Estradiol and the inhibition of hypothalamic gonadotropin-releasing hormone pulse generator activity in the rhesus monkey.

Abstract

In mammals, gonadal function is controlled by a hypothalamic signal generator that directs the pulsatile release of gonadotropin-releasing hormone (GnRH) and the consequent pulsatile secretion of luteinizing hormone. In female rhesus monkeys, the electrophysiological correlates of GnRH pulse generator activity are abrupt, rhythmic increases in hypothalamic multiunit activity (MUA volleys), which represent the simultaneous increase in firing rate of individual neurons. MUA volleys are arrested by estradiol, either spontaneously at midcycle or after the administration of the steroid. Multiunit recordings, however, provide only a measure of total neuronal activity, leaving the behavior of the individual cells obscure. This study was conducted to determine the mode of action of estradiol at the level of single neurons associated with the GnRH pulse generator. Twentythree such single units were identified by cluster analysis of multiunit recordings obtained from a total of six electrodes implanted in the mediobasal hypothalamus of three ovariectomized rhesus monkeys, and their activity was monitored before and after estradiol administration. The bursting of all 23 units was arrested within 4 h of estradiol administration although their baseline activity was maintained. The bursts of most units reappeared at the same time as the MUA volleys, the recovery of some was delayed, and one remained inhibited for the duration of the study (43 days). The results indicate that estradiol does not desynchronize the bursting of single units associated with the GnRH pulse generator but that it inhibits this phenomenon. The site and mechanism of action of estradiol in this regard remain to be determined.

The hypothalamic GnRH pulse generator: multiple regulatory mechanisms

“…However, episodic neuropeptide secretion is an intrinsic property of the GnRH neuron and dependent on intracellular signaling and mechanism(s) leading to coordinated bursts of GnRH release [5–12]. Seminal studies by Ernst Knobil et al in rhesus monkeys defined the importance of episodic pituitary stimulation for optimal gonadotropin secretion, as well as the relationship of GnRH release to electrical activity in the hypothalamus and the essential role of estrogen in promoting the mid-cycle LH surge [13, 14]. …”

Search for Neural Substrates Mediating Inhibitory Effects of Oestrogen on Pulsatile Luteinising Hormone‐Releasing Hormone Release In Vivo in Ovariectomized Female Rhesus Monkeys (Macaca mulatta)

“…Oestrogen suppresses (negative feedback) or stimulates (positive feedback) luteinising hormone (LH) release directly or indirectly by modulating LH‐releasing hormone (LHRH) release depending on the dose and time after its exposure. In adult ovarian intact or ovariectomized (OVX) female monkeys, it was shown that an elevation of oestrogen completely suppressed multiple unit activity recorded from the medial basal hypothalamus concomitant with suppression of LH release (1–3). Similarly, oestrogen decreased pulsatile LHRH release in female pubertal monkeys (4) and OVX ewes (5–7).…”

Toward an optimal contraception dosing strategy

“…A constant intravenous infusion of a low dose of estradiol result in complete shut down of the GnRH pulse generator on female rhesus monkeys for several days or weeks [ 54 , 55 ]. Although endometrial bleeding is rare in this species, a constant administration may induce a growth of female human endometrium exposing to hyperplasia and bleeding.…”