Regulation of progesterone receptors and decidualization in uterine stromaof the estrogen receptor-alpha knockout mouse

Regulation of progesterone receptor (PR) in uterine stroma (endometrial str oma plus myometrium) by estrogen was investigated in estrogen receptor-alph a (ER alpha) knockout (alpha ERKO) mice. 17 beta -Estradiol (E-2) increased PR levels in uterine stroma of ovariectomized alpha ERKO mice, and ICI 182 780 (ICI) inhibited this E-2-induced PR expression. Estrogen receptor-beta (ERP) was detected in both uterine epithelium and stroma of wild-type and alpha ERKO mice by immunohistochemistry. In organ cultures of alpha ERKO ut erus, both E-2 and diethylstilbestrol induced stromal PR, and ICI inhibited this induction. These findings suggest that estrogen induces stromal PR vi a ER beta in alpha ERKO uterus. However, this process is not mediated exclu sively by ER beta, because in ER beta knockout mice, which express ER alpha , PR was up-regulated by E-2 in uterine stroma. In both wild-type and alpha ERKO mice, progesterone and mechanical traumatization were essential and s ufficient to induce decidual cells, even though E-2 and ER alpha were also required for increase in uterine weight. Progesterone receptor was strongly expressed in decidual cells in alpha ERKO mice, and ICI did not inhibit de cidualization or PR expression. This study suggests that up-regulation of P R in endometrial stroma is mediated through at least three mechanisms: 1) c lassical estrogen signaling through ER alpha, 2) estrogen signaling through ER beta, and 3) as a result of mechanical stimulation plus progesterone, w hich induces stromal cells to differentiate into decidual cells. Each of th ese pathways can function independently of the others.