From the Departments of Psychiatry (Dr Yaffe), Medicine (Drs Lieberburg and Grady), Epidemiology and Biostatistics (Drs Sawaya and Grady), and Obstetrics and Gynecology (Dr Sawaya), University of California, San Francisco, and Athena Neurosciences, South San Francisco, Calif (Dr Lieberburg).
Context.— Several studies have suggested that estrogen replacement therapy in
postmenopausal women improves cognition, prevents development of dementia,
and improves the severity of dementia, while other studies have not found
a benefit of estrogen use.
Objective.— To determine whether postmenopausal estrogen therapy improves cognition,
prevents development of dementia, or improves dementia severity.
Data Sources.— We performed a literature search of studies published from January 1966
through June 1997, using MEDLINE, manually searched bibliographies of articles
identified, and consulted experts.
Study Selection.— Studies that evaluated biological mechanisms of estrogen's effect on
the central nervous system and studies that addressed the effect of estrogen
on cognitive function or on dementia.
Data Extraction.— We reviewed studies for methods, sources of bias, and outcomes and performed
a meta-analysis of the 10 studies of postmenopausal estrogen use and risk
of dementia using standard meta-analytic methods.
Data Synthesis.— Biochemical and neurophysiologic studies suggest several mechanisms
by which estrogen may affect cognition: promotion of cholinergic and serotonergic
activity in specific brain regions, maintenance of neural circuitry, favorable
lipoprotein alterations, and prevention of cerebral ischemia. Five observational
studies and 8 trials have addressed the effect of estrogen on cognitive function
in nondemented postmenopausal women. Cognition seems to improve in perimenopausal
women, possibly because menopausal symptoms improve, but there is no clear
benefit in asymptomatic women. Ten observational studies have measured the
effect of postmenopausal estrogen use on risk of developing dementia. Meta-analysis
of these studies suggests a 29% decreased risk of developing dementia among
estrogen users, but the findings of the studies are heterogeneous. Four trials
of estrogen therapy in women with Alzheimer disease have been conducted and
have had primarily positive results, but most have been small, of short duration,
nonrandomized, and uncontrolled.
Conclusions.— There are plausible biological mechanisms by which estrogen might lead
to improved cognition, reduced risk for dementia, or improvement in the severity
of dementia. Studies conducted in women, however, have substantial methodologic
problems and have produced conflicting results. Large placebo-controlled trials
are required to address estrogen's role in prevention and treatment of Alzheimer
disease and other dementias. Given the known risks of estrogen therapy, we
do not recommend estrogen for the prevention or treatment of Alzheimer disease
or other dementias until adequate trials have been completed.
Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen Therapy in Postmenopausal WomenEffects on Cognitive Function and Dementia. JAMA. 1998;279(9):688-695. doi:10.1001/jama.279.9.688