Estrogen receptor (ER) beta, a modulator of ER alpha in the uterus

Many of the effects of estrogens on the uterus are mediated by ER alpha, th e predominant ER in the mature organ. Because of the poor reproductive capa city of ER beta knockout (BERKO) female mice (small litter size, multiple-r esorbed fetuses), the role of uterine ER beta was explored. In the immature uterus, ER alpha and ER beta are expressed at comparable levels in the epi thelium and stroma, and 17 beta-estradiol (E-2) treatment decreases ER beta in the stroma. The immature uterus of untreated BERKO mice exhibits elevat ed levels of progesterone receptor (PR) and the proliferation-associated pr otein, Ki-67. It also exhibits exaggerated responsiveness to E-2, as indica ted by enlargement of the lumen, increase in volume and protein content of uterine secretion, induction of the luminal epithelial secretory protein, c omplement C3, and its regulatory cytokine IL-1 beta, and induction of vascu lar endothelial growth factor and insulin-like growth factor 1 but not its receptor. As expected, E-2 increased PR in the stroma and decreased it in t he luminal epithelium of wild-type mice. In the BERKO uterus, E-2 induced P R in the stroma but did not down-regulate it in the epithelium, Increased c ell proliferation and exaggerated response to E-2 in BERKO suggest that ER beta plays a role in modulation of the effects of ER alpha and in addition (or as a consequence of this) has an antiproliferative function in the imma ture uterus.