Mutual and intercompartmental regulation of estrogen receptor and progesterone receptor expression in the mouse uterus

The epithelial and stromal compartments of the uterus undergo significant estrogen- and progesterone (P-4)-induced changes during the estrous cycle. While in the adult mouse, epithelial proliferation and stromal inflammation are induced by estrogen, P-4 is antiproliferative in the epithelium and both proliferative and anti-inflammatory in the stroma. In light of these compartmentally varying roles, we have immunohistochemically examined estrogen and P-4 regulation of the expression of their receptors (ER and PR) and their epithelial target gene lactoferrin (LF) in wild-type and PR null mutant mice. We demonstrate that estrogen exerts compartment-specific effects on the expression of ER, resulting in decreased levels of stromal and glandular epithelial (GE) ER and increased luminal epithelial (LE) and myometrial ER. Estrogen also has dual effects on PR expression, decreasing levels in the LE while at the same time increasing levels in the stroma and myometrium. Estrogen and P-4 together mediate their effects in part through the ability of P-4 to selectively inhibit myometrial ER expression while preserving CE expression. We also demonstrate a general negative feedback by P-4 on PR expression that is most prominent in the GF. Finally, we demonstrate using the estrogen- and P-4-responsive epithelial target gene LF that the differential regulation of PR in the glandular and luminal epithelium results in different functional responses of these compartments to P-4. Together, our data indicate that the pleiotropic effects of estrogen and P-4 in the adult mouse uterus are mediated by complex hormonal interregulation of ER and PR in specific uterine compartments.