of the germ cells into oogonia that proliferate and enter into the first meiotic division to form primary oocytes. The oocytes, in turn, direct the differentiation of the epithelial cord cells into follicular cells and cells of the surrounding mesenchyme into theca cells. Without Leydig cells, there is not a significant source of testosterone (and therefore DHT) to support the growth of the mesonephric ducts or male external genitalia. Instead, the theca and follicular cells secrete estrogens which promote the growth and development of the paramesonephric ducts and female external genitalia.

The uterine (Fallopian) tubes, uterine corpus, and uterine cervix develop exclusively from the paramesonephric ducts, whereas the vagina has contributions also from the urogenital sinus. The cranial portion of the paramesonephric ducts develop into the uterine (Fallopian) tubes, retaining their funnel-shaped openings into the coelomic cavity, which develop into the infundibulum and fimbriae, while the caudal portion of the paramesonephric ducts, when fused, gives rise to the uterus (Fig. 1.3). At this period, the entire presumptive uterus is a simple canal, without any of the later structural changes found in the adult uterine body or cervix. The uterine canal grows toward and contacts the urogenital sinus at about the 7th week and induces the formation of the paramesonephric tubercle. Concurrent with this process, the endodermal epithelium of the urogenital sinus at the point of contact forms a pair of swellings (sinovaginal bulbs) that fuse into a solid vaginal plate that proliferates and extends cranially, thus pushing the paramesonephric tubercle and forming uterus away from the urogenital sinus. The growth of the vaginal plate and paramesonephric tubercle continues during the 3rd and 4th months followed by a process of canalization that is completed by the 5th month such that the mesenchymal walls of the vaginal fornices are derived from the paramesonephric tubercle and the squamous epithelial surfaces and possibly some of the lowest vagina are of urogenital sinus origin [3]. The initial site where growth of the vaginal plate from the wall of the urogenital sinus commenced usually does not fully canalize, thus leaving a membranous hymen that separates the vaginal canal from the urogenital sinus. While the mesonephric ducts mostly regress in the female, some remnants may remain as rudimentary tubules or cysts found adjacent to the ovary (epoophoron), uterine tube (paroophoron), or along the lateral wall of the uterus and/or vagina (Gartner’s ducts/cysts) (Fig. 1.4).

The development of the external genitalia is apparent by the 4th week of development as the tissue along the rim of the cloacal opening thickens into cloacal folds [9]. Division of the cloaca into urogenital and anal portions occurs during the 5th and 6th weeks by the growth of the urorectal septum, which is a block of mesoderm-derived tissue that grows in between the alimentary and urogenital tracts and eventually fuses with the cloacal folds at the site of the perineal body. Anteriorly, the tissues of the cloacal folds fuse to form the genital tubercle. Posterior to the genital tubercle, the tissue surrounding the opening into the forming urogenital sinus develops into urogenital folds. The posterior-most cloacal folds develop into anal folds that surround the forming anus. Lateral to the urogenital folds, a second set of swellings, the labioscrotal folds, appear. In the male (under androgenic influence, in particular dihydrotestosterone), the genital tubercle develops into the penile glans; the urogenital folds fuse and elongate to form the penile shaft; and the labioscrotal folds fuse to become the scrotum [8]. In the female (under the influence of estrogens rather than androgens), the genital tubercle develops into the clitoral glans, whereas the urogenital and labioscrotal folds give rise to the labia minora and majora, respectively [9] (Fig. 1.5). Anteriorly, the labia majora merge to form the mons pubis, and posteriorly, the labia majora fuse with the perineal body anterior to the anus. The remaining opening of the urogenital sinus exterior to the vaginal introitus (usually completely or partially covered by the hymen) and bounded by the labia minora expands to form the vestibule, the lining of which is thus endoderm derived. This is in contrast to the other structures of the vulva, which are of ectoderm and mesoderm origin and therefore respond differently to hormones or other stimuli evoked in either the normal or diseased state.