The Important Role of Estrogen Receptor-β in Women’s Health

Emily J. Su, M.D., M.S.

Since the initial identification of the estrogen receptor (ER) in the 1950s, its role in several key cellular and physiological processes has been well established. Since the discovery of a second receptor, estrogen receptor-β (ERβ), in the mid-1990s, increasing evidence has indicated that the field of ER biology is multifaceted. Although estrogen receptor-α (ERα) and ERβ share commonalities in parts of their structure and their ability to bind to estrogen response elements, transgenic mouse models knocking out either or both of the genes have demonstrated distinct functions of each receptor. Some cells express only ERα or ERβ; others express both. The presence of various ER isoforms adds to the complexity involved in ER biology. The diversity in ER expression patterns and their function as demonstrated by phenotypes of ER transgenic knockout models suggests that each ER plays a distinct role in various biological processes. The goal of this issue is to highlight the role of ERβ in various physiological and pathological processes specific to women’s health, and, if relevant, to compare this to ERα biology with the hope this will inspire further research surrounding ERβ function and ultimately improve the care of our female patients.

Human breast cancer is a prime example of the importance of understanding ER biology, with ERα continuing to be a leading target for pharmacological treatment and the prevention of breast cancer. Since the discovery of ERβ, however, studies have noted decreased expression levels of ERβ in invasive breast cancer, although it remains present in a significant number of invasive breast cancers. Drs. Murphy and Leygue provide a comprehensive review of the current research on the role of ERβ in breast cancer. They suggest that the possibility of differential functions of ERα and ERβ in breast cancer may yield alternative therapies for patients whose only treatment options historically have been aggressive chemotherapies and surgery. The controversy surrounding the use of menopausal hormone replacement therapy is another illustration of the importance of understanding the individual nature of each of the ERs. Dr. Leitman and colleagues have put together a fascinating review on the tissue-specific regulation of genes by ERs, and they link these concepts with key disease processes related to menopause. Because current hormone replacement therapy in menopause targets ERs nonselectively, these authors make an excellent argument that the similarities and differences between ERα and ERβ may be exploited to provide subtype-specific agonists that can act in a gene-specific and tissue-selective manner. In turn, the benefits of hormone replacement therapy such as bone protection can be capitalized on without incurring the simultaneous risks of hormone therapy such as breast and endometrial cancer and thromboembolism.

One disease process that remains a significant problem in women’s health is endometriosis, and ERβ appears to play a predominant role in its pathogenesis. Dr. Bulun and colleagues eloquently show there is higher ERβ expression expressed in endometriotic stromal cells in comparison with endometrial stromal cells via decreased methylation of a CpG island at the ERβ promoter. This, in turn, suppresses endometriotic stromal cell ERα expression, which then alters progesterone receptor expression and may contribute the progesterone resistance that is seen clinically in women with endometriosis.

The last several articles review the potential role of ERβ in reproduction. Starting with gonadotropin regulation, Dr. Wolfe and colleagues provide an excellent review of the role of ERβ in gonadotropin-releasing hormone (GnRH) neurons. They suggest that although ERα mediates estrogen feedback regulation of GnRH neuronal function, there appears to be an emerging role for ERβ. They suggest that ERβ may contribute to the regulation of several processes, including neuronal activity, gene expression, and pulsatile secretion of GnRH, all of which are key factors in regulating ovulation and menstruation. The ovarian actions of ERβ are aptly summarized by Drs. Drummond and Fuller. They describe evidence demonstrating that ERβ is critical in gonadogenesis; our review on ERβ and human reproduction also supports a role for ERβ in luteinization, which is critical for the maintenance of pregnancy. Other key features critical in pregnancy include physiological adaptations to pregnancy, including uterine blood flow and regulation of fetoplacental blood flow. Dr. Pastore and colleagues comprehensively summarize ERα- and ERβ-mediated regulation of uterine blood flow during pregnancy, and our review includes discussion about the potential role of ERβ in mediating fetoplacental endothelial cell prostanoid biosynthesis in normal pregnancies and those complicated by growth restriction.

These articles, although diverse in the biological processes they discuss, demonstrate the emerging importance of ERβ. Great strides have been made in patient care secondary to the use of estrogens, but simultaneously, unexpected detrimental effects have also been noted. We hope improved understanding of the similarities and differences between ERα and ERβ and continued research on the role of ERβ in health and disease will improve our ability to tailor the actions of ERs in a way that maximizes their benefits and minimizes their risks.