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Embryology of the Urogenital System & Congenital Anomalies of the Female Genital Tract
Saturday, August 16, 2008
The adult genital and urinary systems are distinct both in function and in anatomy, with the exception of the male urethra. During development, however, these 2 systems are closely associated. Primordial elements in the urinary system participate in the formation of genital structures; this requisite initial developmental overlap of the 2 systems occurs during the 4–12 weeks after fertilization. The complexity of developmental events in these systems is evident by the incomplete separation of the 2 systems found in some congenital anomalies (eg, female pseudohermaphroditism with persistent urogenital sinus). For the sake of clarity, this chapter describes the embryology of each system separately, rather than following a strict developmental chronology.
This chapter also presents descriptive overviews of some congenital malformations of the female genital tract and, when possible, an explanation of their embryonic origins. In view of the complexity and duration of differentiation and development of the genital and urinary systems, it is not surprising that the incidence of malformations involving these systems is one of the highest (10%) of all body systems. Etiologies of congenital malformations are sometimes categorized on the basis of genetic, environmental, or genetic-plus-environmental (so-called polyfactorial inheritance) factors. Known genetic and inheritance factors reputedly account for about 20% of anomalies detected at birth, aberration of chromosomes for nearly 5%, and environmental factors for nearly 10%. The significance of these statistics must be viewed against reports that (1) an estimated one-third to one-half of human zygotes are lost during the first week of gestation and (2) the cause of possibly 70% of human anomalies is unknown. Even so, congenital malformations remain a matter of concern because they are detected in nearly 6% of infants, and 20% of perinatal deaths are purportedly due to congenital anomalies.
The inherent pattern of normal development of the genital system can be viewed as one directed toward somatic “femaleness,” unless development is directed by factors for “maleness.” The presence and expression of a Y chromosome (and its testis-determining genes) in a normal 46, XY karyotype of somatic cells directs differentiation toward a testis, and normal development of the testis makes available its steroidal and proteinaceous hormones for the selection and differentiation of the genital ducts. In the normal absence of these testicular products, the “female” paramesonephric (müllerian) ducts persist. Normal feminization or masculinization of the external genitalia is also a result of the respective timely absence or presence of androgen.
An infant usually is reared as female or male according to the appearance of the external genitalia. However, genital sex is not always immediately discernible, and the choice of sex of rearing can be an anxiety-provoking consideration. Unfortunately, even when genital sex is apparent, later clinical presentation may unmask disorders of sexual differentiation that can lead to problems in psychological adjustment. Whether a somatic disorder is detected at birth or later, investigative backtracking through the developmental process is necessary for proper diagnosis and treatment.
OVERVIEW OF THE FIRST FOUR WEEKS OF DEVELOPMENT*
The transformation of the bilaminar embryonic disk into a trilaminar disk composed of ectoderm, mesoderm, and endoderm (the 3 embryonic germ layers) occurs during the third week by a process called gastrulation (Fig 4–1). All 3 layers are derived from epiblast. During this process, a specialized longitudinal thickening of epiblast, the primitive streak, forms near the margin (future caudal region) of the bilaminar disk and eventually elongates cephalad through the midline of the disk and extends to the central region. Some epiblastic cells migrate medially through a midline depression of the streak, to the ventral aspect of the streak, after which they become mesoblastic cells. The mesoblastic cells migrate peripherally between most of the epiblast and the hypoblast, forming the middle layer (embryonic mesoderm) of the now trilaminar disk. Other mesoblastic cells migrate into the hypoblastic layer, causing lateral displacement of most, if not all, of the hypoblastic cells. This new ventral layer of the disk becomes the embryonic endoderm. With formation of the new mesodermal layer, the overlying epiblast becomes the embryonic ectoderm, of which the medial part gives rise to neuroectoderm, the forerunner of the neural tube and neural crest (ie, the nervous system). By the end of the third week, 3 clusters of embryonic mesoderm are organized on both sides of the midline-developing notochord and neural tube.
The medial cluster is a thickened longitudinal column of mesoderm called paraxial mesoderm, from which somites, and in turn much of the axial skeleton, will form. The lateralmost cluster is called lateral plate mesoderm, in which a space (or coelom) develops, creating dorsal and ventral mesodermal layers (Fig 4–2). The intermediate mesoderm is located between the paraxial and lateral plate mesoderm and is the origin of the urogenital ridge and, hence, much of the reproductive and excretory systems (Fig 4–3). The primitive streak regresses after the fourth week. Rarely, degeneration of the streak is incomplete and presumptive remnants form a teratoma in the sacrococcygeal region of the fetus (more common in females than in males).
Weeks 4 through 8 of development are called the embryonic period (the fetal period is from week 9 to term) because formation of all major internal and external structures, including the 2 primary forerunners of the urogenital system (urogenital ridge and urogenital sinus), begins during this time. During this period the embryo is most likely to develop major congenital or acquired morphologic anomalies in response to the effects of various agents. During the fourth week, the shape of the embryo changes from that of a trilaminar disk to that of a crescentic cylinder. The change results from “folding,” or flexion, of the embryonic disk in a ventral direction through both its transverse and longitudinal planes. Flexion occurs as midline structures (neural tube and somites) develop and grow at a faster pace than more lateral tissues (ectoderm, 2 layers of lateral plate mesoderm enclosing the coelom between them, and endoderm). Thus, during transverse folding, the lateral tissues on each side of the embryo curl ventromedially and join the respective tissues from the other side, creating a midline ventral tube (the endoderm-lined primitive gut), a mesoderm-lined coelomic cavity (the primitive abdominopelvic cavity), and the incomplete ventral and lateral body wall. Concurrent longitudinal flexion ventrally of the caudal region of the disk establishes the pouch-like distal end, or cloaca, of the primitive gut as well as the distal attachment of the cloaca to the yolk sac through the allantois of the sac (Fig 4–4).
A noteworthy point (see The Gonads, in text that follows) is that the primordial germ cells of the later-developing gonad initially are found close to the allantois and later migrate to the gonadal primordia. Subsequent partitioning of the cloaca during the sixth week results in formation of the anorectal canal and the urogenital sinus, the progenitor of the urinary bladder, urethra, vagina, and other genital structures (Fig 4–1 and Table 4–1; see Subdivision of the Cloaca & Formation of the Urogenital Sinus in following text).
Another consequence of the folding process is the repositioning of the intermediate mesoderm, the forerunner of the urogenital ridge. Laterally adjacent to developing somites (from paraxial mesoderm) before flexion, the intermediate mesoderm is located after flexion just lateral to the dorsal mesentery of the gut and in the dorsal wall of the new body cavity. Thickening of this intermediate mesoderm with subsequent bulging into the cavity will form the longitudinal urogenital ridge (Fig 4–1 and Fig 4–4). Thus, by the end of the fourth week of development, the principal structures (urogenital ridge and cloaca) and tissues that give rise to the urogenital system are present.
THE URINARY SYSTEM
Three excretory “systems” form successively, with temporal overlap, during the embryonic period. Each system has a different excretory “organ,” but the 3 systems share anatomic continuity through development of their excretory ducts. The 3 systems are mesodermal derivatives of the urogenital ridge (Fig 4–3 and Fig 4–4), part of which becomes a longitudinal mass, the nephrogenic cord. The pronephros, or organ of the first system, exists rudimentarily, is nonfunctional, and regresses during the fourth week. However, the developing pronephric ducts continue to grow and become the mesonephric ducts of the subsequent kidney, the mesonephros. The paired mesonephroi exist during 4–8 weeks as simplified morphologic versions of the third, or permanent, set of kidneys, and they may have transient excretory function. The permanent kidney, the metanephros, begins to form in response to an inductive influence of a diverticulum of the mesonephric ducts during the fifth week and becomes functional at 10–13 weeks. During nephric differentiation, the urogenital mass becomes suspended from the dorsal wall by a double-layered urogenital mesentery.
Pronephros
Segmented clusters of cells form in each urogenital ridge opposite the cervical somitic region and give rise to pronephric tubules. The lateral end of a tubule in one segment of the ridge grows caudally to fuse with the end of the pronephric tubule in the next segment, thus initiating the cephalic portion of each of the bilateral pronephric ducts (Fig 4–3). The pronephroi degenerate by the end of the fourth week, but, by initiating formation of pronephric ducts, they set in motion the developmental sequence for the formation of the permanent excretory ducts and kidneys. The pronephric ducts continue to grow caudally until week 5, when they contact and open into the lateral posterior wall of the cloaca.
Mesonephros
Development of the mesonephric glomerulotubular units begins while the pronephric tubules are regressing. Cells in each nephrogenic cord condense to form cell clusters just caudal to the pronephros and adjacent to the caudally growing pronephric duct (now called the mesonephric duct). Each cluster differentiates into a hollow mesonephric vesicle and then a mesonephric tubule. Subsequently, the lateral end of a tubule joins the mesonephric duct (Fig 4–4 and Fig 4–5), while the medial end of the tubule expands into a double-layered, cup-shaped primitive glomerular capsule (Bowman's capsule; Fig 4–6). The capsule is vascularized by a capillary tuft, the glomerulus, derived from the aorta. Proliferation of the tubule's midportion produces a primitive version of a convoluted tubule.
While differentiation of the mesonephros is taking place in the caudal region, regression of mature tubules in the cranial region is also occurring (Fig 4–7). This craniocaudal gradient of differentiation followed by regression can give the impression that the relatively large, ovoid mesonephric kidney “descends” along the posterior wall of the body cavity during the embryonic period. By the end of this period, most remaining mesonephric tubules and glomeruli have begun to degenerate. Some of these tubules (descriptively called epigenital mesonephric tubules) persist in the mesonephric region laterally adjacent to the developing gonad and will participate in formation of the gonad and the male ductuli efferentes (Fig 4–8). A few tubules at other levels may persist as vestigial remnants near the gonad and sometimes become cystic (see Fig 4–14 and Fig 4–15).
Differentiation of the caudal segment of the mesonephric ducts results in (1) incorporation of part of the ducts into the wall of the urogenital sinus (early vesicular trigone, see following text), and (2) formation of a ductal diverticulum, which plays an essential role in formation of the definitive kidney. If male sex differentiation occurs, the major portion of each duct becomes the epididymis, ductus deferens, and ejaculatory duct. Only small vestigial remnants of the duct sometimes persist in the female (Gartner's duct; duct of the epoophoron).
Metanephros (Definitive Kidney)
A. COLLECTING DUCTS
By the end of the fifth week, a ureteric bud, or metanephric diverticulum, forms on the caudal part of the mesonephric duct close to the cloaca (Fig 4–7). The bud gives rise to the collecting tubules, calices, renal pelvis, and ureter (Fig 4–3). The stalk of the elongating bud will become the ureter when the ductal segment between the stalk and the cloaca becomes incorporated into the wall of the urinary bladder (which is a derivative of the partitioned cloaca, see text that follows; Fig 4–9, Fig 4–10, Fig 4–11 and Fig 4–12). The expanded tip, or ampulla, of the bud grows into the adjacent metanephric mesoderm (blastema), and continued growth of the bud eventually relocates the ampulla and associated blastema dorsal to the mesonephros (ie, “retroperitoneal”).
Between week 6 and weeks 20–24, the ampulla subdivides, and successive divisions yield approximately 12–15 generations of buds, or eventual collecting tubules. From weeks 10–14, dilatation of the early generations of tubular branches successively produces the renal pelvis, the major calices, and the minor calices, while the middle generations form the medullary collecting tubules. The last several generations of collecting tubules grow centrifugally into the cortical region of the kidney between weeks 24 and 36.
B. NEPHRONS
Dorsocranial growth of the ureteric bud into the caudal end of the nephrogenic cord brings the bud into contact with the metanephric mesoderm, or metanephric blastema (Fig 4–7). The blastema becomes a caplike structure over the ampullated end of the bud, and continued maintenance of this intimate relationship is necessary for normal metanephric organogenesis. Formation of the definitive excretory units starts at about the eighth week. Blastemic cells are influenced by the ampulla to form clusters. Subsequent early stages of differentiation of the blastema are similar to those in the development of the mesonephric tubule.
The cell clusters form metanephric vesicles, which elongate and differentiate into metanephric tubules. Differential proliferation of segments of the midportion of the tubule produces the proximal and distal convoluted tubules, whereas the central midportion forms the loop of Henle (Fig 4–3). The loops eventually grow centripetally toward the developing medullary zone. The end of the nephric tubule nearest the ampulla of the subdividing bud joins the newly formed collecting duct of that bud. The other end of the metanephric tubule expands, infolds somewhat, and becomes the cup-shaped Bowman's capsule. The capsule is invaginated by a tuft of capillaries, the glomerulus. Formation of urine purportedly begins at about weeks 10–13, when an estimated 20% of the nephrons are morphologically mature.
The last month of gestation is marked by interstitial growth, hypertrophy of existing components of uriniferous tubules, and the disappearance of bud primordia for collecting tubules. Opinions differ about whether formation of nephrons ceases prenatally at about 28 or 32 weeks or, postnatally, during the first several months. If the ureteric bud fails to form, undergoes early degeneration, or fails to grow into the nephrogenic mesoderm, aberrations of nephrogenesis result. These may be nonthreatening (unilateral renal agenesis), severe, or even fatal (bilateral renal agenesis, polycystic kidney).
C. POSITIONAL CHANGES
Figure 4–13 illustrates relocation of the kidney to a deeper position within the posterior body wall, as well as the approximately 90-degree medial rotation of the organ on its longitudinal axis. Rotation and lateral positioning are probably facilitated by the growth of midline structures (axial skeleton and muscles). The “ascent” of the kidney between weeks 5 and 8 can be attributed largely to differential longitudinal growth of the rest of the lumbosacral area and to the reduction of the rather sharp curvature of the caudal region of the embryo. Some migration of the kidney may also occur. Straightening of the curvature may be attributable also to relative changes in growth, especially the development of the infraumbilical abdominal wall. As the kidney moves into its final position (lumbar 1–3 by the 12th week), its arterial supply shifts to successively higher aortic levels. Ectopic kidneys can result from abnormal “ascent.” During the seventh week, the “ascending” metanephroi closely approach each other near the aortic bifurcation. The close approximation of the 2 developing kidneys can lead to fusion of the lower poles of the kidneys, resulting in formation of a single horseshoe kidney, the ascent of which would be arrested by the stem of the interior mesenteric artery. Infrequently, a pelvic kidney results from trapping of the organ beneath the umbilical artery, which restricts passage out of the pelvis.
THE GENITAL SYSTEM
Sexual differentiation of the genital system occurs in a basically sequential order: genetic, gonadal, ductal, and genital. Genetic sex is determined at fertilization by the complement of sex chromosomes (ie, XY specifies a genotypic male and XX a female). However, early morphologic indications of the sex of the developing embryo do not appear until about the eighth or ninth week after conception. Thus, there is a so-called indifferent stage, when morphologic identity of sex is not clear or when preferential differentiation for one sex has not been imposed on the sexless primordia. This is characteristic of early developmental stages for the gonads, genital ducts, and external genitalia. When the influence of genetic sex has been expressed on the indifferent gonad, gonadal sex is established. The SRY (sex-determining region of the Y chromosome) gene in the short arm of the Y chromosome of normal genetic males is considered the best candidate for the gene encoding for the testis-determining factor (TDF). TDF initiates a chain of events that results in differentiation of the gonad into a testis with its subsequent production of anti-müllerian hormone and testosterone, which influences development of somatic “maleness” (see Testis, in following text). Normal genetic females do not have the SRY gene, and the early undifferentiated medullary region of their presumptive gonad does not produce the TDF (see Ovary).
The testis and ovary are derived from the same primordial tissue, but histologically visible differentiation toward a testis occurs sooner than that toward an ovary. An “ovary” is first recognized by the absence of testicular histogenesis (eg, thick tunica albuginea) or by the presence of germ cells entering meiotic prophase between the eighth and about the 11th week. The different primordia for male and female genital ducts exist in each embryo during overlapping periods, but establishment of male or female ductal sex depends on the presence or absence, respectively, of testicular products and the sensitivity of tissues to these products. The 2 primary testicular products are androgenic steroids (testosterone and nonsteroidal anti-müllerian hormone (see Testis). Stimulation by testosterone influences the persistence and differentiation of the “male” mesonephric ducts (wolffian ducts), whereas anti-müllerian hormone influences regression of the “female” paramesonephric ducts (müllerian ducts). Absence of these hormones in a nonaberrant condition specifies persistence of müllerian ducts and regression of wolffian ducts, ie, initiation of development of the uterus and uterine tubes. Genital sex (external genitalia) subsequently develops according to the absence or presence of androgen. Thus, the inherent pattern of differentiation of the genital system can be viewed as one directed toward somatic “femaleness” unless the system is dominated by certain factors for “maleness” (eg, gene expression of the Y chromosome, androgenic steroids, and anti-müllerian hormone).
THE GONADS
Indifferent (Sexless) Stage
Gonadogenesis temporally overlaps metanephrogenesis and interacts with tissues of the mesonephric system. Formation of the gonad is summarized schematically in Fig 4–8.
About the fifth week, the midportion of each urogenital ridge ventromedially adjacent to the mesonephros thickens as cellular condensation forms the gonadal ridge (Fig 4–6). For the next 2 weeks, this ridge is an undifferentiated cell mass, lacking either testicular or ovarian morphology. As shown in Fig 4–8, the cell mass consists of (1) primordial germ cells, which translocate into the ridge, and a mixture of somatic cells derived by (2) proliferation of the coelomic epithelial cells, (3) condensation of the underlying mesenchyme of part of the urogenital ridge, and (4) in-growth of mesonephric-derived cells. The epithelial cells are not confined to the coelomic surface because the basal lamina of the coelomic epithelium is discontinuous in the area of the gonadal ridge.
The mesonephric-derived cells enter the basal aspect of the undifferentiated gonad, and some of these cells move peripherally, while some epithelial cells penetrate the mesenchyme and move centrally. During the indifferent stage, the germ cells and different somatic cells “intermingle” in the compact mass of the primordium. Later differentiation of the gonadal primordium results from interaction of the germ cells and the 3 types of somatic cells listed above. The end of the gonadal indifferent stage in the male is near the middle of the seventh week, when a basal lamina delineates the coelomic epithelium and the developing tunica albuginea separates the coelomic epithelium from the developing testicular cords. The indifferent stage in the female ends around the ninth week, when the first oogonia enter meiotic prophase.
Primordial germ cells, presumptive progenitors of the gametes, become evident in the late third to early fourth week in the dorsocaudal wall of the yolk sac and the mesenchyme around the allantois. The allantois is a caudal diverticulum of the yolk sac that extends distally into the primitive umbilical stalk and, after embryonic flexion, is adjacent proximally to the cloacal hindgut. The primordial germ cells are translocated from the allantoic region (about the middle of the fourth week) to the urogenital ridge (between the middle of the fifth week and late in the sixth week). The mechanism of translocation is uncertain (perhaps partially by ameboid movement and also passively owing to positional change of tissues). It is not known whether primordial germ cells must be present in the gonadal ridge for full differentiation of the gonad to occur. The initial stages of somatic development appear to occur independently of the germ cells. Later endocrine activity in the testis, but not in the ovary, is known to occur in the absence of germ cells. The germ cells appear to have some influence on gonadal differentiation at certain stages of development.
Testis
During early differentiation of the testis, there are condensations of germ cells and somatic cells (see previous text), which have been described as platelike groups, or sheets. These groups are at first distributed throughout the gonad and then become more organized as primitive testicular cords. The cords begin to form centrally and are somewhat arranged perpendicular to the long axis of the gonad. In response to testis-determining factor (TDF), these cords will differentiate into Sertoli cells (see following text). The first characteristic feature of male gonadal sex differentiation is evident around week 8, when the tunica albuginea begins to form in the mesenchymal tissue underlying the coelomic epithelium. Eventually, this thickened layer of tissue causes the developing testicular cords to be separated from the surface epithelium and placed deeper in the central region of the gonad. The surface epithelium re-forms a basal lamina and later thins to a mesothelial covering of the gonad. The testicular cords coil peripherally and thicken as their cellular organization becomes more distinct. A basal lamina eventually develops in the testicular cords, although it is not known if the somatic cells, germ cells, or both are primary contributors to the lamina.
Throughout gonadal differentiation, the developing testicular cords appear to maintain a close relationship to the basal area of the mesonephric-derived cell mass. An interconnected network of cords, rete cords, develops in this cell mass and gives rise to the rete testis. The rete testis joins centrally with neighboring epigenital mesonephric tubules, which become the efferent ductules linking the rete testis with the epididymis, a derivative of the mesonephric duct. With gradual enlargement of the testis and regression of the mesonephros, a cleft forms between the 2 organs, slowly creating the mesentery of the testis, the mesorchium. The differentiating testicular cords are made up of primordial germ cells (primitive spermatogonia) and somatic “supporting” cells (sustentacular cells, or Sertoli cells). Some precocious meiotic activity has been observed in the fetal testis. Meiosis in the germ cells usually does not begin until puberty; the cause of this delay is unknown. Besides serving as “supporting cells” for the primitive spermatogonia, Sertoli cells also produce a glycoprotein, anti-müllerian hormone (AMH; also called müllerian-inhibiting substance). Antimüllerian hormone causes regression of the paramesonephric (müllerian) ducts, apparently during a very discrete period of ductal sensitivity in male fetuses. At puberty, the seminiferous cords mature to become the seminiferous tubules, and the Sertoli cells and spermatogonia mature.
Shortly after the testicular cords form, the steroid-producing interstitial (Leydig) cells of the extracordal compartment of the testis differentiate from stromal mesenchymal cells, probably due to anti-müllerian hormone. Mesonephric-derived cells may also be a primordial source of Leydig cells. Steroidogenic activity of Leydig cells begins near the tenth week. High levels of testosterone are produced during the period of differentiation of external genitalia (weeks 11–12) and maintained through weeks 16–18. Steroid levels then rise or fall somewhat in accordance with changes in the concentration of Leydig cells. Both the number of cells and the levels of testosterone decrease around the fifth month.
Ovary
A. DEVELOPMENT
In the normal absence of the Y chromosome or the sex-determining region of the Y chromosome (SRY gene; see The Genital System, above), the somatic sex cords of the indifferent gonad do not produce testis-determining factor (TDF). In the absence of TDF, differentiation of the gonad into a testis and its subsequent production of anti-müllerian hormone and testosterone do not occur (see Testis, above). The indifferent gonad becomes an ovary. Complete ovarian differentiation seems to require 2 X chromosomes (XO females exhibit ovarian dysgenesis, in which ovaries have precociously degenerated germ cells and no follicles and are present as gonadal “streaks”). The first recognition of a developing ovary around weeks 9–10 is based on the temporal absence of testicular-associated features (most prominently, the tunica albuginea) and on the presence of early meiotic activity in the germ cells.
Early differentiation toward an ovary involves mesonephric-derived cells “invading” the basal region (adjacent to mesonephros) and central region of the gonad (central and basal regions represent the primitive “medullary” region of the gonad). At the same time, clusters of germ cells are displaced somewhat peripherally into the “cortical” region of the gonad. Some of the central mesonephric cells give rise to the rete system that subsequently forms a network of cords (intraovarian rete cords) extending to the primitive cortical area. As these cords extend peripherally between germ clusters, some epithelial cell proliferations extend centrally, and some mixing of these somatic cells apparently takes place around the germ cell clusters. These early cordlike structures are more irregularly distributed than early cords in the testis and not distinctly outlined. The cords open into clusters of germ cells, but all germ cells are not confined to cords. The first oogonia that begin meiosis are located in the innermost part of the cortex and are the first germ cells to contact the intraovarian rete cords.
Folliculogenesis begins in the innermost part of the cortex when the central somatic cells of the cord contact and surround the germ cells and an intact basal lamina is laid down. These somatic cells are morphologically similar to the mesonephric cells that form the intraovarian rete cords associated with the oocytes and apparently differentiate into the presumptive granulosa cells of the early follicle. Folliculogenesis continues peripherally. Between weeks 12 and 20 of gestation, proliferative activity causes the surface epithelium to become a thickened, irregular multilayer of cells, and in the absence of a basal lamina, the cells and apparent epithelial cell cords mix with underlying tissues. These latter cortical cords often retain a connection to and appear similar to the surface epithelium. The epithelial cells of these cords probably differentiate into granulosa cells and contribute to folliculogenesis, although this is after the process is well under way in the central region of the gonad. Follicles fail to form in the absence of oocytes or with precocious loss of germ cells, and oocytes not encompassed by follicular cells degenerate.
Stromal mesenchymal cells, connective tissue, somatic cells of cords not participating in folliculogenesis, and a vascular complex form the ovarian medulla in the late fetal ovary. Individual primordial follicles containing diplotene oocytes populate the inner and outer cortex of this ovary. The rete ovarii may persist, along with a few vestiges of mesonephric tubules, as the vestigial epoophoron near the adult ovary. Finally, similar to the testicular mesorchium, the mesovarium eventually forms as a gonadal mesentery between the ovary and old urogenital ridge. Postnatally, the epithelial surface of the ovary consists of a single layer of cells continuous with peritoneal mesothelium at the ovarian hilum. A thin, fibrous connective tissue, the tunica albuginea, forms beneath the surface epithelium and separates it from the cortical follicles.
B. ANOMALIES OF THE OVARIES
Anomalies of the ovaries encompass a broad range of developmental errors from complete absence of the ovaries to supernumerary ovaries. The many variations of gonadal disorders usually are subcategorized within classifications of disorders of sex determination. Unfortunately, there is little consensus for a major classification, although most include pathogenetic consideration. Extensive, excellent summaries of the different classifications are offered in the references to this chapter.
Congenital absence of the ovary (no gonadal remnants found) is very rare. Two types have been considered, agenesis and agonadism. By definition, agenesis implies that the primordial gonad did not form in the urogenital ridge, whereas agonadism indicates the absence of gonads that may have formed initially and subsequently degenerated. It can be difficult to distinguish one type from the other on a practical basis. For example, a patient with female genital ducts and external genitalia and a 46, XY karyotype could represent either gonadal agenesis or agonadism. In the latter condition, the gonad may form but undergo early degeneration and resorption before any virilizing expression is made. Whenever congenital absence of the ovaries is suspected, careful examination of the karyotype, the external genitalia, and the genital ducts must be performed.
Descriptions of agonadism have usually indicated that the external genitalia are abnormal (variable degree of fusion of labioscrotal swellings) and that either very rudimentary ductal derivatives are present or there are no genital ducts. The cause of agonadism is unknown, although several explanations have been suggested, such as (1) failure of the primordial gonad to form, along with abnormal formation of ductal anlagen, and (2) partial differentiation and then regression and absorption of testes (accounting for suppression of müllerian ducts but lack of stimulation of mesonephric, or wolffian, ducts). Explanations that include teratogenic effects or genetic defects are more likely candidates in view of the associated incidence of nonsexual somatic anomalies with the disorder. The streak gonad is a product of primordial gonadal formation and subsequent failure of differentiation, which can occur at various stages. The gonad usually appears as a fibrous-like cord of mixed elements (lacking germ cells) located parallel to a uterine tube. Streak gonads are characteristic of gonadal dysgenesis and a 45, XO karyotype (Turner's syndrome; distinctions are drawn between Turner's syndrome and Turner's stigmata when consideration is given to the various associated somatic anomalies of gonadal dysgenesis). However, streak gonads may be consequent to genetic mutation or hereditary disease other than the anomalous karyotype.
Ectopic ovarian tissue occasionally can be found as accessory ovarian tissue or as supernumerary ovaries. The former may be a product of disaggregation of the embryonic ovary, and the latter may arise from the urogenital ridge as independent primordia.
This chapter also presents descriptive overviews of some congenital malformations of the female genital tract and, when possible, an explanation of their embryonic origins. In view of the complexity and duration of differentiation and development of the genital and urinary systems, it is not surprising that the incidence of malformations involving these systems is one of the highest (10%) of all body systems. Etiologies of congenital malformations are sometimes categorized on the basis of genetic, environmental, or genetic-plus-environmental (so-called polyfactorial inheritance) factors. Known genetic and inheritance factors reputedly account for about 20% of anomalies detected at birth, aberration of chromosomes for nearly 5%, and environmental factors for nearly 10%. The significance of these statistics must be viewed against reports that (1) an estimated one-third to one-half of human zygotes are lost during the first week of gestation and (2) the cause of possibly 70% of human anomalies is unknown. Even so, congenital malformations remain a matter of concern because they are detected in nearly 6% of infants, and 20% of perinatal deaths are purportedly due to congenital anomalies.
The inherent pattern of normal development of the genital system can be viewed as one directed toward somatic “femaleness,” unless development is directed by factors for “maleness.” The presence and expression of a Y chromosome (and its testis-determining genes) in a normal 46, XY karyotype of somatic cells directs differentiation toward a testis, and normal development of the testis makes available its steroidal and proteinaceous hormones for the selection and differentiation of the genital ducts. In the normal absence of these testicular products, the “female” paramesonephric (müllerian) ducts persist. Normal feminization or masculinization of the external genitalia is also a result of the respective timely absence or presence of androgen.
An infant usually is reared as female or male according to the appearance of the external genitalia. However, genital sex is not always immediately discernible, and the choice of sex of rearing can be an anxiety-provoking consideration. Unfortunately, even when genital sex is apparent, later clinical presentation may unmask disorders of sexual differentiation that can lead to problems in psychological adjustment. Whether a somatic disorder is detected at birth or later, investigative backtracking through the developmental process is necessary for proper diagnosis and treatment.
OVERVIEW OF THE FIRST FOUR WEEKS OF DEVELOPMENT*
The transformation of the bilaminar embryonic disk into a trilaminar disk composed of ectoderm, mesoderm, and endoderm (the 3 embryonic germ layers) occurs during the third week by a process called gastrulation (Fig 4–1). All 3 layers are derived from epiblast. During this process, a specialized longitudinal thickening of epiblast, the primitive streak, forms near the margin (future caudal region) of the bilaminar disk and eventually elongates cephalad through the midline of the disk and extends to the central region. Some epiblastic cells migrate medially through a midline depression of the streak, to the ventral aspect of the streak, after which they become mesoblastic cells. The mesoblastic cells migrate peripherally between most of the epiblast and the hypoblast, forming the middle layer (embryonic mesoderm) of the now trilaminar disk. Other mesoblastic cells migrate into the hypoblastic layer, causing lateral displacement of most, if not all, of the hypoblastic cells. This new ventral layer of the disk becomes the embryonic endoderm. With formation of the new mesodermal layer, the overlying epiblast becomes the embryonic ectoderm, of which the medial part gives rise to neuroectoderm, the forerunner of the neural tube and neural crest (ie, the nervous system). By the end of the third week, 3 clusters of embryonic mesoderm are organized on both sides of the midline-developing notochord and neural tube.
The medial cluster is a thickened longitudinal column of mesoderm called paraxial mesoderm, from which somites, and in turn much of the axial skeleton, will form. The lateralmost cluster is called lateral plate mesoderm, in which a space (or coelom) develops, creating dorsal and ventral mesodermal layers (Fig 4–2). The intermediate mesoderm is located between the paraxial and lateral plate mesoderm and is the origin of the urogenital ridge and, hence, much of the reproductive and excretory systems (Fig 4–3). The primitive streak regresses after the fourth week. Rarely, degeneration of the streak is incomplete and presumptive remnants form a teratoma in the sacrococcygeal region of the fetus (more common in females than in males).
Weeks 4 through 8 of development are called the embryonic period (the fetal period is from week 9 to term) because formation of all major internal and external structures, including the 2 primary forerunners of the urogenital system (urogenital ridge and urogenital sinus), begins during this time. During this period the embryo is most likely to develop major congenital or acquired morphologic anomalies in response to the effects of various agents. During the fourth week, the shape of the embryo changes from that of a trilaminar disk to that of a crescentic cylinder. The change results from “folding,” or flexion, of the embryonic disk in a ventral direction through both its transverse and longitudinal planes. Flexion occurs as midline structures (neural tube and somites) develop and grow at a faster pace than more lateral tissues (ectoderm, 2 layers of lateral plate mesoderm enclosing the coelom between them, and endoderm). Thus, during transverse folding, the lateral tissues on each side of the embryo curl ventromedially and join the respective tissues from the other side, creating a midline ventral tube (the endoderm-lined primitive gut), a mesoderm-lined coelomic cavity (the primitive abdominopelvic cavity), and the incomplete ventral and lateral body wall. Concurrent longitudinal flexion ventrally of the caudal region of the disk establishes the pouch-like distal end, or cloaca, of the primitive gut as well as the distal attachment of the cloaca to the yolk sac through the allantois of the sac (Fig 4–4).
A noteworthy point (see The Gonads, in text that follows) is that the primordial germ cells of the later-developing gonad initially are found close to the allantois and later migrate to the gonadal primordia. Subsequent partitioning of the cloaca during the sixth week results in formation of the anorectal canal and the urogenital sinus, the progenitor of the urinary bladder, urethra, vagina, and other genital structures (Fig 4–1 and Table 4–1; see Subdivision of the Cloaca & Formation of the Urogenital Sinus in following text).
Another consequence of the folding process is the repositioning of the intermediate mesoderm, the forerunner of the urogenital ridge. Laterally adjacent to developing somites (from paraxial mesoderm) before flexion, the intermediate mesoderm is located after flexion just lateral to the dorsal mesentery of the gut and in the dorsal wall of the new body cavity. Thickening of this intermediate mesoderm with subsequent bulging into the cavity will form the longitudinal urogenital ridge (Fig 4–1 and Fig 4–4). Thus, by the end of the fourth week of development, the principal structures (urogenital ridge and cloaca) and tissues that give rise to the urogenital system are present.
THE URINARY SYSTEM
Three excretory “systems” form successively, with temporal overlap, during the embryonic period. Each system has a different excretory “organ,” but the 3 systems share anatomic continuity through development of their excretory ducts. The 3 systems are mesodermal derivatives of the urogenital ridge (Fig 4–3 and Fig 4–4), part of which becomes a longitudinal mass, the nephrogenic cord. The pronephros, or organ of the first system, exists rudimentarily, is nonfunctional, and regresses during the fourth week. However, the developing pronephric ducts continue to grow and become the mesonephric ducts of the subsequent kidney, the mesonephros. The paired mesonephroi exist during 4–8 weeks as simplified morphologic versions of the third, or permanent, set of kidneys, and they may have transient excretory function. The permanent kidney, the metanephros, begins to form in response to an inductive influence of a diverticulum of the mesonephric ducts during the fifth week and becomes functional at 10–13 weeks. During nephric differentiation, the urogenital mass becomes suspended from the dorsal wall by a double-layered urogenital mesentery.
Pronephros
Segmented clusters of cells form in each urogenital ridge opposite the cervical somitic region and give rise to pronephric tubules. The lateral end of a tubule in one segment of the ridge grows caudally to fuse with the end of the pronephric tubule in the next segment, thus initiating the cephalic portion of each of the bilateral pronephric ducts (Fig 4–3). The pronephroi degenerate by the end of the fourth week, but, by initiating formation of pronephric ducts, they set in motion the developmental sequence for the formation of the permanent excretory ducts and kidneys. The pronephric ducts continue to grow caudally until week 5, when they contact and open into the lateral posterior wall of the cloaca.
Mesonephros
Development of the mesonephric glomerulotubular units begins while the pronephric tubules are regressing. Cells in each nephrogenic cord condense to form cell clusters just caudal to the pronephros and adjacent to the caudally growing pronephric duct (now called the mesonephric duct). Each cluster differentiates into a hollow mesonephric vesicle and then a mesonephric tubule. Subsequently, the lateral end of a tubule joins the mesonephric duct (Fig 4–4 and Fig 4–5), while the medial end of the tubule expands into a double-layered, cup-shaped primitive glomerular capsule (Bowman's capsule; Fig 4–6). The capsule is vascularized by a capillary tuft, the glomerulus, derived from the aorta. Proliferation of the tubule's midportion produces a primitive version of a convoluted tubule.
While differentiation of the mesonephros is taking place in the caudal region, regression of mature tubules in the cranial region is also occurring (Fig 4–7). This craniocaudal gradient of differentiation followed by regression can give the impression that the relatively large, ovoid mesonephric kidney “descends” along the posterior wall of the body cavity during the embryonic period. By the end of this period, most remaining mesonephric tubules and glomeruli have begun to degenerate. Some of these tubules (descriptively called epigenital mesonephric tubules) persist in the mesonephric region laterally adjacent to the developing gonad and will participate in formation of the gonad and the male ductuli efferentes (Fig 4–8). A few tubules at other levels may persist as vestigial remnants near the gonad and sometimes become cystic (see Fig 4–14 and Fig 4–15).
Differentiation of the caudal segment of the mesonephric ducts results in (1) incorporation of part of the ducts into the wall of the urogenital sinus (early vesicular trigone, see following text), and (2) formation of a ductal diverticulum, which plays an essential role in formation of the definitive kidney. If male sex differentiation occurs, the major portion of each duct becomes the epididymis, ductus deferens, and ejaculatory duct. Only small vestigial remnants of the duct sometimes persist in the female (Gartner's duct; duct of the epoophoron).
Metanephros (Definitive Kidney)
A. COLLECTING DUCTS
By the end of the fifth week, a ureteric bud, or metanephric diverticulum, forms on the caudal part of the mesonephric duct close to the cloaca (Fig 4–7). The bud gives rise to the collecting tubules, calices, renal pelvis, and ureter (Fig 4–3). The stalk of the elongating bud will become the ureter when the ductal segment between the stalk and the cloaca becomes incorporated into the wall of the urinary bladder (which is a derivative of the partitioned cloaca, see text that follows; Fig 4–9, Fig 4–10, Fig 4–11 and Fig 4–12). The expanded tip, or ampulla, of the bud grows into the adjacent metanephric mesoderm (blastema), and continued growth of the bud eventually relocates the ampulla and associated blastema dorsal to the mesonephros (ie, “retroperitoneal”).
Between week 6 and weeks 20–24, the ampulla subdivides, and successive divisions yield approximately 12–15 generations of buds, or eventual collecting tubules. From weeks 10–14, dilatation of the early generations of tubular branches successively produces the renal pelvis, the major calices, and the minor calices, while the middle generations form the medullary collecting tubules. The last several generations of collecting tubules grow centrifugally into the cortical region of the kidney between weeks 24 and 36.
B. NEPHRONS
Dorsocranial growth of the ureteric bud into the caudal end of the nephrogenic cord brings the bud into contact with the metanephric mesoderm, or metanephric blastema (Fig 4–7). The blastema becomes a caplike structure over the ampullated end of the bud, and continued maintenance of this intimate relationship is necessary for normal metanephric organogenesis. Formation of the definitive excretory units starts at about the eighth week. Blastemic cells are influenced by the ampulla to form clusters. Subsequent early stages of differentiation of the blastema are similar to those in the development of the mesonephric tubule.
The cell clusters form metanephric vesicles, which elongate and differentiate into metanephric tubules. Differential proliferation of segments of the midportion of the tubule produces the proximal and distal convoluted tubules, whereas the central midportion forms the loop of Henle (Fig 4–3). The loops eventually grow centripetally toward the developing medullary zone. The end of the nephric tubule nearest the ampulla of the subdividing bud joins the newly formed collecting duct of that bud. The other end of the metanephric tubule expands, infolds somewhat, and becomes the cup-shaped Bowman's capsule. The capsule is invaginated by a tuft of capillaries, the glomerulus. Formation of urine purportedly begins at about weeks 10–13, when an estimated 20% of the nephrons are morphologically mature.
The last month of gestation is marked by interstitial growth, hypertrophy of existing components of uriniferous tubules, and the disappearance of bud primordia for collecting tubules. Opinions differ about whether formation of nephrons ceases prenatally at about 28 or 32 weeks or, postnatally, during the first several months. If the ureteric bud fails to form, undergoes early degeneration, or fails to grow into the nephrogenic mesoderm, aberrations of nephrogenesis result. These may be nonthreatening (unilateral renal agenesis), severe, or even fatal (bilateral renal agenesis, polycystic kidney).
C. POSITIONAL CHANGES
Figure 4–13 illustrates relocation of the kidney to a deeper position within the posterior body wall, as well as the approximately 90-degree medial rotation of the organ on its longitudinal axis. Rotation and lateral positioning are probably facilitated by the growth of midline structures (axial skeleton and muscles). The “ascent” of the kidney between weeks 5 and 8 can be attributed largely to differential longitudinal growth of the rest of the lumbosacral area and to the reduction of the rather sharp curvature of the caudal region of the embryo. Some migration of the kidney may also occur. Straightening of the curvature may be attributable also to relative changes in growth, especially the development of the infraumbilical abdominal wall. As the kidney moves into its final position (lumbar 1–3 by the 12th week), its arterial supply shifts to successively higher aortic levels. Ectopic kidneys can result from abnormal “ascent.” During the seventh week, the “ascending” metanephroi closely approach each other near the aortic bifurcation. The close approximation of the 2 developing kidneys can lead to fusion of the lower poles of the kidneys, resulting in formation of a single horseshoe kidney, the ascent of which would be arrested by the stem of the interior mesenteric artery. Infrequently, a pelvic kidney results from trapping of the organ beneath the umbilical artery, which restricts passage out of the pelvis.
THE GENITAL SYSTEM
Sexual differentiation of the genital system occurs in a basically sequential order: genetic, gonadal, ductal, and genital. Genetic sex is determined at fertilization by the complement of sex chromosomes (ie, XY specifies a genotypic male and XX a female). However, early morphologic indications of the sex of the developing embryo do not appear until about the eighth or ninth week after conception. Thus, there is a so-called indifferent stage, when morphologic identity of sex is not clear or when preferential differentiation for one sex has not been imposed on the sexless primordia. This is characteristic of early developmental stages for the gonads, genital ducts, and external genitalia. When the influence of genetic sex has been expressed on the indifferent gonad, gonadal sex is established. The SRY (sex-determining region of the Y chromosome) gene in the short arm of the Y chromosome of normal genetic males is considered the best candidate for the gene encoding for the testis-determining factor (TDF). TDF initiates a chain of events that results in differentiation of the gonad into a testis with its subsequent production of anti-müllerian hormone and testosterone, which influences development of somatic “maleness” (see Testis, in following text). Normal genetic females do not have the SRY gene, and the early undifferentiated medullary region of their presumptive gonad does not produce the TDF (see Ovary).
The testis and ovary are derived from the same primordial tissue, but histologically visible differentiation toward a testis occurs sooner than that toward an ovary. An “ovary” is first recognized by the absence of testicular histogenesis (eg, thick tunica albuginea) or by the presence of germ cells entering meiotic prophase between the eighth and about the 11th week. The different primordia for male and female genital ducts exist in each embryo during overlapping periods, but establishment of male or female ductal sex depends on the presence or absence, respectively, of testicular products and the sensitivity of tissues to these products. The 2 primary testicular products are androgenic steroids (testosterone and nonsteroidal anti-müllerian hormone (see Testis). Stimulation by testosterone influences the persistence and differentiation of the “male” mesonephric ducts (wolffian ducts), whereas anti-müllerian hormone influences regression of the “female” paramesonephric ducts (müllerian ducts). Absence of these hormones in a nonaberrant condition specifies persistence of müllerian ducts and regression of wolffian ducts, ie, initiation of development of the uterus and uterine tubes. Genital sex (external genitalia) subsequently develops according to the absence or presence of androgen. Thus, the inherent pattern of differentiation of the genital system can be viewed as one directed toward somatic “femaleness” unless the system is dominated by certain factors for “maleness” (eg, gene expression of the Y chromosome, androgenic steroids, and anti-müllerian hormone).
THE GONADS
Indifferent (Sexless) Stage
Gonadogenesis temporally overlaps metanephrogenesis and interacts with tissues of the mesonephric system. Formation of the gonad is summarized schematically in Fig 4–8.
About the fifth week, the midportion of each urogenital ridge ventromedially adjacent to the mesonephros thickens as cellular condensation forms the gonadal ridge (Fig 4–6). For the next 2 weeks, this ridge is an undifferentiated cell mass, lacking either testicular or ovarian morphology. As shown in Fig 4–8, the cell mass consists of (1) primordial germ cells, which translocate into the ridge, and a mixture of somatic cells derived by (2) proliferation of the coelomic epithelial cells, (3) condensation of the underlying mesenchyme of part of the urogenital ridge, and (4) in-growth of mesonephric-derived cells. The epithelial cells are not confined to the coelomic surface because the basal lamina of the coelomic epithelium is discontinuous in the area of the gonadal ridge.
The mesonephric-derived cells enter the basal aspect of the undifferentiated gonad, and some of these cells move peripherally, while some epithelial cells penetrate the mesenchyme and move centrally. During the indifferent stage, the germ cells and different somatic cells “intermingle” in the compact mass of the primordium. Later differentiation of the gonadal primordium results from interaction of the germ cells and the 3 types of somatic cells listed above. The end of the gonadal indifferent stage in the male is near the middle of the seventh week, when a basal lamina delineates the coelomic epithelium and the developing tunica albuginea separates the coelomic epithelium from the developing testicular cords. The indifferent stage in the female ends around the ninth week, when the first oogonia enter meiotic prophase.
Primordial germ cells, presumptive progenitors of the gametes, become evident in the late third to early fourth week in the dorsocaudal wall of the yolk sac and the mesenchyme around the allantois. The allantois is a caudal diverticulum of the yolk sac that extends distally into the primitive umbilical stalk and, after embryonic flexion, is adjacent proximally to the cloacal hindgut. The primordial germ cells are translocated from the allantoic region (about the middle of the fourth week) to the urogenital ridge (between the middle of the fifth week and late in the sixth week). The mechanism of translocation is uncertain (perhaps partially by ameboid movement and also passively owing to positional change of tissues). It is not known whether primordial germ cells must be present in the gonadal ridge for full differentiation of the gonad to occur. The initial stages of somatic development appear to occur independently of the germ cells. Later endocrine activity in the testis, but not in the ovary, is known to occur in the absence of germ cells. The germ cells appear to have some influence on gonadal differentiation at certain stages of development.
Testis
During early differentiation of the testis, there are condensations of germ cells and somatic cells (see previous text), which have been described as platelike groups, or sheets. These groups are at first distributed throughout the gonad and then become more organized as primitive testicular cords. The cords begin to form centrally and are somewhat arranged perpendicular to the long axis of the gonad. In response to testis-determining factor (TDF), these cords will differentiate into Sertoli cells (see following text). The first characteristic feature of male gonadal sex differentiation is evident around week 8, when the tunica albuginea begins to form in the mesenchymal tissue underlying the coelomic epithelium. Eventually, this thickened layer of tissue causes the developing testicular cords to be separated from the surface epithelium and placed deeper in the central region of the gonad. The surface epithelium re-forms a basal lamina and later thins to a mesothelial covering of the gonad. The testicular cords coil peripherally and thicken as their cellular organization becomes more distinct. A basal lamina eventually develops in the testicular cords, although it is not known if the somatic cells, germ cells, or both are primary contributors to the lamina.
Throughout gonadal differentiation, the developing testicular cords appear to maintain a close relationship to the basal area of the mesonephric-derived cell mass. An interconnected network of cords, rete cords, develops in this cell mass and gives rise to the rete testis. The rete testis joins centrally with neighboring epigenital mesonephric tubules, which become the efferent ductules linking the rete testis with the epididymis, a derivative of the mesonephric duct. With gradual enlargement of the testis and regression of the mesonephros, a cleft forms between the 2 organs, slowly creating the mesentery of the testis, the mesorchium. The differentiating testicular cords are made up of primordial germ cells (primitive spermatogonia) and somatic “supporting” cells (sustentacular cells, or Sertoli cells). Some precocious meiotic activity has been observed in the fetal testis. Meiosis in the germ cells usually does not begin until puberty; the cause of this delay is unknown. Besides serving as “supporting cells” for the primitive spermatogonia, Sertoli cells also produce a glycoprotein, anti-müllerian hormone (AMH; also called müllerian-inhibiting substance). Antimüllerian hormone causes regression of the paramesonephric (müllerian) ducts, apparently during a very discrete period of ductal sensitivity in male fetuses. At puberty, the seminiferous cords mature to become the seminiferous tubules, and the Sertoli cells and spermatogonia mature.
Shortly after the testicular cords form, the steroid-producing interstitial (Leydig) cells of the extracordal compartment of the testis differentiate from stromal mesenchymal cells, probably due to anti-müllerian hormone. Mesonephric-derived cells may also be a primordial source of Leydig cells. Steroidogenic activity of Leydig cells begins near the tenth week. High levels of testosterone are produced during the period of differentiation of external genitalia (weeks 11–12) and maintained through weeks 16–18. Steroid levels then rise or fall somewhat in accordance with changes in the concentration of Leydig cells. Both the number of cells and the levels of testosterone decrease around the fifth month.
Ovary
A. DEVELOPMENT
In the normal absence of the Y chromosome or the sex-determining region of the Y chromosome (SRY gene; see The Genital System, above), the somatic sex cords of the indifferent gonad do not produce testis-determining factor (TDF). In the absence of TDF, differentiation of the gonad into a testis and its subsequent production of anti-müllerian hormone and testosterone do not occur (see Testis, above). The indifferent gonad becomes an ovary. Complete ovarian differentiation seems to require 2 X chromosomes (XO females exhibit ovarian dysgenesis, in which ovaries have precociously degenerated germ cells and no follicles and are present as gonadal “streaks”). The first recognition of a developing ovary around weeks 9–10 is based on the temporal absence of testicular-associated features (most prominently, the tunica albuginea) and on the presence of early meiotic activity in the germ cells.
Early differentiation toward an ovary involves mesonephric-derived cells “invading” the basal region (adjacent to mesonephros) and central region of the gonad (central and basal regions represent the primitive “medullary” region of the gonad). At the same time, clusters of germ cells are displaced somewhat peripherally into the “cortical” region of the gonad. Some of the central mesonephric cells give rise to the rete system that subsequently forms a network of cords (intraovarian rete cords) extending to the primitive cortical area. As these cords extend peripherally between germ clusters, some epithelial cell proliferations extend centrally, and some mixing of these somatic cells apparently takes place around the germ cell clusters. These early cordlike structures are more irregularly distributed than early cords in the testis and not distinctly outlined. The cords open into clusters of germ cells, but all germ cells are not confined to cords. The first oogonia that begin meiosis are located in the innermost part of the cortex and are the first germ cells to contact the intraovarian rete cords.
Folliculogenesis begins in the innermost part of the cortex when the central somatic cells of the cord contact and surround the germ cells and an intact basal lamina is laid down. These somatic cells are morphologically similar to the mesonephric cells that form the intraovarian rete cords associated with the oocytes and apparently differentiate into the presumptive granulosa cells of the early follicle. Folliculogenesis continues peripherally. Between weeks 12 and 20 of gestation, proliferative activity causes the surface epithelium to become a thickened, irregular multilayer of cells, and in the absence of a basal lamina, the cells and apparent epithelial cell cords mix with underlying tissues. These latter cortical cords often retain a connection to and appear similar to the surface epithelium. The epithelial cells of these cords probably differentiate into granulosa cells and contribute to folliculogenesis, although this is after the process is well under way in the central region of the gonad. Follicles fail to form in the absence of oocytes or with precocious loss of germ cells, and oocytes not encompassed by follicular cells degenerate.
Stromal mesenchymal cells, connective tissue, somatic cells of cords not participating in folliculogenesis, and a vascular complex form the ovarian medulla in the late fetal ovary. Individual primordial follicles containing diplotene oocytes populate the inner and outer cortex of this ovary. The rete ovarii may persist, along with a few vestiges of mesonephric tubules, as the vestigial epoophoron near the adult ovary. Finally, similar to the testicular mesorchium, the mesovarium eventually forms as a gonadal mesentery between the ovary and old urogenital ridge. Postnatally, the epithelial surface of the ovary consists of a single layer of cells continuous with peritoneal mesothelium at the ovarian hilum. A thin, fibrous connective tissue, the tunica albuginea, forms beneath the surface epithelium and separates it from the cortical follicles.
B. ANOMALIES OF THE OVARIES
Anomalies of the ovaries encompass a broad range of developmental errors from complete absence of the ovaries to supernumerary ovaries. The many variations of gonadal disorders usually are subcategorized within classifications of disorders of sex determination. Unfortunately, there is little consensus for a major classification, although most include pathogenetic consideration. Extensive, excellent summaries of the different classifications are offered in the references to this chapter.
Congenital absence of the ovary (no gonadal remnants found) is very rare. Two types have been considered, agenesis and agonadism. By definition, agenesis implies that the primordial gonad did not form in the urogenital ridge, whereas agonadism indicates the absence of gonads that may have formed initially and subsequently degenerated. It can be difficult to distinguish one type from the other on a practical basis. For example, a patient with female genital ducts and external genitalia and a 46, XY karyotype could represent either gonadal agenesis or agonadism. In the latter condition, the gonad may form but undergo early degeneration and resorption before any virilizing expression is made. Whenever congenital absence of the ovaries is suspected, careful examination of the karyotype, the external genitalia, and the genital ducts must be performed.
Descriptions of agonadism have usually indicated that the external genitalia are abnormal (variable degree of fusion of labioscrotal swellings) and that either very rudimentary ductal derivatives are present or there are no genital ducts. The cause of agonadism is unknown, although several explanations have been suggested, such as (1) failure of the primordial gonad to form, along with abnormal formation of ductal anlagen, and (2) partial differentiation and then regression and absorption of testes (accounting for suppression of müllerian ducts but lack of stimulation of mesonephric, or wolffian, ducts). Explanations that include teratogenic effects or genetic defects are more likely candidates in view of the associated incidence of nonsexual somatic anomalies with the disorder. The streak gonad is a product of primordial gonadal formation and subsequent failure of differentiation, which can occur at various stages. The gonad usually appears as a fibrous-like cord of mixed elements (lacking germ cells) located parallel to a uterine tube. Streak gonads are characteristic of gonadal dysgenesis and a 45, XO karyotype (Turner's syndrome; distinctions are drawn between Turner's syndrome and Turner's stigmata when consideration is given to the various associated somatic anomalies of gonadal dysgenesis). However, streak gonads may be consequent to genetic mutation or hereditary disease other than the anomalous karyotype.
Ectopic ovarian tissue occasionally can be found as accessory ovarian tissue or as supernumerary ovaries. The former may be a product of disaggregation of the embryonic ovary, and the latter may arise from the urogenital ridge as independent primordia.
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