Estrogen, Menopause, and the Aging Brain: How Basic Neuroscience Can Inform Hormone Therapy in Women

Abstract

IntroductionAs neuroscientists, we can be so taken by the complexity and unique capabilities of the brain that we occasionally forget that it is part of a larger integrated biological system reliant on signaling and communication throughout the organism. The interactions between key organs that release hormones (e.g., gonads) and the nervous system are an excellent reflection of this "whole-brain, whole-body" level of integration. For example, effects of estrogens such as 17-␤-estradiol (the major estrogen in most mammals, including women, referred to henceforward as estradiol) on a broad array of brain regions and the widespread distribution of estrogen receptors throughout the entire brain highlight the extraordinary integrative power of this hormone. An important concept in this interaction is that the brain both controls estrogen release through the hypothalamus-pituitary-gonadal (HPG) axis and responds to estrogen. Neuroendocrine function initiates in the hypothalamus (see below, section by A.C.G.) (Fig. 1), but the circuits that respond to estrogens go well beyond the hypothalamus to include neocortex, hippocampus, and brainstem. In addition, estradiol plays a key role in the neurobiology of aging, because endocrine and neural senescence overlap in time and are mechanistically intertwined in complex feedback loops. This aspect of aging is fundamental for humans, because all women will experience a dramatic drop in circulating estrogens if they live long enough to reach the menopause transition. Interestingly, at the turn of the past century, both life expectancy and the average age of onset of menopause for women in America was slightly over 50 years, whereas currently women can expect to live until 80 years of age, although the average age of menopause remains in

Post-synaptic Density-95 (PSD-95) Binding Capacity of G-protein-coupled Receptor 30 (GPR30), an Estrogen Receptor That Can Be Identified in Hippocampal Dendritic Spines

“…GPR30 Receptor and Estrogen Sensitivity in the Hippocampus-E2 governs several aspects of the central nervous system (CNS), including cognitive performance, behavior, mood, stress responses, and aging (53).…”

Progesterone enhances performance of aged mice in cortical or hippocampal tasks

“…Elucidating the potential for steroids to mitigate age-related factors is critical given the increasing proportion of the population that will be aged, age-related decline in cognitive performance, and increases in dementia with aging [24]. Evidence in support of P 4 and/or E 2 's effects on these processes is as follows.…”

EstradiolIn VivoRegulation of Brain Mitochondrial Proteome

“…Moreover, estrogen in the same model systems activated biochemical, genomic, cellular, and behavioral mechanisms of memory (Singh et al, 1994;Simpkins et al, 1997;Woolley, 1999;Toran-Allerand, 2000;Brinton, 2001;McEwen, 2002;Brinton, 2004). Estrogen's neuroprotective effects are multifaceted, encompassing chemical, biochemical, and genomic mechanisms and falling into three mechanistic categories: antioxidant, defense, and viability (Nilsen and Brinton, 2004;Morrison et al, 2006). Our findings demonstrate that a protein/protein interaction between estrogen receptor and the regulatory subunit p85 activates the phosphoinositide kinase-3 (PI3K) signaling cascade, simultaneously activating both the Akt and extracellular signal-regulated kinase (ERK) pathways which ultimately converge on mitochondria (Mannella and Brinton, 2006).…”