REGULATION OF PROGESTERONE-RECEPTOR GENE-EXPRESSION AND GROWTH IN THERAT UTERUS - MODULATION OF ESTROGEN ACTIONS BY PROGESTERONE AND SEX STEROID-HORMONE ANTAGONISTS

Although the rat uterus has often been used as a model to study estrog en action, relatively little is known of the mechanism(s) by which est rogen regulates uterine progesterone receptor (PR) levels in this spec ies. In the present study, we used immature ovariectomized rats to exa mine the regulation of PR gene expression and growth in the uterus by estradiol (E2) as well as hormonal modulators of E2 action, namely pro gesterone (P), the antiestrogen LY117018 (LY), and the antiprogestin R U486. Northern blot analyses revealed eight PR mRNA species ranging in size from 3.3-14 kilobases, with the most abundant being 7.1 kilobase s. 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 pro portionally in response to E2. Immunoblot analyses indicated that thes e changes were accompanied by increases in PR protein (6-fold increase by 48 h), which continued to accumulate over time, unlike PR mRNA, wh ich decreased despite continued E2 exposure. In contrast to the stimul atory effect of E2 on PR, the levels of immunoreactive estrogen recept or were reduced to about 15% of the control value by E2 within 48 h an d remained low throughout the remaining treatment period. Treatment wi th P blocked the stimulatory effects of E2 on both PR mRNA and protein . These antagonistic actions of P were prevented by simultaneous admin istration of RU486. LY, which caused a slight (approximately 2.5-fold) increase in PR mRNA when administered alone, was an effective antagon ist of E2-stimulated increases in PR mRNA. However, LY was incapable o f completely antagonizing E2-stimulated increases in PR protein. The d ifferences between the profiles of the time-dependent increases in PR mRNA and protein in response to E2, as well as the different sensitivi ties of these two end points to the antagonistic actions of LY, highli ght the lack of direct correspondence between these two end points and suggest that E2 may be acting through distinct mechanisms (transcript ional and posttranscriptional, for example) to increase the levels of PR in the rat uterus. Our results indicate that E2 rapidly increases u terine PR expression and growth, and that P as well as sex steroid hor mone antagonists are important modulators of these E2 actions in the r at uterus.