Hypothalamic Regulation of Pituitary Gonadotropin-Releasing Hormone Receptors: Effects of Hypothalamic Lesions and a Gonadotropin-Releasing Hormone Antagonist*

The role of the hypothalamus in maintenance of pituitary gonadotropin-releasing hormone receptors (GnRH-R) and gonadotropin secretion was investigated by ablation of endogenous GnRH secretion and subsequent analysis of the receptor and serum LH responses to orchidectomy. The effects of continuous infusion of a potent GnRH antagonist analog, [N-acetyl- Ala1,D-p-chloro-Phe2,D-Trp3,6]GnRH, upon these same responses were also examined. Median eminence destruction before orchidectomy prevented the characteristic 2-fold increase in GnRH-R and 10-fold increase in serum LH, measured 6 days post castration. GnRH-R values in the median eminence lesion (MEL)-bearing animals were 30% (P < 0.01) lower than in the intact controls. In chronically orchidectomized animals, MEL also reduced GnRH-R and serum LH values to below those of intact controls. Exogenous GnRH administration alone to MEL-bearing chronically castrated rats reversed the effects of the lesion, with GnRH-R and serum LH being restored to castrate control values. GnRH antagonist infusion for 6 days prevented the acute postorchidectomy GnRH-R and serum LH increases in a dose-dependent manner. Furthermore, antagonist infusion to chronically orchidectomized and intact animals reduced GnRH-R values to 25% of intact controls and rendered serum LH undetectable, whereas pituitary LH was increased by 50%. This apparent GnRH-R loss could largely be accounted for by occupancy of receptors by the antagonist. Nevertheless, these data indicate that the postorchidectomy rise in GnRH-R requires interaction of the decapeptide with its own receptors. These data demonstrate that pituitary GnRH-R are regulated in a positive manner by GnRH and imply that the postcastration GnRH-R and gonadotropin responses depend upon increased hypothalamic GnRH secretion. Thus, measurement of pituitary GnRH-R may provide an index of prior pituitary exposure to endogenous GnRH and therefore a qualitative measurement of hypothalamic function in different physiological conditions.