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New roles for estrogen receptor beta in behavior and neuroendocrinology.

In this review we critically examine the data on functions of the estrogen receptor beta (ERbeta) in both behavior and neuroendocrinology. The influence of estradiol via the ERbeta has been assessed using several methods: estrogen receptor knockout mice, specific ERbeta selective agonists, and phytoestrogens which preferentially bind to ERbeta rather than ERalpha. The behavior for which a solid database and consensus is forming is anxiety; activation of ERbeta reduces anxiety on a number of tasks and in several species. Moreover, the relationship between ERbeta and serotonin may be critical for the regulation of this behavior by estradiol. There have been very few studies on learning and memory but the little we know suggests that ERbeta is involved in visuospatial learning; in its absence learning is inhibited. Recent work has suggested a unique function for ERbeta in sexual differentiation; its activation in male neonates may promote defeminization of sexual behavior. Several neurotransmitter-containing neurons in the rat paraventricular nucleus coexpress ERbeta including; vasopressin, oxytocin, prolactin, and to a lesser extent corticotrophin releasing hormone. Given the potential for ERbeta to interact with these important neurotransmitters and its co-expression in gonadotropin releasing hormone neurons it is surprising how normal the hypothalamic-pituitary-adrenal and -gonadal axes appear to be in ERbeta knockout mice. Either this represents a species difference (the neuroanatomy has been conducted in the rat) or compensatory actions of ERalpha or other mechanisms. Exciting avenues for future research include; in vivo interactions between ERalpha and ERbeta, actions of non-estrogenic ligands with ERbeta, and the role of ERbeta in sexual differentiation.