Paracrine regulation of epithelial progesterone receptor by estradiol in the mouse female reproductive tract

Regulation of progesterone receptor (PR) by estradiol-17 beta (E-2) in mous e uterine and vaginal epithelia was studied. In ovariectomized mice, PR exp ression was low in both vaginal stroma and epithelium, but high in uterine epithelium. E-2 induced PR in vaginal epithelium and stroma, but down-regul ated PR in uterine epithelium. Analysis of estrogen receptor alpha (ER alph a) knockout (ERKO) mice showed that ER alpha is essential for E-2-induced P R expression in both vaginal epithelium and stroma, and for E-2-induced dow n-regulation, but not constitutive expression of PR in uterine epithelium. Regulation of PR by E-2 was studied in vaginal and uterine tissue recombina nts made with epithelium and stroma from wild-type and ERKO mice. In the va ginal tissue recombinants, PR was induced by E-2 only in wild-type epitheli um and/or stroma. Hence, in vagina, E-2 induces PR directly via ER alpha wi thin the tissue. Conversely, E-2 down-regulated epithelial PR only in uteri ne tissue recombinants constructed with wildtype stroma. Therefore, down-re gulation of uterine epithelial PR by E-2 requires stromal, but not epitheli al, ER alpha. In vitro, isolated uterine epithelial cells retained a high P R level with or without E-2, which is consistent with an indirect regulatio n of uterine epithelial PR in vivo. Thus, E-2 down-regulates PR in uterine epithelium through paracrine mechanisms mediated by stromal ER alpha.