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The Women’s Health Research Institute, Wyeth-Ayerst Research, Radnor, Pennsylvania 19087
Address all correspondence and requests for reprints to: Dr. Paul J. Shughrue, Department of Functional Morphology, Wyeth-Ayerst Research, 145 King of Prussia Road, Radnor, Pennsylvania 19087. E-mail: shughrp{at}war.wyeth.com
Progesterone receptor (PR) messenger RNA (mRNA) is concentrated in
neurons of the preoptic area and other regions of the rat hypothalamus
where it is colocalized with the estrogen receptor and regulated by
changes in the steroid hormonal milieu. To date, little is known about
the regulation of PR mRNA by estrogens and whether antiestrogenic
compounds are capable of modulating its expression. The present studies
used in situ hybridization to ascertain the time course
of PR mRNA regulation in the medial preoptic nucleus by
17ß-estradiol, determine the effective dose required to elicit a
response, and compare the efficacy of 17ß-estradiol with a variety of
estrogenic or antiestrogenic compounds. The first series of studies
revealed that the treatment of ovariectomized rats with 17ß-estradiol
resulted in an increase in PR expression within 2 h, after which
it remained elevated until 10 h postinjection and then returned to
baseline levels. When ovariectomized rats were injected with 25–1000
ng/kg of 17ß-estradiol and euthanized 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 estrogenic
and antiestrogenic compounds in the rat preoptic nucleus.
17ß-Estradiol, diethylstilbestrol, and 17
-estradiol all
significantly increased the level of PR mRNA, although the degree of
induction varied with each compound. The injection of tamoxifen,
raloxifene, toremifene, droloxifene, clomiphene, GW 5638, or ICI
182,780 had no significant estrogenic effect on PR gene expression at
the dose evaluated. In contrast, when tamoxifen or raloxifene, but not
ICI 182,780, was administered 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 expression in the rat preoptic area is rapidly
stimulated by a small dose of 17ß-estradiol. Moreover, the present
report has also shown that the estrogenic nature of compounds such as
tamoxifen, raloxifene, toremifene, droloxifene, clomiphene, and GW 5638
cannot be predicted by their activity in peripheral tissues. Together,
the results of these studies provide important information about the
central activity of estrogens and provide evidence for their
tissue-specifc actions in the rat.
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