Ovarian gonadotropin-releasing hormone receptors. II. Regulation and effects on ovarian development.

Abstract

The direct antagonistic actions of gonadotropinreleasing hormone (GnRH) and its agonist analogs on hormonal (hCG and epinephrine) activation of progesterone and cAMP production in isolated luteal cells were described in the preceding paper. These effects are mediated by specific, high affinity GnRH receptors demonstrated in both ovarian membranes and isolated luteal cells. The present studies show that the administration of GnRH agonist analogs in vivo markedly inhibits PMS gonadotropin (PMSG)-induced follicular development and the increased formation of LH receptors after hCG-induced luteinization. Three GnRH agonist analogs with structural modifications at positions 6 and 10 given by osmotic minipump infusion, caused complete inhibition of the trophic actions of both gonadotropins. An antagonist analog which binds to the ovarian GnRH receptor with high affinity did not inhibit the gonadotropin-induced changes. Using the PMSG/hCG-primed immature rat, the effects of a single injection of GnRH were studied and compared to the action of hCG. Whereas the latter caused a marked loss of GnRH and LH receptors, GnRH caused a loss of ovarian LH receptors but a consistent increase in ovarian GnRH receptors; PRL receptors also showed a transient decline, and there was a fall in serum progesterone. In hypophysectomized rats, GnRH and hCG similarly caused a decrease in ovarian LH receptors and a transient change in the PRL receptor concentration. The GnRHinduced decrease in LH and PRL receptors in hypophysectomized animals indicates that GnRH analogs can act directly on the ovary and that their effects are not only due to the secondary release of gonadotropins from the pituitary gland. The direct inhibitory actions of this class of GnRH peptides upon gonadal function constitutes an important component of the antifertility effects of these compounds.