Recent clinical studies have spurred rigorous debate about the benefits of hormone therapy (HT) for postmenopausal women. Controversy first emerged based on a sharp increase in the risk of cardiovascular disease in participants of the Women’s Health Initiative (WHI) studies, suggesting that decades of empirical research in animal models was not necessarily applicable to humans. However, a reexamination of the data from the WHI studies suggests that the timing of HT might be a critical factor and that advanced age and/or length of estrogen deprivation might alter the body's ability to respond to estrogens. Dichotomous estrogenic effects are mediated primarily by the actions of two high-affinity estrogen receptors alpha and beta (ERα & ERβ). The expression of the ERs can be overlapping or distinct, dependent upon brain region, sex, age, and exposure to hormone, and, during the time of menopause, there may be changes in receptor expression profiles, post-translational modifications, and protein:protein interactions that could lead to a completely different environment for E2 to exert its effects. In this review, factors affecting estrogen-signaling processes will be discussed with particular attention paid to the expression and transcriptional actions of ERβ in brain regions that regulate cognition and affect. 1. Introduction According to the CDC (2008), the average lifespan for women in the USA is ~81 years of age. While the average lifespan has been steadily increasing over the past century (~48 years in 1900), the average age at which reproductive senescence, menopause, occurs has remained relatively constant between 45–55 years of age [1, 2]. Including the prepubescent years, this leaves women living about half of their lives without high levels of circulating ovarian hormones. The two primary ovarian hormones are 17β-estradiol (E2) and progesterone, both of which are required for female reproduction. Many positive anecdotal experiences are reported during times in the reproductive cycle when E2 is high, sparking further investigation into the role of E2 in various nonreproductive processes, including those pertaining to cognition and mood. The vast majority of basic science studies have described positive effects of E2 on cognitive processes at a molecular level, and, importantly, older postmenopausal females exhibit significant deficits when performing tasks that require the use of working memory, attentional processing, and executive function [3–8]. The natural aging process is coincident with menopause, which confounds studies attempting to
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