Development of the ovary

As discussed in Chapter 21, Sperm Transport and Maturation, the cortical region of the primitive gonad develops into an ovary. The cortical region of the indifferent gonad initially contains the primary sex cords (fifth week of development).

One week later, cells of the primary cell cords degenerate and are replaced by secondary sex cords that surround individual oogonia (Figure 22-1).

Figure 22-1 From the indifferent gonad to the ovary and testis

Oogonia result from the mitotic division of migrating primordial germinal cells derived from the yolk sac. Primordial germinal cells contain two X chromosomes. The testis-determining factor (TDF), encoded by the gene SRY, on the sex-determining region of the Y chromosome, is obviously not present.

In the fetal ovary, oogonia enter meiotic prophase I to become primary oocytes. Primary oocytes are arrested after completion of crossing over (exchange of genetic information between nonsister chromatids of homologous chromosomes). Meiotic prophase arrest continues until puberty, when one or more ovarian follicles are recruited to initiate their development.

Development of the female genital ducts

During development, the cranial ends of the müllerian ducts remain separated to form the oviducts, which open into the coelomic cavity (the future peritoneal cavity). The caudal segments of the müllerian ducts fuse to develop into the uterovaginal primordium that becomes the uterus and upper part of the vagina. The broad ligaments of the uterus, derived from two peritoneal folds, approach each other when the müllerian ducts fuse.

The primitive cloaca is divided by the urorectal septum into two regions: (1) the ventral urogenital sinus and (2) the dorsal anorectal canal.

The urorectal septum fuses with the cloacal membrane (the future site of the perineal body), which is divided into the dorsal anal membrane and the larger ventral urogenital membrane. By week 7, the membranes rupture.

The contact of the uterovaginal primordium with the urogenital sinus results in the formation of the vaginal plate. The canalization of the vaginal plate results in the development of the middle and lower portions of the vagina:

The urogenital sinus also gives rise to the urinary bladder, urethra, vestibular glands, and hymen.

Development of the external genitalia

By week 4, the genital tubercle, or phallus, develops at the cranial end of the cloacal membrane. Then, labioscrotal swellings and urogenital folds develop at either side of the cloacal membrane.

The genital tubercle enlarges in both the female and male. In the absence of androgens, the external genitalia are feminized: the phallus develops into the clitoris. The urogenital folds form the labia minora, and the labioscrotal swellings develop into the labia majora.

Clinical significance: Developmental anomalies of the female genital tract

Imperforate hymen results from the incomplete canalization of the vaginal plate. This condition obstructs the passage of menstrual blood when menarche occurs and is accompanied by pain in the lower abdomen and bulging of the vaginal introitus. Hymenotomy is the definitive treatment.

In müllerian agenesis (Rokitansky-Küster-Hauser syndrome), the uterus, cervix, and upper vagina are absent. Although normal ovulation occurs, there is no menstruation. In addition to agenesis of the müllerian duct, renal anomalies (unilateral kidney agenesis) occur in 25% to 30% of cases.

Clinical significance: Developmental anomalies of the ovary: Turner’s syndrome

The fundamental genetic defect recognized in prepubertal and pubertal girls with Turner’s syndrome is the absence of all or part of a second X chromosome (45,X) and no Barr bodies.

Both the short arm and the long arm of the X chromosome contain genes important for ovarian function. At birth, the ovaries are represented by streaks. Loss of the short arm (Xp, p for petite) results in short stature and the typical skeletal changes. A deletion on the Xp regions (Xp11.4) causes lymphedema, another typical feature of Turner’s syndrome.

Ovarian failure is characterized by decreased or absent production of estrogens in association with elevated levels of gonadotropins, resulting in a failure to establish secondary sexual development (because of a lack of estrogens).

Recombinant growth hormone administration is recommended when there is evidence of growth failure. Hormone replacement therapy (estrogen and progesterone) compensates for ovarian atrophy.

Ovarian cycle

The three phases of the ovarian cycle are the follicular phase, ovulatory phase, and luteal phase.

The follicular phase consists of the development of several primordial follicles into one antral, preovulatory or graafian follicle (Figures 22-3 and 22-4) normally selected to ovulate. The time interval from recruitment of primordial follicle cohorts to the development of a preovulatory graafian follicle averages about 3 to 6 months. During this time, follicles acquire follicle-stimulating hormone (FSH), estrogen and androgen receptors and granulosa cells and primary oocytes become functionally coupled by gap junctions.

Figure 22-3 From primordial to primary follicle

Figure 22-4 From a secondary to a graafian follicle

The predominant and smallest follicle (25 μm in diameter) is the primordial follicle, which is surrounded by squamous, flattened granulosa cells (see Figure 22-3).

Primordial follicles leaving the resting phase are called primary follicles. This transition represents a commitment of primary follicles to subsequent stages of follicular development. Primary follicles are lined by a single layer of cuboidal granulosa cells that become proliferative and separated from the stroma of the ovary by a basal lamina.

Granulosa cells continue to proliferate into several layers, forming multilayered secondary follicles. Three events characterize the development of secondary follicles: (1) the initiation of the assembly of the zona pellucida; (2) the accumulation of fluid (liquor folliculi) between the granulosa cells; and (3) the distinction of a cellular shell or theca (theca folliculi; Greek theke, box) that separates the ovarian stroma from the granulosa cell multilayer. The theca cells, recruited from surrounding stromal cells, organize into two distinct layers around each follicle: (1) the theca interna and (2) the theca externa.

Zona pellucida is a glycoprotein coat that progressively separates granulosa cells from the primary oocyte. The zona pellucida is penetrated by thin cytoplasmic processes of the granulosa cells that contact microvilli of the oocyte. Gap junctions, present at granulosa cell-oocyte contact sites, enable molecular communication that prevents the untimely completion of meiotic prophase of the primary oocyte (Figure 22-5). Gap junctions are also seen between granulosa cells.

Figure 22-5 Cranulosa cell-primary oocyte interaction through gap junctions

The small intercellular spaces—Call-Exner bodies—between granulosa cells contain follicular fluid and coalesce later to form a large space, the antrum. A secondary follicle with granulosa intercellular spaces containing fluid has acquired vesicular or preantral characteristics.

During the subsequent developmental phase, the graafian follicle—also known as preovulatory or antral follicle—the formation of the antrum soon segregates the granulosa cells with respect to the primary oocyte into two specific regions: the cumulus granulosa cell region (cumulus oophorous), in close proximity to the primary oocyte, and the mural granulosa cell region lining the wall of the follicle (see Figure 22-4). The layer of granulosa cells firmly anchored to the zona pellucida is referred to as the corona radiata (Figures 22-5 and 22-6). A preovulatory graafian follicle reaches about 20 mm in diameter (as compared to the 25 μm in diameter of a primordial follicle).

Figure 22-6 Early follicular steroidogenesis

The theca externa is a connective tissue capsule-like layer, continuous with the ovarian stroma. In contrast, the theca interna is a well-vascularized cell layer adjacent to the basal lamina of the developing follicle. It consists of elongated cells with small lipid droplets in the cytoplasm acquiring the characteristics of steroid-secreting cells. Cells of the theca interna secrete androstenedione, an androgen precursor that is transferred across the basal lamina to the granulosa cells for the production of testosterone (see Figure 22-6). Testosterone is then converted to estradiol by aromatase. Granulosa cells lack enzymes required for the direct production of estrogens. As a result, granulosa cells cannot produce steroid precursors during folliculogenesis.

Primary oocyte-granulosa cell communication during folliculogenesis

Bidirectional communication between the oocyte and granulosa cells occurs during folliculogenesis. Figure 22-7 provides a summary of the molecular intercellular communication events. Connexin 37 is present in gap junctions linking granulosa cells of the corona radiata and the primary oocyte. Connexin 43 is found in gap junctions connecting granulosa cells. A lack of connexin 37 results in a defect in the capacity of the primary oocyte to resume meiosis and epigenetic modifications essential for fetal development. A lack of connexin 43 disrupts folliculogenesis during the preantral phase.

Figure 22-7 Primary oocyte-granulosa cell cooperation

Oocyte-derived factors include growth differentiation factor–9 (GDF-9) and bone morphogenetic protein-15 (BMP-15). GDF-9 and BMP-15, members of the transforming growth factor-β (TGF-β) superfamily proteins, function in a cooperative manner to maintain the integrity of the cumulus granulosa cells and enhance female fertility.

Granulosa cell-derived factors include c-kit ligand (or stem cell factor ligand) which binds to the oocyte c-kit receptor and stimulates oocyte growth and survival. As you remember, c-kit receptor and its ligand play significant roles in the migration of primordial germinal cells to the gonadal ridges during gonadogenesis (see Chapter 21, Sperm Transport and Maturation).

There members of the TGF-β superfamily are involved in the regulation of granulosa cell function: anti-müllerian hormone (AMH), inhibins and activins. AMH appears to control the rate at which follicles become available for preovulatory development. Activins enhance granulosa cell proliferation and facilitate their responsivenes to FSH. Inhibins promote luteinizing hormone (LH)-stimulated androgen synthesis.

Note the clinical significance of activins and inhibins: activins enhance granulosa cell responsiveness to FSH which results in the production of inhibins. Inhibins help LH to stimulate androgen synthesis and an androgen precursor is required for estrogen production. The key principle is to sustain androgen synthesis, without which there is no estrogen synthesis necessary for endometrial proliferation.

As you realize, many proteins of the TGF-β superfamily coordinate folliculogenesis and help to produce a competent primary oocyte

Follicular atresia or degeneration

Several primary follicles initiate the maturation process (see Box 22-A), but only one follicle completes its development; the remainder degenerate by an apoptotic process called atresia. Follicles can become atretic at any stage of development.

Atretic follicles (Figure 22-8) are identified by a thick folded basement membrane material, the glassy membrane, a relatively intact zona pellucida, remnants of degenerated oocytes and granulosa cells, and invading macrophages.

Figure 22-8 Atretic follicle

Ovulatory phase

At the time of ovulation, the mature follicle protrudes from the ovarian surface, forming the stigma. Proteolytic activity within the theca externa and tunica albuginea, induced by a surge of LH, facilitates the rupture of the now mature graafian follicle. The released gamete enters the closely apposed uterine tube or oviduct. A few hours before ovulation, the mural granulosa cell layer and the theca interna

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