Hypothalamic Regulation of Pituitary Gonadotropin-Releasing Hormone Receptors: Effects of Gonadotropin-Releasing Hormone Immunoneutralization*

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Abstract
To further evaluate the role of GnRH in the regulation of pituitary gonadotropin-releasing hormone receptors (GnRH-R) in male rats in vivo, endogenous GnRH was neutralized with a high-titer GnRH antiserum (GnRH-AS). When administered daily from the time of orchidectomy, GnRHAS prevented the 70–100% increase in GnRH-R and the 10-fold rise in serum LH occurring 6 days postcastration. GnRH-R concentration fell to values 30% below those of intact controls (P < 0.01). The effect of the antiserum was dose related, with as little as 0.01 ml/day significantly (P < 0.05) inhibiting the postorchidectomy GnRH-R increase, whereas 0.25 ml/day was required for full suppression of postcastration GnRH-R and serum LH responses. GnRH-AS administration also reduced GnRH-R to values 30% below intact controls in chronically (2 weeks) castrated and intact male rats. In the same animals serum LH was reduced to below intact control values, while pituitary LH was reduced in the intact group and further increased in the chronic castrates. GnRH-R recovery, after suppression for 6 days with GnRHAS treatment, began 8 days after cessation of the treatment and was complete between 15 and 30 days. However, recovery of LH secretion began some 4 days before GnRH-R. The GnRH-AS induced suppression of GnRH-R could be partially reversed with twice daily injections of a potent GnRH agonist analog (GnRHA), which does not cross-react with the antiserum. The suppressive effect of the antiserum could not be attributed to its binding to GnRH-R either in vivo or in vitro. The receptors remaining in pituitaries of GnRH-AS-treated rats were fully functional, as judged by their ability to release LH after administration of GnRH-A in vivo. These data demonstrate 1) that endogenous GnRH secretion is essential for maintenance of pituitary GnRH-R and hence gonadotropin secretion, as well as increases in these variables after orchidectomy; 2) consistent suppression of GnRH-R to values below intact controls indicates that these represent “background” or “basal” levels, increases above which are proportional to the extent of pituitary exposure to endogenous GnRH; 3) that a GnRH-A can effectively induce GnRH-R to a similar extent as the natural decapeptide; 4) that functional responsivity of GnRH receptors, although reduced in magnitude, is retained after GnRH-AS treatment.