The estrogen receptor β subtype: A novel mediator of estrogen action in neuroendocrine systems

The recent discovery that an additional estrogen receptor (ERβ) subtype is present in many rat, mouse, and human tissues has advanced our understanding of the mechanisms underlying estrogen signalling. Ligand- binding experiments have shown specific binding of 17β-estradiol by ERβ with an affinity similar to that of ERa. The rat tissue distribution and/or the relative level of ERα and ERβ expression seems to be quite different, i.e., moderate to high expression in uterus, testis, pituitary, ovary, kidney, epididymis, and adrenal for ERα and prostate, ovary, lung, bladder, brain, bone, uterus, and testis for ERβ. Within the same organ it often appears that the ER subtypes are expressed in different cell types, supporting the hypothesis that the ER's may have different biological functions. The cell type-specific expression of ERa and ERβ in rat prostate, testis, uterus, ovary, and brain and the distribution of ERβ mRNA in the EPα knock-out mouse brain are discussed. The discovery of ERβ suggests the existence of two previously unrecognized pathways of estrogen signalling; via the ERβ subtype in tissues exclusively expressing this subtype and via the formation of heterodimers in tissues expressing beth ER subtypes. The existence of two ER subtypes, their differential expression pattern, and different actions on certain response elements could provide explanations for the striking species-, cell-, and promoter-specific actions of estrogens and antiestrogens. The challenge for the future is to unravel the detailed physiological role of each subtype and to use this knowledge to develop the next generation of ER-targeted drugs with improved therapeutic profiles in the treatment or prevention of osteoporosis, cardiovascular system disorders, Alzheimer's disease, breast cancer, and disorders of the urogenital tract.