The main physiologically active steroid produced by the follicle is estradiol, a steroid with 18 carbons. Steroidogenesis, the process of steroid hormone production, depends on the availability of cholesterol, which originates from several sources and serves as the main precursor for all of steroidogenesis. Ovarian cholesterol can come from plasma lipoproteins, de novo synthesis in ovarian cells, and cholesterol esters within lipid droplets in ovarian cells. For ovarian steroidogenesis, the primary source of cholesterol is low-density lipoprotein (LDL).
The conversion of cholesterol to pregnenolone by cholesterol side-chain cleavage enzyme is a rate-limiting step regulated by LH using the second messenger cAMP (Fig. 38.5). LH binds to specific membrane receptors on theca cells, activates adenylyl cyclase through a G protein, and increases the production of cAMP. cAMP increases LDL receptor mRNA, the uptake of LDL cholesterol, and cholesterol ester synthesis. cAMP also increases the transport of cholesterol from the outer to the inner mitochondr-ial membrane, the site of pregnenolone synthesis, using a unique protein called steroidogenic acute regulatory protein (StAR). Pregnenolone, a 21-carbon steroid of the progestin family, diffuses out of the mitochondria and enters the ER, the site of subsequent steroidogenesis.
Two steroidogenic pathways may be used for subsequent steroidogenesis (see Fig. 37.9). In theca cells, the delta 5 pathway is predominant; in granulosa cells and the corpus luteum, the delta 4 pathway is predominant. Pregnenolone gets converted to either progesterone by 3^-hy-droxysteroid dehydrogenase in the delta 4 pathway or to 17a-hydroxypregnenolone by 17a-hydroxylase in the delta 5 pathway. In the delta 4 pathway, progesterone gets converted to 17a-hydroxyprogesterone (by 17a-hydroxy-lase), which is subsequently converted to androstenedione and testosterone by 17,20-lyase and 17^-hydroxysteroid dehydrogenase (17-ketosteroid reductase), respectively. In the delta 5 pathway, 17a-hydroxypregnenolone gets converted to dehydroepiandrosterone (by 17,20-lyase), which is subsequently converted to androstenedione by 3^-hy-droxysteroid dehydrogenase. The androgens contain 19 carbons. Testosterone and androstenedione diffuse from the thecal compartment, cross the basement membrane, and enter the granulosa cells.
In the granulosa cell, under the influence of FSH, with cAMP as a second messenger, testosterone and androstene-dione are then converted to estradiol and estrone, respectively, by the enzyme aromatase, which aromatizes the A ring of the steroid and removes one carbon (see Fig. 38.5; see Fig. 37.9). Estrogens typically have 18 carbons. Estrone can then be converted to estradiol by 17^-hydroxysteroid dehydrogenase in granulosa cells.
In summary, estradiol secretion by the follicle requires cooperation between granulosa and theca cells and coordination between FSH and LH. An understanding of this two-cell, two-gonadotropin hypothesis requires recognition that the actions of FSH are restricted to granulosa cells because all other ovarian cell types lack FSH receptors. LH actions, on the other hand, are exerted on theca, granulosa, and stromal (interstitial) cells and the corpus luteum. The expression of LH receptors is time-dependent because theca cells acquire LH receptors at a relatively early stage, whereas LH receptors on granulosa cells are induced by FSH in the later stages of the maturing follicle.
The biosynthetic enzymes are differentially expressed in the two cells. Aromatase is expressed only in granulosa cells, and its activation and induction are regulated by FSH. Granulosa cells are deficient in 17a-hydroxylase and cannot proceed beyond the C-21 progestins to generate C-19 androgenic compounds (see Fig. 38.5). Consequently, estrogen production by granulosa cells depends on an adequate supply of exogenous aromatizable androgens, provided by theca cells. Under LH regulation, theca cells produce androgenic substrates, primarily an-drostenedione and testosterone, which reach the granulosa cells by diffusion. The androgens are then converted to estrogens by aromatization.
In follicles, theca and granulosa cells are exposed to different microenvironments. Vascularization is restricted to the theca layer because blood vessels do not penetrate the
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