The current studies evaluated the effects of the synthetic glucocorticoid receptor (GR) agonist, RU 28362, and the endogenous, non-selective receptor ligand, corticosterone (Cort), on pituitary luteinizing hormone (LH) secretion in male rats. Steroids were injected subcutaneously (s.c.) in animals previously implanted with intracardiac venous catheters, or administered intracerebroventricularly (i.c.v.) to other groups of animals. A dose-proportionate decrease in plasma LH was observed following either s.c. or i.c.v. administration of RU 28362; pretreatment with the GR antagonist, RU 38486, blunted the inhibitory impact of RU 28362 on circulating LH. In other experiments, s.c. injection of Cort elicited divergent, dose-dependent patterns of LH release. While the lowest peripheral dose (0.25 mg Cort/kg) promoted a transient elevation in plasma LH, higher doses exerted a progressively greater inhibitory effect on hormone release. The suppressive effects of the highest s.c. dose (2.5 mg Cort/kg) were reversed by pretreatment with the RU 38486, but not by the mineralocorticoid receptor antagonist, RU 26752. Plasma LH levels were transiently elevated following i.c.v, administration of graded doses of Cort. The lowest dose (0.1 mu g Cort/rat) only facilitated LH release, but higher doses (1.0 and 10.0 mu g/animal) elicited a biphasic LH response, which was characterized by an initial elevation, then subsequent reduction in plasma LH below preinjection baseline levels. Prior administration of the mineralocorticoid receptor antagonist, RU 26752, attenuated the stimulatory impact of i.c.v. Cort on LH release, while both RU 26752 and RU 38486 reversed the secondary decline in plasma LH. In summary, the present studies provide evidence that GR are inhibitory to LH release and that glucocorticoids may act to diminish LH, in part, through mechanisms initiated within the CNS. Systemic administration of the non-selective ligand, Cort, resulted in divergent, dose-dependent effects on LH release; the inhibitory effects of high doses of this steroid are apparently mediated by GR. In contrast to the bidirectional effects of s.c. Cort, i.c.v. delivery of the glucocorticoid resulted in a transient elevation in plasma LH; attenuation of this increase in hormone release by prior administration of RU 26752 supports the involvement of Cort-preferring mineralocorticoid receptors (CR) in central facilitory actions of Cort. The current results suggest that CR and GR mediate divergent effects of circulating glucocorticoids on LH release, and that the dose-dependent LH response to systemic injections of Cort may reflect specific patterns of occupancy of high affinity CR versus low affinity GR.
