Estrogens, brain and behavior: studies in fundamental neurobiology and observations related to women's health

Mechanisms and consequences of the effects of estrogen on the brain have be en studied both at the fundamental level and with therapeutic applications in mind. Estrogenic hormones binding in particular neurons in a limbic-hypo thalamic system and their effects on the electrophysiology and molecular bi ology of medial hypothalamic neurons were central in establishing the first circuit for a mammalian behavior, the female-typical mating behavior, lord osis. Notably, the ability of estradiol to facilitate transcription from si x genes whose products are important for lordosis behavior proved that horm ones can turn on genes in specific neurons at specific times, with sensible behavioral consequences. The use of a gene knockout for estrogen receptor alpha (ER alpha) revealed that homozygous mutant females simply would not d o lordosis behavior and instead were extremely aggressive, thus identifying a specific gene as essential for a mammalian social behavior. In dramatic contrast, ERP knockout females can exhibit normal lordosis behavior. With t he understanding, in considerable mechanistic detail, of how the behavior i s produced, now we are also studying brain mechanisms for the biologically adaptive influences which constrain reproductive behavior. With respect to cold temperatures and other. environmental or metabolic circumstances which are not consistent with successful reproduction, we are interested in thyr oid hormone effects in the brain. Competitive relations between two types o f transcription factors - thyroid hormone receptors and estrogen receptors have the potential of subserving the blocking effects of inappropriate envi ronmental circumstances on female reproductive behaviors. TRs can compete w ith ER alpha both for DNA binding to consensus and physiological EREs and f or nuclear coactivators. In the presence of both TRs and ERs, in transfecti on studies, thyroid hormone coadministration can reduce estrogen-stimulated transcription. These competitive relations apparently have behavioral cons equences, as thyroid hormones will reduce lordosis, and a TR beta gene knoc kout will increase it. In sum, we not only know several genes that particip ate in the selective control of this sex behavior, but also, for two genes, we know the causal routes. Estrogenic hormones are also the foci of widesp read attention for their potential therapeutic effects improving, for examp le, certain aspects of mood and cognition. The former has an efficient anim al analog, demonstrated by the positive effects of estrogen in the Porsolt forced swim test. The: latter almost certainly depends upon trophic actions of estrogen on several fundamental features of nerve cell survival and gro wth. The hypothesis is raised that the synaptic effects of estrogens are se condary to the trophic actions of this type of hormone in the nucleus and n erve cell body. (C) 2000 Elsevier Science Ltd. All rights reserved.