Inhibitory actions of a gonadotropin-releasing hormone agonist on ovarian follicle-stimulating hormone receptors and adenylate cyclase in vivo

Abstract

The regulation of ovarian gonadotropin-sensitive adenylate cyclase and FSH receptors was studied in hypophysectomized diethylstilbestrol-primed rats treated with FSH and/or the potent GnRH agonist [D-Ala6]des-Gly10-GnRH N-ethylamide (GnRHa). The animals were treated with 7.5 micrograms ovine FSH twice daily for 2 days, either alone or with 10 micrograms GnRHa. FSH-stimulated adenylate cyclase activity was augmented by 2.5- to 3.5-fold in the presence of 5'-guanyl-imidodiphosphate. Adenylate cyclase responses to FSH were almost completely abolished by GnRHa treatment in ovarian homogenates from control animals and rats treated with FSH. This inhibition was receptor specific, since GnRHa did not block adenylate cyclase stimulation by prostaglandin E2 or isoproterenol. No inhibition of 5'-guanyl-imidodiphosphate- or sodium fluoride-stimulated adenylate cyclase activity was noted after any hormone treatment. When GnRHa treatment was initiated at 12, 24, or 36 h during the 2-day period of FSH treatment, inhibition of both FSH- and LH-stimulated adenylate cyclase was observed in ovaries collected at 48 h. Whereas FSH treatment increased the ovarian FSH receptor concentration by more than 100%, concomitant treatment with GnRHa prevented this increase and reduced FSH receptors to 60% of the control level. Treatment with GnRHa alone caused a 65% decrease in FSH receptor levels below the untreated control values. Histological analysis of hormone-treated ovaries indicated that FSH stimulated follicle growth and antrum formation, but caused little luteinization. GnRHa did not completely prevent the effects of FSH on follicle growth, but did induce degeneration and premature cleavage of ova. GnRHa alone suppressed the diethylstilbestrol-stimulated mitotic activity, slightly increased degenerative changes in granulosa cells, and caused oocyte cleavage and premature antrum formation. These findings demonstrate that GnRHa inhibits FSH-dependent adenylate cyclase by a mechanism involving the loss of binding sites for FSH. It is also evident that only short term exposure to GnRHa is necessary for expression of the inhibitory action of the peptide upon FSH- and LH-stimulated adenylate cyclase.