Female Reproductive Tract

Ovaries

The adult human ovaries are paired, flattened ellipsoid structures that measure about 5 cm in their longest dimension. They lie within the pelvic area of the abdominal cavity attached to the broad ligaments that extend from either side of the uterus by peritoneal folds called the mesovaria. Both the gamete-producing and hormone-producing functions of the ovary take place in the outer or cortical portion. It is within the ovarian cortex that the precursors of the female gametes, the oocytes, are stored and develop into ova (eggs). The functional unit is the ovarian follicle, which initially consists of a single oocyte surrounded by a layer of granulosa cells enclosed within a basement membrane, the basal lamina, which separates the follicle from cortical stroma. When they emerge from the resting stage, follicles become ensheathed in a layer of specialized cells called the theca folliculi. Follicles in many stages of development are found in the cortex of the adult ovary along with structures that form when the mature ovum is released by the process of ovulation. Ovarian follicles, in which the ova develop and the corpora lutea derived from them, are also the sites of ovarian hormone production. The inner portion of the ovary, the medulla, consists chiefly of vascular elements that arise from anastomoses of the uterine and ovarian arteries. A rich supply of unmyelinated nerve fibers also enters the medulla along with blood vessels (Fig. 1).

Folliculogenesis

In contrast to the testis, which produces hundreds of millions of sperm each day, the ovary normally produces a single mature ovum about once each month. The testis must continuously renew its pool of germ cell precursors

FIGURE 1 Mammalian ovary showing the various stages of follicular and luteal development. Obviously, events depicted occur sequentially and are not all present in any section of a human ovary. (From Turner CD, Bagnara JT. General endocrinology, 6th ed., Philadelphia: W.B. Saunders, 1976, p. 453. With permission.)

FIGURE 1 Mammalian ovary showing the various stages of follicular and luteal development. Obviously, events depicted occur sequentially and are not all present in any section of a human ovary. (From Turner CD, Bagnara JT. General endocrinology, 6th ed., Philadelphia: W.B. Saunders, 1976, p. 453. With permission.)

throughout reproductive life in order to sustain this rate of sperm production, while the ovary must draw upon its initial endowment of primordial oocytes to provide the approximately 500 mature ova ovulated during the four decades of a woman's reproductive life. Although ovulation, the hallmark of ovarian activity, occurs episodically at 28-day intervals, examination of the ovary at any time during childhood or the reproductive life of a mature woman reveals continuous activity with multiple follicles at various stages in their life cycle.

Folliculogenesis begins in fetal life. Primordial germ cells multiply by mitosis. They begin to differentiate into primary oocytes and enter meiosis between the 11th and 20th weeks after fertilization. Primary oocytes remain arrested in prophase of the first meiotic division until meiosis resumes at the time of ovulation, which may be more than four decades later for some oocytes. Meiosis is not completed until the second polar body is extruded at the time of fertilization. Around the 20th week of fetal life, about 6 to 7 million oocytes are available to form primordial follicles, but the human female is born with about only 300,000 to 400,000 primordial follicles in each ovary. Oocytes that fail to form into primordial follicles are lost by apoptosis. The vast majority of primordial follicles remain in a resting state for many years. In a seemingly random process, some follicles enter into a growth phase and begin the long journey toward ovulation, but the vast majority of developing follicles become atretic. This process begins during the fetal period and continues until menopause at around age 50, when all of the primordial follicles are exhausted.

As primordial follicles emerge from the resting stage, the oocyte grows from a diameter of about 20 mm to about 100 mm, and a layer of extracellular mucopolysaccharides and proteins called the zona pellucida forms around it (Fig. 2). Growth of primary follicles is accompanied by migration and differentiation of mesenchymal cells to form the theca folliculi. Its inner layer, the theca interna, is composed of secretory cells with an extensive smooth endoplasmic reticulum characteristic of steroidogenic cells. The theca externa is formed by reorganization of surrounding stromal cells. At this time, also, a dense capillary network develops around the follicle. The oocyte completes its growth by accumulating stored nutrients and the messenger RNA and protein synthesizing apparatus that will be activated upon fertilization. As the follicle continues to grow, granulosa cells increase in number and begin to form multiple layers. The innermost granulosa cells are in intimate contact with the oocyte through cellular processes that penetrate the zona pellucida and form gap junctions with its plasma membrane. Granulosa cells also form gap junctions with each other and function as nurse cells supplying nutrients to the oocyte, which is primordial follicle 40 |jm primary follicle 100 |jm secondary follicle 200 |m

„basement laminae — dictyate oocyte granulosa cells early antral follicle 400 |m

multiple layers of granulosa cells theca interna basement laminae granulosa cells fully grown oocyte - zona pellucida basement laminae granulosa cells zona pellucida fully grown oocyte presumptive theca theca external basement laminae steroid secreting cells antrum blood vessel zona pellucida fully grown oocyte multiple layers of granulosa cells theca interna graafian follicle 20 mm membrana granulosa cells theca interna loose connective tissue corona radiata granulosa cells basal lamina

FIGURE 2 Stages of human follicular development. (From Erickson GF. In: Felig P, Baxter JJ, Frohman LA, Eds. Endocrinology and metabolism, 3rd ed., New York: McGraw-Hill, 1995, pp. 973-1015. With permission.)

theca interstitial cells antrum (follicular fluid)

capillaries zona pellucida cumulus oophorous granulosa cells theca externa

FIGURE 2 Stages of human follicular development. (From Erickson GF. In: Felig P, Baxter JJ, Frohman LA, Eds. Endocrinology and metabolism, 3rd ed., New York: McGraw-Hill, 1995, pp. 973-1015. With permission.)

separated from direct contact with capillaries by the basal lamina and the granulosa cells.

Follicular development continues with further proliferation of granulosa cells and gradual elaboration of fluid within the follicle. Follicular fluid is derived from blood plasma and contains plasma proteins, including hormones, and various proteins and steroids secreted by the granulosa cells and the ovum. Accumulation of follicular fluid brings about further enlargement of the follicle and the formation of a central fluid-filled cavity called the antrum. Follicular growth up to this stage is independent of pituitary hormones, but, without support from follicle-stimulating hormone (FSH; see Chapters 38 and 45), further development is not possible and the follicles become atretic. Any follicle can be arrested at any stage of its development and undergo the

FIGURE 3 Follicular development through the life of a woman. Note the gradual depletion of the pool of primary follicles. (Adapted from McGee EA, Hsueh AJW. Endocrine Rev 2000; 21:200-214.)

degenerative changes of atresia. Atresia is the fate of all of the follicles that enter the growth phase before puberty, and more than 99% of the 200,00 to 400,000 remaining at puberty. The physiological mechanisms that control this seemingly wasteful process are poorly understood.

In the presence of FSH, antral follicles continue to develop slowly for about 2 months until they reach a critical size. About 20 days before ovulation, a group or cohort of 6 to 12 of these follicles enters into the final rapid growth phase, but in each cycle normally only one survives and ovulates, while the others become atretic and die (Fig. 3). The surviving follicle has been called the dominant follicle because it may contribute to the demise of other developing follicles. As the dominant follicle matures, the fluid content in the antrum increases rapidly, possibly in response to increased colloid osmotic pressure created by partial hydrolysis of dissolved mucopolysaccharides. The ripe, preovulatory follicle reaches a diameter of 20 to 30 mm and bulges into the peritoneal cavity. At this time it consists of about 60 million granulosa cells arranged in multiple layers around the periphery. The ovum and its surrounding layers of granulosa cells, the corona radiata, are suspended by a narrow bridge of granulosa cells (the cumulus oophorous) in a pool of more than 6 ml of follicular fluid. At ovulation, a point opposite the ovum in the follicle wall, called the stigma, erodes and the ovum with its corona of granulosa cells is extruded into the peritoneal cavity in a bolus of follicular fluid (Fig. 4).

Ovulation is followed by ingrowth and differentiation of the remaining mural granulosa cells, thecal cells, and some stromal cells, which fill the cavity of the collapsed follicle to form a new endocrine structure, the corpus luteum. The process by which granulosa and thecal cell are converted to luteal cells is called luteinization (meaning yellowing) and is the morphological reflection of the accumulation of lipid. Luteinization also involves biochemical changes that enable the corpus luteum to become the most active of all steroid-producing tissues per unit weight. The corpus luteum consists of large polygonal cells containing smooth endoplasmic reticulum and a rich supply of fenestrated capillaries. Unless

FIGURE 4 Ovulation in a rabbit. Follicular fluid, granulosa cells, some blood, and cellular debris continue to ooze out of the follicle even after the egg mass has been extruded. (From Hafez ESE, Blandau RJ. In: Hafez ESE, Blandau RJ, Eds., The mammalian oviduct, Chicago: University of Chicago Press, 1969. With permission.)

FIGURE 4 Ovulation in a rabbit. Follicular fluid, granulosa cells, some blood, and cellular debris continue to ooze out of the follicle even after the egg mass has been extruded. (From Hafez ESE, Blandau RJ. In: Hafez ESE, Blandau RJ, Eds., The mammalian oviduct, Chicago: University of Chicago Press, 1969. With permission.)

mesovarium (attaches ovary to mesovarium (attaches ovary to

FIGURE 5 Uterus and associated female reproductive structures. The left side of the figure has been sectioned to show the internal structures. (From Tortora GJ, Anagnostakos NP. Principles of anatomy and physiology, 3rd ed., New York: Harper & Row, 1981, p. 721. With permission.)

pregnancy ensues, the corpus luteum regresses after 2 weeks, leaving a scar on the surface of the ovary.

Oviducts and Uterus

The primitive miillerian ducts that develop during early embryonic life give rise to the duct system that in primitive organisms provides the route for ova to escape to the outside (Fig. 5). In mammals, these tubes are adapted to provide a site for fertilization of ova and nurture of embryos. In female embryos, the mullerian ducts are not subjected to the destructive effects of the anti-mullerian hormone (see Chapter 45) and, instead, develop into the oviducts, uterus, and upper portion of the vagina. Unlike the development of the sexual duct system in the male fetus, this differentiation is independent of gonadal hormones.

The paired oviducts (fallopian tubes) are a conduit for transfer of the ovum to the uterus (see Chapter 47). The ovarian end comes in close contact with the ovary and has a funnel-shaped opening, the infundibulum, surrounded by finger-like projections called fimbriae. The oviduct, particularly the infundibulum, is lined with ciliated cells, the synchronous beating of which plays an important role in egg transport. The lining of the oviduct also contains secretory cells whose products provide nourishment for the zygote in its 3- to 4-day journey to the uterus. The walls of the oviducts contain layers of smooth muscle cells oriented either longitudinally or circumferentially.

Distal portions of the mullerian ducts fuse to give rise to the uterus. In the nonpregnant woman, the uterus is a small, pear-shaped structure extending about 6 to 7 cm in its longest dimension. It is capable of enormous expansion, partly by passive stretching and partly by growth, so that at the end of pregnancy it may reach 35 cm or more in its longest dimension. Its thick walls consist mainly of smooth muscle and are called the myometrium. The secretory epithelial lining is called the endometrium and varies in thickness with changes in the hormonal environment, as discussed below. The oviducts join the uterus at the upper, rounded end. The caudal end constricts to a narrow cylinder called the uterine cervix, whose thick wall is composed largely of dense connective tissue rich in collagen fibers and some smooth muscle. The cervical canal is lined with mucus-producing cells and is usually filled with mucus. The cervix bulges into the upper reaches of the vagina, which forms the final link to the outside. The lower portion of the vagina, which communicates with the exterior, is formed from the embryonic urogenital sinus.

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