Reflections on the discovery and significance of estrogen receptor β

We have known for many years that estrogen is more than the female hormone. It is essential in the male gonads, and in both sexes, estrogen has functions in the skeleton and central nervous system, on behavior, and in the cardiovascular and immune systems. An important aspect of the discovery of estrogen receptor (ER) β is that the diverse functions of estrogen can now be divided into those mediated by ERα and those mediated by ERβ. Pharmacological exploitation of this division of the labors of estrogen is facilitated by the ligand-binding specificity and selective tissue distribution of the two ERs. Because the ligand binding domains of ERα and ERβ are significantly different from each other, selective ligands can be (and have been) developed to target the estrogenic pathway that is malfunctioning, without interfering with the other estrogen-regulated pathways. Because of the absence of ERβ from the adult pituitary and endometrium, ERβ agonists can be used to target ERβ with no risk of adverse effects from chemical castration and uterine cancer. Some of the diseases in which there is hope that ERβ agonists will be of benefit are prostate cancer, autoimmune diseases, colon cancer, malignancies of the immune system, and neurodegeneration.