In vivo regulation of granulosa cell type I insulin-like growth factor receptors: evidence for an inhibitory role for the putative endogenous ligand(s) of the ovarian gonadotropin-releasing hormone receptor.

Abstract

The putative endogenous occupant(s) of the ovarian GnRH receptor may play a role as an intraovarian regulator. In this communication we explore the possibility that in vivo activation of the ovarian GnRH receptor may prove heteroregulatory to the murine granulosa type I insulin-like growth factor (IGF) receptor complement. To eliminate potentially confounding pituitary involvement, exclusive use was made of hypophysectomized rats, thereby allowing study of the direct ovarian effect(s) of GnRH receptor ligands. Treatment of immature hypophysectomized rats, thereby allowing study of the direct ovarian effect(s) of GnRH receptor ligands. Treatment of immature hypophysectomized diethylstilbestrol-primed rats with a GnRH agonist (25 micrograms/rat, twice daily) for 2.5 days resulted in a 2.1-fold decrease in FSH (10 micrograms/rat, twice daily)-inducible (but not basal) specific [125I]IGF-I binding to isolated granulosa cells. Scatchard analysis of the binding data revealed this effect to be due in large measure to decreased binding capacity (46% inhibition) rather than affinity (2.5 x 10(-9) M). Although in vivo treatment with a GnRH antagonist (25 micrograms/rat, twice daily) by itself proved without significant effect on the specific binding of IGF-I to isolated granulosa cells, the concurrent provision of a minimally effective dose of FSH (1 microgram/rat, twice daily) resulted in a 2.8-fold amplification of the FSH effect consequent to enhanced binding capacity (110%), but not affinity (2.2 x 10(-9) M). Significantly, this level of binding proved comparable to that induced by a maximally effective dose of FSH when used by itself. Combined pretreatment with identical doses of both peptide analogs had little or no effect on granulosa cell IGF-I binding, suggesting stereospecificity of action and mutual neutralization by the opposing actions of the GnRH receptor ligands employed. The ability of ligands of the GnRH receptor to alter the granulosa cell type I IGF receptor complement proved functionally significant, as assessed by corresponding alterations in IGF-I hormonal action. Indeed, pretreatment with a GnRH antagonist resulted in a 2.1-fold enhancement of IGF-I (50 ng/ml)-supported proteoglycan biosynthesis, with the agonistic analog producing a diametrically opposite effect. Moreover, the ovarian effects of GnRH receptor ligands were not limited to type I IGF receptor binding; comparable effects were noted on basal and hCG-stimulated accumulation of progesterone by cultured granulosa cells, ovarian weight, ovarian protein content, as well as size and number of antral follicles.(ABSTRACT TRUNCATED AT 400 WORDS)