Glucocorticoid Modulation of Follicle-Stimulating Hormone-Mediated Granulosa Cell Differentiation*

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Abstract
A relationship between hyperactivity of the adrenal gland and inhibition of normal ovarian function has been proposed; however, the importance of direct glucocorticoid effects in determining the extent of follicle differentiation is unclear. In view of the critical role of an increase in granulosa cell LH/hCG [lutropin/human chorionic gonadotropin] receptor in the development of preovulatory follicles, direct glucocorticoid effects on the FSH induction of LH/hCG receptor in cutlured rat granulosa cells were examined. This action was correlated with 2 other important differentiative functions of granulosa cells, namely estrogen and progesterone production. Granulosa cells from immature hypophysectomized diethylstibestrol-treated rats were cultured in serum-free medium containing FSH in the presence or absence of dexamethasone. After 2 days of exposure to 10 ng/ml FSH, the granulosa cells exhibited a 12-fold increase in specific [125I] iodo-hCG binding (control, 0.7 .+-. 0.1; FSH-treated, 8.2 .+-. 0.6 fmol/106 cells). In contrast, exposure to a combination of FSH plus 1 .mu.M dexamethasone resulted in a marked decrease in [125I] iodo-hCG binding (FSH- and dexamethasone-treated, 2.2 .+-. 0.3 fmol/106 cells). Scatchard analysis demonstrated that dexamethasone decreased the concentration of specific high affinity LH/hCG-binding sites without influencing receptor affinity. The distribution of [125I]iodo-hCG binding, as determined by autoradiography, revealed a heterogeneity in granulosa cells with respect to the capacity to acquire LH/hCG receptor in response to FSH (only 56% of the granulosa cells acquired LH/hCG receptor) and the ability of granulosa cells to respond to glucocorticoids (dexamethasone did not fully suppress FSH induction of LH/hCG receptor). In addition to its effects on LH/hCG receptor, dexamethasone also inhibited FSH-stimulated aromatase activity, but stimulated progesterone production. Each of these responses was dose dependent and was not attributable to a reduction in cell viability or number. Further, treatment with various corticoid hormones suggested that these responses were a function of the glucocorticoid rather than the mineralocorticoid potencies of the corticoid hormones administered. Adrenal glucocorticoids may act directly on follicles to modulate FSH-dependent granulosa cell differentiation; ovarian failure associated with adrenal hyperactivity can be explained, at least in part, by direct glucocorticoid actions in the ovary.