Antagonism of Type II, but Not Type I Glucocorticoid Receptors Results in Elevated Basal Luteinizing Hormone Release in Male Rats

Abstract

The present studies utilized a phaimacologic approach to evaluate the role of corticosterone-preferring mineralocorticoid receptors (type I or MR) versus classic glucocorticoid receptors (type II or GR) in the regulation of basal pituitary luteinizing hormone (LH) secretion in vivo in male rats. Animals bearing indwelling intracardiac venous catheters received a subcutaneous (s.c.) injection of either vehicle, the MR antagonist, RU 752 (0.5 or 5.0 mg/kg body weight), or the GR antagonist, RU 486 (0.5 or 5.0 mg/kg body weight). Additional groups of rats were implanted with indwelling intracerebroventricular (i.c.v.) cannulas and intravenous catheters for drug administration and blood withdrawal, respectively, and injected i.c.v. with vehicle or graded doses (0.1, 1.0 or 10.0 µg/rat) of RU 752 or RU 486. The MR RU 752 failed to alter plasma LH concentrations regardless of dose or route of administration. In contrast, the GR antagonist, RU 486, elicited significant, dose-dependent increases in circulating LH when given either s.c. or i.c.v. Animals injected s.c. with either 0.5 or 5.0 mg RU 486/kg body weight showed elevated plasma LH levels; while the magnitude of this secretory response was not different between the two drug-treated groups, hormone levels remained elevated over baseline for a longer period of time in rats given the higher dose. Central administration of RU 486 at a dose of either 1.0 or 10.0 µg also resulted in elevated LH release; both the magnitude and duration of this increase in plasma LH were dose-dependent. In additional experiments, groups of rats were pretreated with vehicle or the synthetic GR agonist, RU 362, before administration of RU 486. These studies showed that the stimulatory effect of RU 486 on peripheral LH was abolished by prior interaction of GR with the exogenous ligand. In summary, the ability of the GR antagonist, RU 486, to promote an increase in plasma LH concentrations in intact male rats suggests that endogenous glucocorticoids exert a tonic inhibitory tonus on in vivo LH release in these animals, and that GR mediate these suppressive effects. Observations that drug-induced elevations in circulating LH were abolished by pretreatment with the GR agonist, RU 362, suggest that the stimulatory effects of RU 486 on hormone release were achieved by an antiglucocorticoid action. The current findings that plasma LH was increased following intracranial administration of RU 486 implicate central GR in neuroendocrine mechanisms governing pituitary LH.

The Antiglucocorticoid, RU486, Attenuates Stress-Induced Decreases in Plasma-Luteinizing Hormone Concentrations in Male Rats

“…The present findings that the GR antagonist, RU486, attenuates stress-induced decreases in circulating LH sup port a role for endogenous glucocorticoids in the suppres sive effects of immobilization stress on LH release, and suggest that inhibitory steroid action involves GR-dependent mechanisms. GR have been localized within pitu itary gonadotropes [34]; these receptors probably mediate direct inhibitory effects of glucocorticoids, since exoge nous receptor ligands have been reported to diminish GnRH-stimulated LH release from perfused pituitary' tis sue in vitro [24,25], GR are also characterized by a wide spread distribution within the rat brain, including the hypothalamus [26][27][28][29]; the functional significance of cen tral GR to the regulation of pituitary LH is supported by observations that icv administration of receptor agonists or antagonists results in altered peripheral LH levels [25,32,35], The current data are consistent with the view that glucocorticoids elicit multiple actions within the brainpituitary LH neuroendocrine axis under physiological conditions of stress. Indeed, our observations that intra cranial injections of RU486 diminish acute and chronic stress-induced decreases in LH suggest that glucocorticoid inhibition of circulating LH is mediated, in part, by cen tral GR.…”

“…Imme diately alter collection of the sample at -1 0 min, the animals were injected sc with either 2.5 mg RU486/kg [32] (group 1) or the vehicle, propylene glycol (PG, groups 2 and 3). Beginning at time zero, the animals in groups 1 and 2 were completely immobilized for a total of 5 h. by encasement within plastic-backed, laboratory bench paper Effects o f sc administration of RU486 on acute immobilization stress-in duced alterations in circulating LH.…”

“…and injected iev with 10.0 pg RU486/ 3-Opl/rat [32] (group 1) or PG alone (group 2). Beginning at time zero, all animals were immobilized within paper cocoons for 5 con secutive hours.…”

“…and that a component of the suppressive impact of GR activation is achieved by neuroendocrine mechanisms [32], In the current study, we investigated the role of GR in stress-induced decreases in circulating LH by evaluating the effects of GR antagonism on pat terns of LH release during exposure to acute and chronic inhibitory stress stimuli. The GR antagonist, RU486, was administered prior to stress by either a systemic or intracerebroventricular (icv) route in order to determine whether glucocorticoid inhibition of LH, under these physiologic circumstances, is mediated in part by central receptors.…”

Estradiol Enables Cortisol to Act Directly upon the Pituitary to Suppress Pituitary Responsiveness to GnRH in Sheep

“…Direct actions of estradiol could include modulation of glucocorticoid receptors or downstream cross-talk between glucocorticoid receptors and estrogen receptors. The pituitary actions of cortisol to inhibit LH responses to GnRH are mediated via the type II glucocorticoid receptor [23,24,25,26]. Since type II glucocorticoid receptors are present in gonadotropes [27], gonadotropes are a potential cell type mediating the direct pituitary actions of cortisol on LH secretion.…”