REGULATION OF PROGESTERONE-RECEPTOR MESSENGER-RIBONUCLEIC-ACID IN THERAT MEDIAL PREOPTIC NUCLEUS BY ESTROGENIC AND ANTIESTROGENIC COMPOUNDS - AN IN-SITU HYBRIDIZATION STUDY

Progesterone receptor (PR) messenger RNA (mRNA) is concentrated in neu rons of the preoptic area and other regions of the rat hypothalamus wh ere it is colocalized with the estrogen receptor and regulated by chan ges in the steroid hormonal milieu. To date, little is known about the regulation of PR mRNA by estrogens and whether antiestrogenic compoun ds are capable of modulating its expression. The present studies used in situ hybridization to ascertain the time course of PR mRNA regulati on in the medial preoptic nucleus by 17 beta-estradiol, determine the effective dose required to elicit a response, and compare the efficacy of 17 beta-estradiol with a variety of estrogenic or antiestrogenic c ompounds. The first series of studies revealed that the treatment of o variectomized rats with 17 beta-estradiol resulted in an increase in P R expression within 2 h, after which it remained elevated until 10 h p ostinjection and then returned to baseline levels. When ovariectomized rats were injected with 25-1000 ng/kg of 17 beta-estradiol and euthan ized 6 h later, a dose-dependent increase in the level of PR mRNA was observed, with a maximal response at 1000 ng/kg and an EC50 of 93.5 ng /kg. Subsequent studies evaluated the efficacy of a variety of estroge nic and antiestrogenic compounds in the rat preoptic nucleus. 17 beta- Estradiol, diethylstilbestrol, and 17 alpha-estradiol all significantl y increased the level of PR mRNA, although the degree of induction var ied with each compound. The injection of tamoxifen, raloxifene, toremi fene, droloxifene, clomiphene, GW 5638, or ICI 182,780 had no signific ant estrogenic effect on PR gene expression at the dose evaluated. In contrast, when tamoxifen or raloxifene, but not ICI 182,780, was admin istered in the antagonist mode, a significant dose-related decrease in the estradiol-induced level of PR mRNA was seen in the preoptic area. The results of these studies clearly demonstrate that PR mRNA express ion in the rat preoptic area is rapidly stimulated by a small dose of 17 beta-estradiol. Moreover, the present report has also shown that th e estrogenic nature of compounds such as tamoxifen, raloxifene, toremi fene, droloxifene, clomiphene, and GW 5638 cannot be predicted by thei r activity in peripheral tissues. Together, the results of these studi es provide important information about the central activity of estroge ns and provide evidence for their tissue-specifc actions in the rat.