Endocrinology, Vol 132, 2371-2379, Copyright © 1993 by Endocrine Society

ARTICLES

Regulation of progesterone receptor gene expression and growth in the rat uterus: modulation of estrogen actions by progesterone and sex steroid hormone antagonists

WL Kraus and BS Katzenellenbogen
Department of Physiology and Biophysics, University of Illinois, Urbana 61801.

Although the rat uterus has often been used as a model to study estrogen action, relatively little is known of the mechanism(s) by which estrogen regulates uterine progesterone receptor (PR) levels in this species. In the present study, we used immature ovariectomized rats to examine the regulation of PR gene expression and growth in the uterus by estradiol (E2) as well as hormonal modulators of E2 action, namely progesterone (P), the antiestrogen LY117018 (LY), and the antiprogestin RU486. Northern blot analyses revealed eight PR mRNA species ranging in size from 3.3-14 kilobases, with the most abundant being 7.1 kilobases. E2 treatment caused rapid time- and dose-dependent increases in the steady state levels of PR mRNA, which peaked at 24 h (6-fold increase) and declined thereafter. All eight PR mRNA transcripts increased proportionally in response to E2. Immunoblot analyses indicated that these changes were accompanied by increases in PR protein (6-fold increase by 48 h), which continued to accumulate over time, unlike PR mRNA, which decreased despite continued E2 exposure. In contrast to the stimulatory effect of E2 on PR, the levels of immunoreactive estrogen receptor were reduced to about 15% of the control value by E2 within 48 h and remained low throughout the remaining treatment period. Treatment with P blocked the stimulatory effects of E2 on both PR mRNA and protein. These antagonistic actions of P were prevented by simultaneous administration of RU486. LY, which caused a slight (approximately 2.5-fold) increase in PR mRNA when administered alone, was an effective antagonist of E2-stimulated increases in PR mRNA. However, LY was incapable of completely antagonizing E2-stimulated increases in PR protein. The differences between the profiles of the time-dependent increases in PR mRNA and protein in response to E2, as well as the different sensitivities of these two end points to the antagonistic actions of LY, highlight the lack of direct correspondence between these two end points and suggest that E2 may be acting through distinct mechanisms (transcriptional and posttranscriptional, for example) to increase the levels of PR in the rat uterus. Our results indicate that E2 rapidly increases uterine PR expression and growth, and that P as well as sex steroid hormone antagonists are important modulators of these E2 actions in the rat uterus.

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