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

Estrogen therapy and cognition: a review of the cholinergic hypothesis

Open access
Gibbs, Robert B.·2010·Endocrine Reviews

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1210/er.2009-0036

Cites

313 of 313 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Estradiol effects on dopaminergic striatal circuits, by reducing dopamine receptors and increasing dopamine release, may mediate these effects, particularly in the prefrontal cortex.

    “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).”

    From Reproductive steroids and ADHD symptoms across the menstrual cycle (2018) · cites this paper as Gibbs, 2010

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Gibbs R 2006 Preclinical data relating to estrogen's effects on cognitive performance. In: Rasgon NL, ed. The effects of estrogen on brain function. Baltimore, MD: The Johns Hopkins University Press; 9 -45
  2. Rasgon NL, Zappert LN, Williams KE 2006 Clinical data on estrogen's effects on mood. In: Rasgon NL, ed. The effects of estrogen on brain function. Baltimore, MD: The Johns Hopkins University Press; 95-115 299.

Cited by

Sorted by citations

Authors
Gibbs, R. B.
Affiliations
University of Pittsburgh (US)
Corresponding author
Gibbs, Robert B.
Venue
Endocrine Reviews
Published
2010-04-01
Volume
31
Issue
2
Pages
224-253
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
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
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 › Genetics › Estrogen and related hormone effects
  • Health Sciences › Medicine › Pharmacology › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review