Gonadotropin-Releasing Hormone Modulation of Its Own Pituitary Receptors: Evidence for Biphasic Regulation*

Abstract

To determine whether pituitary gonadotroph desensitization is a consequence of loss of gonadotropin-releasing hormone (GnRH) receptors (GnRH-R), these were analyzed in pituitaries from animals continuously infused with native GnRH or a superagonist analog (GnRH-A). Continuous infusion, for 6 days, of low doses of GnRH (<3.4 μg/day) and GnRH-A (<340 ng/day) to intact male rats resulted in a 37% and 75% increase in GnRH-R, respectively. At the time of sacrifice, basal serum LH levels were either unchanged (GnRH) or doubled (GnRH-A), and plasma concentrations of GnRH and GnRH-A were less than 0.05 nM or undetectable. There was no change in pituitary LH content under these circumstances. Infusion of doses of GnRH that induced GnRHR in the intact animals did not affect the GnRH-R, serum LH, or pituitary LH content measured 6 days after orchidectomy. However, the receptor-inducing dose of GnRH-A (340 ng/day) dramatically reduced the acute GnRH-R, serum LH, and pituitary LH responses to castration. In intact rats, 10- and 100-fold increases in the infusion dose of GnRH or GnRH-A resulted in progressive reduction in both GnRH-R and pituitary LH, while basal serum LH values increased after 6 days. Infusion of the same doses of both agonists, commencing at the time of orchidectomy, caused progressive falls in GnRH-R, basal serum LH, and pituitary LH. Similarly, a progressive reduction in GnRH-R and pituitary LH content was observed with increasing doses of GnRH and GnRH-A infusion in chronically orchidectomized rats, while basal serum LH values were only reduced by 40%. There was no LH release in response to exogenous GnRH administration to chronically castrated animals receiving receptor-lowering infusions of GnRH or GnRH-A. The reduction in GnRH-R in pituitaries continuously exposed to high doses of GnRH-A was not due to lowered receptor affinity and could not be entirely explained by continuous receptor occupancy, indicating that net receptor loss, or down-regulation, was achieved. The present data demonstrate biphasic autoregulation of pituitary GnRH-R: 1) Up-regulation is consistently observed with low dose continuous infusion of native GnRH and GnRHA. Thus, continuous exposure to GnRH at low concentrations does not produce desensitization. 2) Net loss of GnRH-R is produced by continuous exposure to high agonist ligand concentrations and is partially responsible for desensitization of gonadotropin secretion. 3) Significant depletion of pituitary LH stores also contributes to the mechanism (s) of desensitization, and functional GnRH-R are evidently necessary for a normal rate of gonadotropin synthesis.