Estrogen Actions in the Central Nervous System

Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, Rockefeller University, New York, New York 10021, USA.
Endocrine Reviews (Impact Factor: 21.06). 07/1999; 20(3):279-307. DOI: 10.1210/edrv.20.3.0365
Source: PubMed
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    • "Following the discovery of estrogens in 1929 (Butenandt, 1929), research on this class of steroid hormones focused on their role in reproduction and the menstrual/estrous cycle in females (Doisy, 1972). In 1966, an ER was characterized in breast and uterine tissue (Toft and Gorski, 1966), and this ER was also localized to brain regions typically associated with endocrine or reproductive functions, such as the hypothalamus (for review see McEwen and Alves, 1999). This receptor, now known as ERα, was observed primarily in cell nuclei, typical for steroid hormone receptors. "
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    ABSTRACT: Over the past 30 years, research has demonstrated that estrogens are not only important for female reproduction, but play a role in a diverse array of cognitive functions. Originally, estrogens were thought to have only one receptor, localized exclusively to the cytoplasm and nucleus of cells. However, it is now known that there are at least three estrogen receptors (ERs): ERα, ERβ and G-protein coupled ER1 (GPER1). In addition to being localized to nuclei, ERα and ERβ are localized to the cell membrane, and GPER1 is also observed at the cell membrane. The mechanism through which ERs are associated with the membrane remains unclear, but palmitoylation of receptors and associations between ERs and caveolin are implicated in membrane association. ERα and ERβ are mostly observed in the nucleus using light microscopy unless they are particularly abundant. However, electron microscopy has revealed that ERs are also found at the membrane in complimentary distributions in multiple brain regions, many of which are innervated by dopamine inputs and were previously thought to contain few ERs. In particular, membrane-associated ERs are observed in the prefrontal cortex, dorsal striatum, nucleus accumbens, and hippocampus, all of which are involved in learning and memory. These findings provide a mechanism for the rapid effects of estrogens in these regions. The effects of estrogens on dopamine-dependent cognition likely result from binding at both nuclear and membrane-associated ERs, so elucidating the localization of membrane-associated ERs helps provide a more complete understanding of the cognitive effects of these hormones. Copyright © 2015. Published by Elsevier Inc.
    Hormones and Behavior 06/2015; 74. DOI:10.1016/j.yhbeh.2015.06.010 · 4.63 Impact Factor
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    • "Neural mechanisms for chronic and acute effects of estrogens Background Ample evidence exists that estrogens cause morphologic and neurochemical changes in many areas of the brain when given acutely or chronically to animals or humans. Chronic treatments alter the major neuronal systems of the brain including, but not limited to, cholinergic, monoaminergic, GABAergic and glutaminergic neurons in both animals and humans (Gibbs, 2010; McEwen and Alves, 1999 "
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    ABSTRACT: A historical perspective on estradiol’s enhancement of cognitive function is presented, and research, primarily in animals, but also in humans, is reviewed. Data regarding the mechanisms underlying the enhancements are discussed. Newer studies showing rapid effects of estradiol on consolidation of memory through membrane interactions and activation of inter-cellular signaling pathways are reviewed as well as studies focused on traditional genomic mechanisms. Recent demonstrations of intra-neuronal estradiol synthesis and possible actions as a neurosteroid to promote memory are discussed. This information is applied to the critical issue of the current lack of effective hormonal (or other) treatments for cognitive decline associated with menopause and aging. Finally, the critical period hypothesis for estradiol effects is discussed along with novel strategies for hormone/drug development. Overall, the historical record documents that estradiol positively impacts some aspects of cognitive function, but effective therapeutic interventions using this hormone have yet to be realized.
    Hormones and Behavior 09/2014; 66(4). DOI:10.1016/j.yhbeh.2014.08.011 · 4.63 Impact Factor
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    • "These include negative modulators, such as glucocorticoids and interleukin-6 [34] [51], and positive modulators, such as serotonin, N-methyl-aspartate receptor antagonists and dehydroepiandrosterone [1] [24]. Estrogens have been shown as regulators of synaptic plasticity , cognitive function, memory, mood and behavior [32]; however, their roles in the control of neuronal and glial prolif- 0361-9230/$ – see front matter © 2006 Elsevier Inc. All rights reserved. "
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    ABSTRACT: Estradiol (E) has been suggested to have a neuroprotective effect in young animals but has neutral or harmful effects when it is administered to aged animals. In the present study, we determined whether the post-ovariectomy (post-OVX) timeframe elapsed before the initiation of chronic E treatment is critical for the estrogenic induction of neurotrophins (brain-derived neurotrophic factor, BDNF, and synaptophysin, SYN) in the rodent hippocampus. Adult mice were OVX and, a short period (short-term E (STE) animals) or a long period (long-term E (LTE) animals) after the OVX, were daily treated with E. Control animals were treated with sesame oil (short-term control (STC) and long-term control (LTC) animals). Protein expression was determined using an immunohistochemical approach. Transcriptional activity in the hippocampus of individual BDNF promoters was assessed by real-time quantitative RT-PCR, and the methylation levels of regulatory regions were analyzed by methylation-specific PCR and combined bisulfite restriction analysis. STE animals showed increased BDNF and SYN protein expression and a higher activity of BDNF II, IV and V promoters. In contrast, LTE animals did not show E induction of neurotrophins. In these animals, the methylation levels of regulatory sequences of the BDNF were higher than in the STE animals in a CpG island of promoter V and in the CRE regulatory site located in promoter IV. With this experiment, we determined that a prolonged period of hypoestrogenicity disrupts the E-induction of neurotrophins, and we postulated that DNA methylation is one of the epigenetic mechanisms that could explain the E-insensitivity of the BDNF after a long period post-OVX.
    The Journal of Steroid Biochemistry and Molecular Biology 08/2014; 144. DOI:10.1016/j.jsbmb.2014.08.001 · 3.63 Impact Factor
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