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cells, each stimulated by its own gonadotropin, accounts for the requirement of both pituitary hormones for adequate estrogen production and hence for follicular development.

Follicular Development

Under the influence of FSH, granulosa cells in the follicle destined to ovulate increase by more than 100fold and the follicle expands about 10-fold in diameter, mainly because of the increase in follicular fluid. Differentiation of granulosa cells leads to increased expression of a number of genes including that for the LH receptor. In early antral follicles, granulosa cells have few if any receptors for LH and are unresponsive to it. By about the middle of the follicular phase, granulosa cell begin to express increasing amounts of LH receptor (Fig. 8), which becomes quite abundant just prior to ovulation. Acquisition of LH receptors in response to FSH enables granulosa cells to respond to both FSH and LH.

lamina

FIGURE 7 Theca and granulosa cell cooperation in estrogen synthesis. Theca cells produce androgens in response to LH. Granulosa cells respond to FSH by aromatizing androgens to estrogens. LDL, low density lipoproteins; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; DNA, deoxyribonucleic acid; CREB, cAMP response element binding protein; StAR, steroid acute regulatory protein; P450c17, 17a dehydrogenase/lyase; 3ßDH, 3ß hydroxysteroid dehydrogenase; 17ßDH, 17ß hydroxysteroid dehydrogenase. Dashed arrows indicate minor or questionable effect.

lamina

FIGURE 7 Theca and granulosa cell cooperation in estrogen synthesis. Theca cells produce androgens in response to LH. Granulosa cells respond to FSH by aromatizing androgens to estrogens. LDL, low density lipoproteins; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; DNA, deoxyribonucleic acid; CREB, cAMP response element binding protein; StAR, steroid acute regulatory protein; P450c17, 17a dehydrogenase/lyase; 3ßDH, 3ß hydroxysteroid dehydrogenase; 17ßDH, 17ß hydroxysteroid dehydrogenase. Dashed arrows indicate minor or questionable effect.

Induction of LH receptors and other actions of FSH on follicular development are amplified by paracrine actions of peptide growth factors and steroid hormones. In response to FSH, granulosa cells secrete insulin-like growth factor II (IGF-II), inhibin, activin, and other growth factors, including vascular endothelial growth factor (VEGF), which greatly increases vascularization around the theca. IGF-II not only stimulates the growth and secretory capacity of granulosa cells but also acts synergistically with LH to increase synthesis of andro-gens by cells of the theca interna. Similarly, inhibin produced by granulosa cells in response to FSH also stimulates thecal cell production of androgens, while activin enhances FSH-induced expression of P450 aromatase in the granulosa cells. Thus, even though theca cells lack FSH receptors, they nevertheless respond indirectly to FSH with increased production of the androgens required by the granulosa cells for estrogen secretion. Similarly, by stimulating thecal cells to produce androgens, LH augments growth and development of granulosa cells through the paracrine actions of both estrogen and androgens, the receptors of which are abundantly expressed in these cells. These events constitute a local positive feedback circuit that gives the follicle progressively greater capacity to produce estradiol and makes it increasingly sensitive to FSH and LH as it matures.

Cellular Actions

Follicle stimulating hormone and LH each bind to specific G-protein-coupled receptors on the surface of granulosa or theca cells and activate adenylyl cyclase in the manner already described (Chapters 2 and 45). Increased concentrations of cAMP activate protein kinase A, which catalyzes phosphorylation of cAMP response element binding (CREB) protein and other nuclear and cytoplasmic proteins that ultimately lead to increased transcription of genes that encode growth factors and other proteins critical for cell growth and steroid hormone production. As described for adrenal cortical (Chapter 40) and Leydig cells (Chapter 45), the rate-limiting step in steroid hormone synthesis requires synthesis of the steroid acute regulatory protein (StAR) to deliver cholesterol to the intramitochondrial enzyme P450scc, which converts it to pregnenolone (Fig. 6). In addition, activation of protein kinase A results in increased expression of P450c17 in theca cells and P450 aromatase in granulosa cells. Along with increased expression of growth factors, the ripening follicle also expresses increased amounts of a protease that specifically cleaves IGF-4 binding protein (IGFBP-4) which is present in follicular fluid and thereby increases availability of free IGF-II.

Ovulation

Luteinizing hormone is the physiological signal for ovulation. Its concentration in blood rises sharply and reaches a peak about 16 hours before ovulation (see below). Blood levels of FSH also increase at this time, and, although large amounts of FSH can also cause ovulation, the required concentrations are not achieved during the normal reproductive cycle. The events that lead to follicular rupture and expulsion of the ovum are not fully understood, but the process is known to be initiated by increased production of cAMP in theca and granulosa cells in response to LH and the consequent release of paracrine factors and enzymes.

As the follicle approaches ovulation, it accumulates follicular fluid, but, despite the preovulatory swelling, intrafollicular pressure does not increase. The follicular wall becomes increasingly distensible due to activity of proteolytic enzymes that digest the collagen framework and other proteins of the intercellular matrix. One of these enzymes, plasmin, accumulates in follicular fluid in the form of its inactive precursor, plasminogen. Granulosa cells secrete plasminogen activator in response to hormonal stimulation. Because of their newly acquired receptors, granulosa cells of the preovulatory follicle respond to LH by secreting progesterone, which is thought to induce the formation of prostaglandins. The finding that pharmacological blockade of either prosta-glandin or progesterone synthesis prevents ovulation indicates that these agents play essential roles in the ovula-tory process. Prostaglandins appear to activate release of lysosomal proteases in a discrete region of the follicle wall called the stigma. Breakdown of the extracellular matrix of the theca and the surface epithelium of the ovary facilitates extrusion of the ovum into the abdominal cavity.

Although little or no progesterone is produced throughout most of the follicular phase, granulosa cells of the preovulatory follicle acquire the capacity for progesterone production. Stimulation by LH evokes expression of LDL receptors, P450scc, and doubtless other relevant proteins, enabling them to take up cholesterol and convert it to pregnenolone. Because the capacity to remove the side chain at carbon 17 remains limited, 21-carbon steroids are formed faster than they can be processed to estradiol and hence are secreted as progesterone. Furthermore, as granulosa cells acquire the ability to respond to LH, they also begin to lose aromatase activity (Fig. 8). This is reflected in the abrupt decline in estrogen production that just precedes ovulation.

Corpus Luteum Formation

Luteinizing hormone was named for its ability to induce formation of the corpus luteum after ovulation; however, as already mentioned, luteinization may actually begin before the follicle ruptures. Granulosa cells removed from mature follicles complete their luteinization in tissue culture without further stimulation by gonadotropin. Nevertheless, luteinization within the ovary depends on LH and is accelerated by the increased concentration of LH that precedes ovulation. Occasionally, luteinization occurs in the absence of ovulation and results in the syndrome of luteinized unruptured follicles, which may be a cause of infertility in some women whose reproductive cycles seem otherwise normal.

Development of a vascular supply is critical for development of the corpus luteum and its function. Although granulosa cells of the preovulatory follicle are avascular, the corpus luteum, is highly vascular, and when fully developed each steroidogenic cell appears to be in contact with at least one capillary. After extrusion of the ovum infolding of the collapsing follicle causes the highly vascular theca interna to interdigitate with layers of granulosa cells that line the follicular wall. Under the influence of LH, granulosa cells express high levels of VEGF, which stimulates growth and differentiation of capillary endothelial cells. It has been estimated that vascular endothelial cells make up fully half of the cells of the mature corpus luteum.

Oocyte Maturation

Granulosa cells not only provide nutrients to the ovum but may also prevent it from completing its meiotic division until the time of ovulation. Granulosa cells are thought to secrete a substance called oocyte maturation inhibitor (OMI) into follicular fluid. LH triggers resumption of meiosis at the time of ovulation, perhaps by blocking production of this factor or interfering with its action.

phase phase phase

FIGURE 8 Proliferation and differentiation of granulosa cells during follicular development. Initially, granulosa cells are few and have receptors only for FSH on their surface. In response to continued stimulation with FSH, granulosa cells proliferate and by the midfollicular phase LH receptors begin to appear. By late in the follicular phase a large number of granulosa cells are present and they are responsive to both LH and FSH. They are now competent to secrete sufficient estradiol to trigger the ovulatory surge of gonado-tropins. FR, FSH receptor; LR, LH receptor.

phase phase phase

FIGURE 8 Proliferation and differentiation of granulosa cells during follicular development. Initially, granulosa cells are few and have receptors only for FSH on their surface. In response to continued stimulation with FSH, granulosa cells proliferate and by the midfollicular phase LH receptors begin to appear. By late in the follicular phase a large number of granulosa cells are present and they are responsive to both LH and FSH. They are now competent to secrete sufficient estradiol to trigger the ovulatory surge of gonado-tropins. FR, FSH receptor; LR, LH receptor.

Corpus Luteal Function

Maintenance of steroid production by the corpus luteum depends on continued stimulation with LH. Decreased production of progesterone and premature demise of the corpus luteum is seen in women whose secretion of LH is blocked pharmacologically. In this respect, LH is said to be luteotropic. The corpus luteum has a finite life-span, however, and about a week after ovulation becomes progressively less sensitive to LH and finally regresses despite continued stimulation with LH. Estradiol and prostaglandin F2a, which are produced by the corpus luteum, can hasten luteolysis and may be responsible for its demise. We do not understand the mechanisms that limit the functional life-span of the human corpus luteum.

Ovarian Blood Flow

Luteinizing hormone also increases blood flow to the ovary and produces ovarian hyperemia throughout the cycle. In addition to increased angiogenesis, blood flow may be enhanced by release of histamine or perhaps prostaglandins. Increased ovarian blood flow increases the opportunity for delivery of steroid hormones to the general circulation and for delivery to the ovary of cholesterol-laden LDL needed to support high rates of steroidogenesis. Increased blood flow to the developing follicle may also be important for preovulatory swelling of the follicle, which depends on increased elaboration of fluid from blood plasma.

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