Indifferent (Sexless) Stage
Two pairs of genital ducts are initially present in both sexes: (1) the mesonephric (wolffian) ducts, which give rise to the male ducts and a derivative, the seminal vesicles; and (2) the paramesonephric (müllerian) ducts, which form the oviducts, uterus, and part of the vagina. When the adult structures are described as derivatives of embryonic ducts, this refers to the epithelial lining of the structures. Muscle and connective tissues of the differentiating structures originate from splanchnic mesoderm and mesenchyme adjacent to ducts. Mesonephric ducts are originally the excretory ducts of the mesonephric "kidneys" (see previous text), and they develop early in the embryonic period, about 2 weeks before development of paramesonephric ducts (weeks 6–10). The 2 pairs of genital ducts share a close anatomic relationship in their bilateral course through the urogenital ridge. At their caudal limit, both sets contact the part of the cloaca that is later separated as the urogenital sinus (Figs. 2–5, 2–6, and 2–10). Determination of the ductal sex of the embryo (ie, which pair of ducts will continue differentiation rather than undergo regression) is established initially by the gonadal sex and later by the continuing influence of hormones.
Formation of each paramesonephric duct begins early in the sixth week as an invagination of coelomic epithelium in the lateral wall of the cranial end of the urogenital ridge and adjacent to each mesonephric duct. The free edges of the invaginated epithelium join to form the duct except at the site of origin, which persists as a funnel-shaped opening, the future ostium of the oviduct. At first, each paramesonephric duct grows caudally through the mesenchyme of the urogenital ridge and laterally parallel to a mesonephric duct. More inferiorly, the paramesonephric duct has a caudomedial course, passing ventral to the mesonephric duct. As it follows the ventromedial bend of the caudal portion of the urogenital ridge, the paramesonephric duct then lies medial to the mesonephric duct, and its caudal tip lies in close apposition to its counterpart from the opposite side (Fig. 2–10). At approximately the eighth week, the caudal segments of the right and left ducts fuse medially and their lumens coalesce to form a single cavity. This conjoined portion of the Y-shaped paramesonephric ducts becomes the uterovaginal primordium, or canal.
The mesonephric ducts persist in the male and, under the stimulatory influence of testosterone, differentiate into the internal genital ducts (epididymis, ductus deferens, and ejaculatory ducts). Near the cranial end of the duct, some of the mesonephric tubules (epigenital mesonephric tubules) of the mesonephric kidney persist lateral to the developing testis. These tubules form a connecting link, the ductuli efferentes, between the duct and the rete testis (Fig. 2–10). The cranial portion of each duct becomes the convoluted ductus epididymis. The ductus deferens forms when smooth muscle from adjacent splanchnic mesoderm is added to the central segment of the mesonephric duct. The seminal vesicle develops as a lateral bud from each mesonephric duct just distal to the junction of the duct and the urogenital sinus (Fig. 2–7). The terminal segment of the duct between the sinus and seminal vesicle forms the ejaculatory duct, which becomes encased by the developing prostate gland early in the 12th week (see Differentiation of the Urogenital Sinus). A vestigial remnant of the duct may persist cranially near the head of the epididymis as the appendix epididymis, whereas remnants of mesonephric tubules near the inferior pole of the testis and tail of the epididymis may persist as the paradidymis (Fig. 2–10).
The paramesonephric ducts begin to undergo morphologic regression centrally (and progress cranially and caudally) about the time they meet the urogenital sinus caudally (approximately the start of the ninth week). Regression is effected by nonsteroidal antimüllerian hormone produced by the differentiating Sertoli cells slightly before androgen is produced by the Leydig cells (see Testis). Antimüllerian hormone is produced from the time of early testicular differentiation until birth (ie, not only during the period of regression of the paramesonephric duct). However, ductal sensitivity to antimüllerian hormone in the male seems to exist for only a short "critical" time preceding the first signs of ductal regression. Vestigial remnants of the cranial end of the ducts may persist as the appendix testis on the superior pole of the testis (Fig. 2–10). Caudally, a ductal remnant is considered to be part of the prostatic utricle of the seminal colliculus in the prostatic urethra.
Relocation of the Testes & Ducts
Around weeks 5–6, a bandlike condensation of mesenchymal tissue in the urogenital ridge forms near the caudal end of the mesonephros. Distally, this gubernacular precursor tissue grows into the area of the undifferentiated tissue of the anterior abdominal wall and toward the genital swellings. Proximally, the gubernaculum contacts the mesonephric duct when the mesonephros regresses and the gonad begins to form. By the start of the fetal period, the mesonephric duct begins differentiation and the gubernaculum adheres indirectly to the testis via the duct, which lies in the mesorchium of the testis. The external genitalia differentiate over the seventh to about the 19th week. By the 12th week, the testis is near the deep inguinal ring, and the gubernaculum is virtually at the inferior pole of the testis, proximally, and in the mesenchyme of the scrotal swellings, distally.
Although the testis in early development is near the last thoracic segment, it is still close to the area of the developing deep inguinal ring. With rapid growth of the lumbar region and "ascent" of the metanephric kidney, the testis remains relatively immobilized by the gubernaculum, although there is the appearance of a lengthy transabdominal "descent" from an upper abdominal position. The testis descends through the inguinal canal around the 28th week and into the scrotum about the 32nd week. Testicular blood vessels form when the testis is located on the dorsal body wall and retain their origin during the transabdominal and pelvic descent of the testis. The mesonephric duct follows the descent of the testis and hence passes anterior to the ureter, which follows the retroperitoneal ascent of the kidney (Fig. 2–10).
Hutson JM, Balic A, Nation T, Southwell B. Cryptorchidism. Semin Pediatr Surg
Shaw CM, Stanczyk FZ, Egleston BL, et al. Serum antimüllerian hormone in healthy premenopausal women. Fertil Steril
Turner ME, Ely D, Prokop J, Milsted A. Sry, more than testis determination? Am J Physiol Regul Integr Comp Physiol
Vallerie AM, Breech LL. Update in Müllerian anomalies: diagnosis, management, and outcomes Curr Opin Obstet Gynecol
Female: Uterus & Uterine Tubes
Virtually all portions of these paired ducts degenerate in the female embryo, with the exception of the most caudal segment between the ureteric bud and the cloaca, which is later incorporated into the posterior wall of the urogenital sinus (Figs. 2–5 and 2–6) as the trigone of the urinary bladder. Regression begins just after gonadal sex differentiation and is finished near the onset of the third trimester. Cystlike or tubular vestiges of mesonephric duct (Fig. 2–11) may persist to variable degrees parallel with the vagina and uterus (Gartner's cysts). Other mesonephric remnants of the duct or tubules may persist in the broad ligament (epoophoron).
Female genital tract. Gubernacular derivatives and mesonephric vestiges are shown.
Differentiation of müllerian ducts in female embryos produces the uterine tubes, uterus, and probably the fibromuscular wall of the vagina. In contrast to the ductal/gonadal relationship in the male, ductal differentiation in the female does not require the presence of ovaries. Formation of the bilateral paramesonephric ducts during the second half of the embryonic period has been described [see Indifferent (Sexless) Stage]. By the onset of the fetal period, the 2 ducts are joined caudally in the midline, and the fused segment of the new Y-shaped ductal structure is the uterovaginal primordium (Fig. 2–8). The nonfused cranial part of each paramesonephric duct gives rise to the uterine tubes (oviducts), and the distal end of this segment remains open and will form the ostium of the oviduct.
Early in the ninth week, the uterovaginal primordium contacts medianly the dorsal wall of the urogenital sinus. This places the primordium at a median position between the bilateral openings of the mesonephric ducts, which joined the dorsal wall during the fifth week before subdivision of the urogenital sinus from the cloaca occurred (Figs. 2–8 and 2–9). A ventral protrusion of the dorsal wall of the urogenital sinus forms at the area of contact of the uterovaginal primordium with the wall and between the openings of the mesonephric ducts. In reference to its location, this protrusion is called the sinusal tubercle (sinus tubercle, paramesonephric tubercle, müllerian tubercle). This tubercle may consist of several types of epithelia derived from the different ducts as well as from the wall of the sinus.
Shortly after the sinusal tubercle forms, midline fusion of the middle and caudal portions of the paramesonephric ducts is complete, and the vertical septum (apposed walls of the fused ducts) within the newly established uterovaginal primordium degenerates, creating a single cavity or canal (Fig. 2–12). The solid tip of this primordium continues to grow caudally, while a mesenchymal thickening gradually surrounds the cervical region of the uterovaginal primordium. The primordium gives rise to the fundus, body, and isthmus of the uterus, specifically the endometrial epithelium and glands of the uterus. The endometrial stroma and smooth muscle of the myometrium are derived from adjacent splanchnic mesenchyme. The epithelium of the cervix forms from the lower aspect of the primordium. Development of the various components of the uterus covers the 3 trimesters of gestation. The basic structure is generated during the latter part of the first trimester. The initial formation of glands and muscular layer occurs near midgestation, whereas mucinous cells in the cervix appear during the third trimester.
Sagittal cutaway view of female urogenital sinus and uterovaginal primordium (fused paramesonephric ducts). Sinovaginal bulbs form in the 10th week.
The formation of the vagina is discussed in Differentiation of the Urogenital Sinus, even though the question of whether the vaginal epithelium is a sinusal or paramesonephric derivative (or both) has not been resolved. The fibromuscular wall of the vagina is generally considered to be derived from the uterovaginal primordium (Fig. 2–13).
Schematic drawing of differentiation of urogenital sinus and paramesonephric ducts in the female; formation of urinary bladder, urethra, uterine tubes, uterus, and vagina. (Explanatory symbols are given in Fig. 2–1.)
Relocation of the Ovaries & Formation of Ligaments
Transabdominal "descent" of the ovary, unlike that of the testis, is restricted to a relatively short distance, presumably (at least partly) because of attachment of the gubernaculum to the paramesonephric duct. Hence, relocation of the ovary appears to involve both (1) a passive rotatory movement of the ovary as its mesentery is drawn by the twist of the developing ductal mesenteries and (2) extensive growth of the lumbosacral region of the fetus. The ovarian vessels (like the testicular vessels) originate or drain near the point of development of the gonad, the arteries from the aorta just inferior to the renal arteries and the veins to the left renal vein or to the vena cava from the right gonad.
Initial positioning of the ovary on the anteromedial aspect of the urogenital ridge is depicted in Figure 2–10, as is the relationship of the paramesonephric duct lateral to the degenerating mesonephros, the ovary, and the urogenital mesentery. The urogenital mesentery between the ridge and the dorsal body wall represents the first mesenteric support for structures developing in the ridge.
Alterations within the urogenital ridge eventually result in formation of contiguous double-layered mesenteries supporting the ovary and segments of the paramesonephric ducts. Enlargement of the ovary and degeneration of the adjacent mesonephric tissue bring previously separated layers of coelomic mesothelium into near apposition, establishing the mesentery of the ovary, the mesovarium. Likewise, mesonephric degeneration along the region of differentiation of the unfused cranial segment of the paramesonephric ducts establishes the mesosalpinx. Caudally, growth and fusion ventromedially of these bilateral ducts "sweep" the once medially attached mesenteries of the ducts toward the midline. These bilateral mesenteries merge over the fused uterovaginal primordium and extend laterally to the pelvic wall to form a continuous double-layered "drape," the mesometrium of the broad ligament, between the upper portion of the primordium and the posterolateral body wall. This central expanse of mesentery creates the rectouterine and vesicouterine pouches. The midline caudal fusion of the ducts also alters the previous longitudinal orientation of the upper free segments of the ducts (the oviducts) to a near transverse orientation. During this alteration, the attached mesovarium is drawn from a medial relationship into a posterior relationship with the paramesonephric mesentery of the mesosalpinx and the mesometrium.
The suspensory ligament of the ovary, through which the ovarian vessels, nerves, and lymphatics traverse, forms when cranial degeneration of the mesonephric tissue and regression of the urogenital ridge adjacent to the ovary reduce these tissues to a peritoneal fold.
The round ligament of the uterus and the proper ovarian ligament are both derivatives of the gubernaculum, which originates as a mesenchymal condensation at the caudal end of the mesonephros and extends over the initially short distance to the anterior abdominal wall (see Relocation of the Testes and Ducts). As the gonad enlarges and the mesonephric tissue degenerates, the cranial attachment of the gubernaculum appears to "shift" to the inferior aspect of the ovary. Distally, growth of the fibrous gubernaculum continues into the inguinal region. However, the midportion of the gubernaculum becomes attached, inexplicably, to the paramesonephric duct at the uterotubal junction. Formation of the uterovaginal primordium by caudal fusion of the paramesonephric ducts apparently carries the attached gubernaculum medially within the cover of the encompassing mesentery of the structures (ie, the parts of the developing broad ligament). This fibrous band of connective tissue eventually becomes 2 ligaments.
Cranially, the band is the proper ligament of the ovary, extending between the inferior pole of the ovary and the lateral wall of the uterus just inferior to the oviduct. Caudally, it continues as the uterine round ligament from a point just inferior to the proper ovarian ligament and extending through the inguinal canal to the labium majus.
Anomalies of the Uterine Tubes (Oviducts, Fallopian Tubes)
The uterine tubes are derivatives of the cranial segments of the paramesonephric (müllerian) ducts, which differentiate in the urogenital ridge between the sixth and ninth weeks (Fig. 2–10). Ductal formation begins with invagination of the coelomic epithelium in the lateral coelomic bay. The initial depression remains open to proliferate and differentiate into the ostium (Fig. 2–10). Variable degrees of duplication of the ostium sometimes occur; in such cases, the leading edges of the initial ductal groove presumably did not fuse completely or anomalous proliferation of epithelium around the opening occurred.
Absence of a uterine tube is very rare when otherwise normal ductal and genital derivatives are present. This anomaly has been associated with (1) ipsilateral absence of an ovary and (2) ipsilateral unicornuate uterus (and probable anomalous broad ligament). Bilateral absence of the uterine tubes is most frequently associated with lack of formation of the uterus and anomalies of the external genitalia. Interestingly, absence of the derivatives of the lower part of the müllerian ducts with persistence of the uterine tubes occurs more frequently than the reverse condition. This might be expected, as the müllerian ducts form in a craniocaudal direction.
Partial absence of a uterine tube (middle or caudal segment) also has been reported. The cause of partial absence is unknown, although several theories have been advanced. One theory holds that when the unilateral anomaly coincides with ipsilateral ovarian absence, a "vascular accident" might occur following differentiation of the ducts and ovaries. Obviously, various factors resulting in somewhat localized atresia could be proposed. From a different perspective, bilateral absence of the uterine tubes as an associated disorder in a female external phenotype is characteristic of testicular feminization syndrome or androgen insensitivity syndrome (nonpersistence of the rest of the paramesonephric ducts, anomalous external genitalia, hypoplastic male genital ducts, and testicular differentiation with usual ectopic location).
The epithelium of the uterus and cervix and the fibromuscular wall of the vagina are derived from the paramesonephric (müllerian) ducts, the caudal ends of which fuse medially to form the uterovaginal primordium. Most of the primordium gives rise to the uterus (Fig. 2–13). Subsequently, the caudal tip of the primordium contacts the pelvic part of the urogenital sinus, and the interaction of the sinus (sinovaginal bulbs) and primordium leads to differentiation of the vagina. Various steps in this sequential process can go awry, such as (1) complete or partial failure of one or both ducts to form (agenesis), (2) lack of or incomplete fusion of the caudal segments of the paired ducts (abnormal uterovaginal primordium), or (3) failure of development after successful formation (aplasia or hypoplasia). Many types of anomalies may occur because of the number of sites for potential error, the complex interactions necessary for the development of the müllerian derivatives, and the duration of the complete process.
Complete agenesis of the uterus is very rare, and associated vaginal anomalies are usually expected. Also, a high incidence of associated structural or positional abnormalities of the kidney has been reported; there has been speculation that the initial error in severe cases may be in the development of the urinary system and then in the formation of the paramesonephric ducts.
Aplasia of the paramesonephric ducts (müllerian aplasia) is more common than agenesis and could occur after formation and interaction of the primordium with the urogenital sinus. A rudimentary uterus or a vestigial uterus (ie, varying degrees of fibromuscular tissue present) is most frequently accompanied by partial or complete absence of the vagina. As in uterine agenesis, ectopic kidney or absence of a kidney is frequently associated with uterine aplasia (in about 40% of cases). Uterine hypoplasia variably yields a rudimentary or infantile uterus and is associated with normal or abnormal uterine tubes and ovaries. Unilateral agenesis or aplasia of the ducts gives rise to uterus unicornis, whereas unilateral hypoplasia may result in a rudimentary horn that may or may not be contiguous with the lumen of the "normal" horn (uterus bicornis unicollis with one unconnected rudimentary horn; Fig. 2–14). The status of the rudimentary horn must be considered for potential hematometra, or blood in the uterus that cannot exit, at puberty.
Uterine anomalies. (*Redrawn and reproduced, with permission, from Toaff R. A major genital malformation: communicating uteri. Obstet Gynecol 1974;43:221.)
Anomalous unification caudally of the paramesonephric ducts results in many uterine malformations (Fig. 2–14). The incidence of defective fusion is estimated to be 0.1–3% of females. Furthermore, faulty unification of the ducts has been cited as the primary error responsible for most anomalies of the female genital tract. Partial or complete retention of the apposed walls of the paired ducts can produce slight (uterus subseptus unicollis) to complete (uterus bicornis septus) septal defects in the uterus. Complete failure of unification of the paramesonephric ducts can result in a double uterus (uterus didelphys) with either a single or double vagina.
Because the cervix forms as an integral part of the uterus, cervical anomalies are often the same as uterine anomalies. Thus, absence or hypoplasia of the cervix is rarely found with a normal uterovaginal tract. The cervix appears as a fibrous juncture between the uterine corpus and the vagina.
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