EFFECTS OF PERIPHERAL VERSUS CENTRAL ADMINISTRATION OF THE ENDOGENOUSGLUCOCORTICOID, CORTICOSTERONE, AND THE GLUCOCORTICOID RECEPTOR AGONIST, RU-28362, ON LH-RELEASE IN MALE-RATS

The current studies evaluated the effects of the synthetic glucocortic oid receptor (GR) agonist, RU 28362, and the endogenous, non-selective receptor ligand, corticosterone (Cort), on pituitary luteinizing horm one (LH) secretion in male rats. Steroids were injected subcutaneously (s.c.) in animals previously implanted with intracardiac venous cathe ters, or administered intracerebroventricularly (i.c.v.) to other grou ps of animals. A dose-proportionate decrease in plasma LH was observed following either s.c. or i.c.v. administration of RU 28362; pretreatm ent with the GR antagonist, RU 38486, blunted the inhibitory impact of RU 28362 on circulating LH. In other experiments, s.c. injection of C ort elicited divergent, dose-dependent patterns of LH release. While t he lowest peripheral dose (0.25 mg Cort/kg) promoted a transient eleva tion in plasma LH, higher doses exerted a progressively greater inhibi tory 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, administr ation of graded doses of Cort. The lowest dose (0.1 mu g Cort/rat) onl y 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 recepto r antagonist, RU 26752, attenuated the stimulatory impact of i.c.v. Co rt on LH release, while both RU 26752 and RU 38486 reversed the second ary decline in plasma LH. In summary, the present studies provide evid ence 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, result ed in divergent, dose-dependent effects on LH release; the inhibitory effects of high doses of this steroid are apparently mediated by GR. I n 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 administratio n of RU 26752 supports the involvement of Cort-preferring mineralocort icoid receptors (CR) in central facilitory actions of Cort. The curren t results suggest that CR and GR mediate divergent effects of circulat ing glucocorticoids on LH release, and that the dose-dependent LH resp onse to systemic injections of Cort may reflect specific patterns of o ccupancy of high affinity CR versus low affinity GR.