Direct Inhibitory Effect of Gonadotropin-Releasing Hormone upon Follicle-Stimulating Hormone Induction of Luteinizing Hormone Receptor and Aromatase Activity in Rat Granulosa Cells*

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Abstract
The effect of gonadotropin-releasing hormone (GnRH) and its agonists upon FSH induction of LH/hCG receptor and aromatases was studied. Immature, hypophysectomized, estrogen-treated female rats were injected with FSH and/or GnRH agonists twice daily for 2 days. FSH (100 μg/injection) increased LH/hCG receptor in granulosa cells by 66-fold, whereas concomitant treatments with GnRH (100 μg/injection) or GnRH agonist (50 μg [d-Leu6(N0Me)Leu7]GnRH or 10 μg des-Gly10-[d-Trp6,Pro9-NHEt]GnRH) inhibited the FSH-induced increase in LH/hCG receptor by 95%. Incubation of granulosa cells obtained from FSH-treated animals with graded doses of aromatase substrate (Δ4-androstenedione) resulted in a dose-dependent increase in estrogen production (maximal production, 1.65 ng/105 cells; ED50 = 3 × 10−8m). In contrast, concomitant treatment with GnRH agonists depressed estrogen production. Histological examination of the ovaries from animals treated with FSH plus GnRH agonist indicated the presence of antrumcontaining follicles. Some ova in these follicles had resumed meiotic maturation and appeared to be undergoing fragmentation. Granulosa cells were cultured for 2 days with FSH (100 ng/ml) and/or GnRH or GnRH agonist. Compared to control cells, FSH induced a 12-fold increase in LH/hCG receptor, whereas concomitant GnRH or GnRH agonist (10−m) treatment completely abolished the FSH effect. Likewise, concomitant treatment with GnRH or GnRH agonist resulted in a dose-dependent inhibition of FSH-induced steroidogenesis. Furthermore, GnRH was shown to inhibit granulosa cell estrogen production induced by cholera toxin and prostaglandin E2. The present study extends our previous studies in demonstrating the direct inhibitory effect of GnRH and its agonists on ovarian LH/hCG receptor formation and steroidogenesis in vivo and in vitro. This provides the basis for understanding the inhibitory effect of these peptides on various female reproductive functions. (Endocrinology106: 1697, 1980)