Estrogen receptor (ER) b, a modulator of ERa in the uterus

Many of the effects of estrogens on the uterus are mediated by ERa, the predominant ER in the mature organ. Because of the poor reproductive capacity of ERb knockout (BERKO) female mice (small litter size, multiple-resorbed fetuses), the role of uterine ERb was explored. In the immature uterus, ERa and ERb are expressed at comparable levels in the epithelium and stroma, and 17b-estradiol (E2) treatment decreases ERb in the stroma. The immature uterus of untreated BERKO mice exhibits elevated levels of progesterone receptor (PR) and the proliferation-associated protein, Ki-67. It also exhibits exaggerated responsiveness to E2, as indicated by enlargement of the lumen, increase in volume and protein content of uterine secretion, induction of the luminal epithelial secretory protein, complement C3, and its regulatory cytokine IL-1b, and induction of vascular endothelial growth factor and insulin-like growth factor 1 but not its receptor. As expected, E2 increased PR in the stroma and decreased it in the luminal epithelium of wild-type mice. In the BERKO uterus, E2 induced PR in the stroma but did not down-regulate it in the epithelium. Increased cell proliferation and exaggerated response to E2 in BERKO suggest that ERb plays a role in modulation of the effects of ERa and in addition (or as a consequence of this) has an antiproliferative function in the immature uterus.