Cited by 206Menopause: Health Impacts and TreatmentsEstrogen and related hormone effectsCholinesterase and Neurodegenerative Diseases

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Estrogen Therapy and Cognition: A Review of the Cholinergic Hypothesis

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Gibbs, Robert B.·2010·Endocrine Reviews

DOI 10.1210/er.2009-0036PMC PMC2852210

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Abstract

The pros and cons of estrogen therapy for use in postmenopausal women continue to be a major topic of debate in women's health.Much of this debate focuses on the potential benefits vs. harm of estrogen therapy on the brain and the risks for cognitive impairment associated with aging and Alzheimer's disease.Many animal and human studies suggest that estrogens can have significant beneficial effects on brain aging and cognition and reduce the risk of Alzheimer's-related dementia; however, others disagree.Important discoveries have been made, and hypotheses have emerged that may explain some of the inconsistencies.This review focuses on the cholinergic hypothesis, specifically on evidence that beneficial effects of estrogens on brain aging and cognition are related to interactions with cholinergic projections emanating from the basal forebrain.These cholinergic projections play an important role in learning and attentional processes, and their function is known to decline with advanced age and in association with Alzheimer's disease.Evidence suggests that many of the effects of estrogens on neuronal plasticity and function and cognitive performance are related to or rely upon interactions with these cholinergic projections; however, studies also suggest that the effectiveness of estrogen therapy decreases with age and time after loss of ovarian function.We propose a model in which deficits in basal forebrain cholinergic function contribute to age-related changes in the response to estrogen therapy.Based on this model, we propose that cholinergic-enhancing drugs, used in combination with an appropriate estrogencontaining drug regimen, may be a viable therapeutic strategy for use in older postmenopausal women with early evidence of mild cognitive decline.(Endocrine Reviews 31: 224 -253, 2010) I. Introduction II.The Neurobiology of Cognition III.Estrogens and Cognition A. Animal studies B. Studies in humans IV.The Role of Basal Forebrain Cholinergic Neurons in Cognitive Performance A. Alzheimer's disease B. Cholinergic lesion studies C. Effects on visuospatial attention and stimulus processing V. Effects of Estrogen Therapy on Basal Forebrain Cholinergic Function VI.Evidence That Effects on Basal Forebrain Cholinergic Projections Are Relevant to Estrogen Effects on Cognitive Performance A. Relevance to navigational performance in humans VII.Estrogen Therapy for the Prevention and Treatment of Cognitive Decline Associated with Aging and AD A. The importance of timing VIII.The Cholinergic Basis of the Critical Period Hypothesis IX.Testing the Cholinergic Hypothesis X. Cellular Mechanisms Underlying Estrogen Effects on Cholinergic Function and Cognitive Performance A. Hippocampus B. The role of specific estrogen receptors C. Mood/affect and effects on monoamines XI.

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Authors: Gibbs, R. B.
Affiliations: University of Pittsburgh (US)
Corresponding author: Gibbs, Robert B.
Venue: Endocrine Reviews
Publisher: The Endocrine Society
Published: 2010-04-01
Volume: 31
Issue: 2
Pages: 224-253
ISSN: 0163-769X (ISSN-L)
1945-7189
DOI: 10.1210/er.2009-0036
PMC: PMC2852210
OpenAlex: W2009343153
Cited by: 206
References: 313
Citations by year: 2026: 10 · 2025: 7 · 2024: 10 · 2023: 6 · 2022: 5 · 2021: 13 · 2020: 11 · 2019: 12 · 2018: 16 · 2017: 8 · 2016: 15 · 2015: 15 · 2014: 14 · 2013: 14 · 2012: 19
FWCI: 2.91
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Endocrine Reviews (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Science Foundation
University of Pittsburgh
Duquesne University
National Institutes of Health
University of Pittsburgh School of Pharmacy
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
Keywords: estrogen therapy, cholinergic hypothesis, postmenopausal women, cognitive decline, Alzheimer's disease, brain aging, estrogen receptor, hippocampus, critical period hypothesis, mild cognitive impairment, visuospatial attention, ovarian function, neuroprotection, neuroplasticity, mood and cognition
MeSH terms: Aging, Animals, Cognition, Estrogens, Female, Humans, Models, Neurological, Estrogen Replacement Therapy, Prosencephalon, Cholinergic Agents

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Estrogen Therapy and Cognition: A Review of the Cholinergic Hypothesis

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