Endogenous and Exogenous Estrogen, Cognitive Function, and Dementia in Postmenopausal Women: Evidence from Epidemiologic Studies and Clinical Trials

Elizabeth Barrett-Connor, M.D.; Gail A. Laughlin, Ph.D.


Semin Reprod Med. 2009;27(3):275-282. 

In This Article

Epidemiologic Studies of Postmenopausal Estrogen Therapy and Cognitive Function or Dementia

There exist many observational studies and several meta-analyses of these epidemiologic studies of postmenopausal estrogen use and cognitive performance. Favorable results from these studies, reviewed below, drove the widespread enthusiasm for use of postmenopausal estrogen therapy to protect the brain and the subsequent clinical trials.

Observational studies of elective medications may be misleading if the characteristics of women who are prescribed and take the medications differ from characteristics of women who do not. It was recognized early on that hormone replacement was more often used by women with more education and/or higher socioeconomic status, who had more favorable heart disease risk factors even before the menopause.[28a] These differences would also be expected to be associated with better cognitive function. Interpretation of results from the following articles should be considered with this healthy-user self-selection bias in mind.

One of the first reviews of studies of postmenopausal estrogen and brain function was published by Haskell in 1997,[28b] who reviewed papers published between 1970 and 1996. Among these studies, 5 of 8 observational studies suggested benefit, 8 of 10 controlled trials showed improvement in at least one cognitive function test, and 3 of the 5 studies that included tests of memory showed "either large improvement or small deterioration." This review foretold the confusing results and interpretation of subsequent studies.

The first meta-analysis to review epidemiologic studies of postmenopausal estrogen use and dementia included 14 cohort or case-cohort studies; although few individual study associations were statistically significant, the pooled analysis suggested a 34% benefit.[29] Another meta-analysis of 12 studies published between 1966 and August 2000 also showed mixed results, with a 29% reduced risk of dementia in the pooled analysis.[30]

The Nurses' Health Study is one of the largest prospective studies of estrogen therapy and cognitive decline, including 13,087 women aged 70 to 81 years with hormone use data for more than 27 years.[31] Cognitive function tests (obtained by telephone interview 2 years apart) included global cognition, verbal memory, category fluency, and attention. Non-estrogen users showed the least decline in any test performance. Decline was significantly greater in women who started estrogen years after menopause, raising the possibility that women with memory problems may have begun estrogen to treat perceived memory loss.

The Study of Osteoporotic Fractures included 9655 postmenopausal women, mean age 71 years, from four U.S. sites.[32] Women completed three cognitive function tests (mMMSE, Digit Symbol Test, Trails B) at baseline, and 67% repeated these tests 4 to 6 years later. Past but not current hormone users had smaller declines in mMMSE and Trails B at the second testing compared with that of never-users. Only formal education was protective in the cohort overall.

The Kame Project, a prospective study of the 2-year rate of cognitive change in 837 older Japanese women (age 65+ years) living in Seattle, found that women using unopposed estrogen had improved global cognitive function (Cognitive Abilities Screening Instrument), whereas women taking estrogen plus a progestin had poorer function, compared with that of nonusers.[33]

Some longitudinal studies of postmenopausal estrogen use and dementia were based on death certificate diagnosis. In a 3-year follow-up of 800 women aged 65 to 95 years from the Rancho Bernardo Study, the relative risk of dementia (listed anywhere on the death certificate) among baseline estrogen users was increased (OR, 1.90; 95% CI, 1.10 to 4.39) compared with that of nonusers.[34] In contrast, another larger California community-based study with Alzheimer's diagnosis (also based only on the death certificate) reported the risk of dementia was significantly reduced in estrogen users (OR, 0.65; 95% CI, 0.49 to 0.88). These authors also reported better protection with higher doses or longer duration of hormone use.[35]

The Cache County Study followed 1889 older postmenopausal women (mean age 75 years) for 3 years and identified 88 new cases of probable Alzheimer's dementia (confirmed by clinical evaluation in 84%). Prior estrogen use reported at baseline, but not current estrogen use at baseline, was associated with a reduced risk of dementia.[36] Data from the UK General Practice Research Database (300 practices with patients followed for as long as 11 years) were used for a matched nested case-control study of older women, comparing the records of prior prescriptions in women with (n = 59) and without (n = 221) a clinical diagnosis of Alzheimer's disease.[37] In this study, use of postmenopausal estrogen was not associated with incident Alzheimer's dementia.

It is impossible to synthesize these divergent results for a meaningful conclusion.


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