THE ESTROGEN-RECEPTOR-BETA SUBTYPE - A NOVEL MEDIATOR OF ESTROGEN ACTION IN NEUROENDOCRINE SYSTEMS

The recent discovery that an additional estrogen receptor (ER beta) su btype is present in many rat, mouse, and human tissues has advanced ou r understanding of the mechanisms underlying estrogen signalling. Liga nd-binding experiments have shown specific binding of 17 beta-estradio l by ER beta with an affinity similar to that of ER alpha. The rat tis sue distribution and/or the relative level of ER alpha and ER beta exp ression seems to be quite different, i.e., moderate to high expression in uterus, testis, pituitary, ovary, kidney, epididymis, and adrenal for ER alpha and prostate, ovary, lung, bladder, brain, bone, uterus, and testis for ER beta. Within the same organ it often appears that th e ER subtypes are expressed in different cell types, supporting the hy pothesis that the ER's may have different biological functions. The ce ll type-specific expression of ER alpha and ER beta in rat prostate, t estis, uterus, ovary, and brain and the distribution of ER beta mRNA i n the ER alpha knock-out mouse brain are discussed. The discovery of E R beta suggests the existence of two previously unrecognized pathways of estrogen signalling; via the ER beta subtype in tissues exclusively expressing this subtype and via the formation of heterodimers in tiss ues expressing both ER subtypes. The existence of two ER subtypes, the ir differential expression pattern, and different actions on certain r esponse 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 gen eration of ER-targeted drugs with improved therapeutic profiles in the treatment or prevention of osteoporosis, cardiovascular system disord ers, Alzheimer's disease, breast cancer, and disorders of the urogenit al tract. (C) 1998 Academic Press.