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Estrogen Therapy and Cognition: A Review of the Cholinergic Hypothesis
Open accessAbstract
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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“E2 effects on dopaminergic striatal circuits by reducing dopamine receptors and increasing dopamine release may therefore mediate these effects (Archer, 1999; Gibbs, 2010), particularly in the prefrontal cortex (Berman et al., 1997).”
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Espinosa‐Raya, J., Neri-Gómez, T., Orozco-Suárez, S. A., Campos, M. G., & Guerra‐Araiza, C. (2011) · Hormones and Behavior · doi:10.1016/j.yhbeh.2011.10.005 · Cited by 24
Long, T., Yao, J. K., Li, J., Kirshner, Z. Z., Nelson, D., Dougherty, G. G., & Gibbs, R. B. (2019) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2019.110533 · Cited by 23
Self-citationLi, J., Oberly, P. J., Poloyac, S. M., & Gibbs, R. B. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.04.013 · Cited by 22
Self-citationEffects of sex steroid hormones on memory
Pompili, A., Iorio, C., & Gasbarri, A. (2020) · Acta Neurobiologiae Experimentalis · doi:10.21307/ane-2020-012 · Cited by 22
Dumas, J. A., McDonald, B. C., Saykin, A. J., McAllister, T. W., Hynes, M. L., West, J. D., & NEWHOUSE, P. A. (2010) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0b013e3181e04db9 · Cited by 22
Kirshner, Z. Z., Yao, J. K., Li, J., Long, T., Nelson, D., & Gibbs, R. B. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117975 · Cited by 21
Self-citationGibbs, R. B., Chipman, A. M., & Nelson, D. A. (2011) · Hormones and Behavior · doi:10.1016/j.yhbeh.2011.01.011 · Cited by 21
Self-citationPollard, K. J., Wartman, H. D., & Daniel, J. M. (2018) · Hormones and Behavior · doi:10.1016/j.yhbeh.2018.05.002 · Cited by 20
The role of estrogen receptor β and nicotinic cholinergic receptors in postpartum depression
Fernandez, J. W., Grizzell, J. A., & Wecker, L. (2012) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2012.10.002 · Cited by 20
Metadata
- 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
- 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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