Receptor-weighted mechanistic approach to analysis of the actions of estrogen and progesterone on gonadotropin secretion.

Abstract

This presentation has touched upon three experimental designs which we have used to examine the single premise that analysis of steroid hormone receptor activity is a viable approach to an increased understanding of steroid-gonadotropin feedback mechanisms and reproductive function. In the study of LH suppressibility in the castrate animal, we observed strikingly similar patterns of receptor turnover and LH suppression-recovery. By discriminate choice of stimulating and blocking agents which had differential access to hypothalamic sites of action, we accumulated data suggesting that the inhibitory effects of estradiol on LH secretion are transient at the pituitary level and of longer duration in the hypothalamus. This was based on the different responses to alterations in nuclear receptor retention time in the two tissues. This initial analysis of the negative segment of the feedback will need to be extended to an animal model in which positive feedback comes into play before a full picture of the receptor correlations can be drawn. The ability of LHRH to selectively stimulate estrogen receptor activity in the nucleus using isolated pituitary cells provides a mechanistic explanation for the self-priming action of LHRH. By enhancing receptor activity, LHRH increases the responsiveness of the pituitary to estrogen. This in turn intensifies the sensitivity to LHRH, and a secondary LHRH stimulus will elicit a magnified response. The ability to demonstrate selective augmentation of the functional matrix-associated receptor population, and our recent results showing that gonadotropes are indeed the responsive cells (Singh P, Muldoon TG, unpublished observations) speak to the specificity and relevance of these findings. The equal ability of LHRH to reduce nuclear estrogen receptor binding in whole cells and in isolated nuclei indicates that internalized LHRH may be capable of recognizing secondary intracellular receptors, and the system is amenable to exploration of this phenomenon. Using a combination of estrogen receptor and progesterone receptor measurements, we have begun to unravel the interrelationships between these two hormones at this level apropos of their interplay in gonadotropin regulation. The kinetics of progesterone receptor induction by estrogen are consistent with an inability of the system to respond acutely to progesterone in the absence of strong estrogen backing, but with the capability of inhibiting long-term responses to estrogen. The acute capability of progesterone, acting through its receptors, to depress nuclear estrogen receptor activity, correlates with its acute antiestrogenic stimulation of gonadotropin secretion.(ABSTRACT TRUNCATED AT 400 WORDS)