Regulation of Progesterone Receptors and Decidualization in Uterine Stroma of the Estrogen Receptor-α Knockout Mouse1

Abstract

Regulation of progesterone receptor (PR) in uterine stroma (endometrial stroma plus myometrium) by estrogen was investigated in estrogen receptor- (ER) knockout (ERKO) mice. 17-Estradiol (E 2 ) increased PR levels in uterine stroma of ovariectomized ERKO mice, and ICI 182 780 (ICI) inhibited this E 2induced PR expression. Estrogen receptor- (ER) was detected in both uterine epithelium and stroma of wild-type and ERKO mice by immunohistochemistry. In organ cultures of ERKO uterus, both E 2 and diethylstilbestrol induced stromal PR, and ICI inhibited this induction. These findings suggest that estrogen induces stromal PR via ER in ERKO uterus. However, this process is not mediated exclusively by ER, because in ER knockout mice, which express ER, PR was up-regulated by E 2 in uterine stroma. In both wild-type and ERKO mice, progesterone and mechanical traumatization were essential and sufficient to induce decidual cells, even though E 2 and ER were also required for increase in uterine weight. Progesterone receptor was strongly expressed in decidual cells in ERKO mice, and ICI did not inhibit decidualization or PR expression. This study suggests that up-regulation of PR in endometrial stroma is mediated through at least three mechanisms: 1) classical estrogen signaling through ER, 2) estrogen signaling through ER, and 3) as a result of mechanical stimulation plus progesterone, which induces stromal cells to differentiate into decidual cells. Each of these pathways can function independently of the others.