Decreased Pituitary Responsiveness and Inhibition of the Luteinizing Hormone Surge and Ovulation in the Stumptailed Monkey (Macaca arctoides) by Chronic Treatment with an Agonist of Luteinizing Hormone-Releasing Hormone

Abstract

The purpose of this investigation was to determine if chronic treatment with D-Ser-(Bu^t)⁶-des-Gly¹⁰ LHRH ethylamide (LHRH agonist) could lead to an inhibitory effect on reproduction in the stumptailed macaque (Macaca arctoides). Nine adult monkeys, weighing 8–10.5 kg, with regular menstrual cycles of 29.7 ± 0.3 days (mean ± SEM) were selected. A single sc injection of 5 μg LHRH agonist stimulated LH secretion for 8 h; this was associated with an increased secretion of 17β-estradiol from the ovaries. Beginning on days 1-5 of the cycle, the monkeys were given daily sc injections of 5 fig LHRH agonist for 20 days. Blood samples were taken two or three times weekly (four monkeys) or daily (five monkeys) and assayed for progesterone, 17β-estradiol, and LH. Sampling was done 24 h after each injection of agonist and at regular intervals after the first and last injections. The normal rise in progesterone levels in the blood was prevented by agonist treatment in seven of the nine monkeys and in the remaining two monkeys when the daily dose of LHRH agonist was increased to 20 μg, indicating that ovulation had been inhibited. Plasma levels of 17β-estradiol generally rose during the first 10 days of treatment and then fell to low levels. This fall in estrogen in the absence of ovulation was associated with endometrial bleeding. The normal preovulatory LH surge was absent during agonist treatment. Once treatment was stopped, follicular development resumed, and ovulation occurred 12.1 ± 1 days after cessation of treatment, followed by a normal luteal phase and menstruation after 28.6 ± 1.3 days (mean ± SEM). The pituitary LH release in response to the final injection of agonist was lower than that achieved by the first injection. Therefore, the principal way in which LHRH exerts its inhibitory action seems to be by a decreased responsiveness of the pituitary, thus preventing the LH surge. Although no change in the basal LH concentration was found between injections in the intact monkeys, it was reduced in a treated ovariectomized monkey, indicating a decreased responsiveness to endogenous LHRH. It is concluded that the stumptailed macaque can be used as a model to study possible contraceptive effects of chronic treatment with LHRH agonists, but long term studies are required to see if the inhibitory effect of the treatment continues and whether a low level of estrogen secretion can be maintained. (Endocrinology106: 452, 1980)