Suppression of the positive feedback of estradiol benzoate on gonadotropin secretion by an inhibitory analog of luteinizing hormone-releasing hormone (lrh) in oophorectomized rhesus monkeys: Evidence for a necessary synergism between lrh and estrogens

Estrogens have a biphasic effect on gonadotropin (FSH and LH) secretion in human and nonhuman primates. Recent studies suggest that estrogens induce negative as well as positive feedback on gonadotropin secretion by a direct action at the pituitary gland. To further investigate the mechanism by which estrogens modulate gonadotropin secretion, the following experiments were performed. Oophorectomized rhesus monkeys were injected with estradiol benzoate (EB) at a dose of 40 μg/kg sc at zero time (controls). Three groups of animals received, additionally, an inhibitory analog of LRH, [Ac-D-p-Cl-Phe^1,2, D-Trp³,D-Arg⁶,d-Ala¹⁰] LRH (200 μg, sc, daily) at 1) -48 to 48 h, 2) 0-48 h, and 3) 24-48 h from EB treatment, respectively. Blood was collected at -72, -48, -24, and 0 h, every 6 h from 6-84 h, and 96 and 116 h after EB; FSH and LH levels were measured by RIA. Control animals had a 70-80% decrease in baseline FSH and LH levels during the first 24 h after EB injection, followed by a sharp rise to 60-80% above basal levels 42-48 h post-EB. In contrast, animals that received the inhibitory analog of LRH in different regimens had more pronounced and prolonged negative feedback of EB on gonadotropin concentrations. The positive feedback release of FSH and LH was significantly diminished or delayed compared to control values. The results of this study indicate that this inhibitory analog of LRH potentiates the negative feedback and suppresses the positive feedback of EB on gonadotropin, suggesting that estrogens induce the secretion of FSH and LH through a mechanism that involves the action of LRH at the gonadotroph.