Estrogen receptor β: the guardian of the endometrium

Background: The endometrium is the primary target organ for the 'female' sex steroid hormone estrogen, which exerts effects in the endometrium via two main classical estrogen receptor (ER) isoforms, ER alpha and ER beta. The main function of the endometrium, embryo implantation, appears unperturbed in ER beta knockout mice, which has led researchers to disregard other potentially important functional roles that ER beta may have in endometrium. This review focuses on ER beta in the human endometrium and its protective role from the undesired effects of ER alpha. Methods: We conducted a systematic search using PubMed and Ovid for publications between January 1996 and February 2014. All studies that examined ER beta expression or function in non-pregnant endometrium or cells derived from the endometrium were considered, including human and animal studies. Results: Studies of the basic function of ER beta isoforms in restraining ER alpha-mediated cell-specific trophic/mitotic responses to estrogen in other tissues has allowed appreciation of the important potential role of ER beta in the regulation of cell fate in the human endometrium. Our current understanding of ER beta expression and function in endometrium is, however, incomplete. ER beta is dynamically expressed in healthy premenstrual endometrium, persists in post-menopausal atrophic endometrium and may play an important role in endometrial disease. All endometrial cell types express ER beta and aberrations in ER beta expression have been reported in almost all benign and malignant endometrial proliferative disease. Conclusions: The collective evidence suggests that ER beta has an important role in normal endometrial function and also in most, if not all, benign and malignant endometrial diseases. However, the conduct of studies of endometrial ER beta expression needs to be standardized: agreement is needed regarding the most appropriate control tissue for endometrial cancer studies as well as development of standardized methods for the quantification of ER beta immunohistochemical data, similar to those scoring systems employed for other hormonally regulated tissues such as breast cancer, since these data may have direct clinical implications in guiding therapy.