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

Endogenous Estrogen

Results from observational studies of endogenous estrogen and cognitive function are inconclusive. Some report harmful associations, some protective, and many fail to identify any clinically meaningful association between serum estrogen levels and cognitive ability.

This may be due, in part, to the difficulty of measuring circulating estradiol in older women. Even the best assay methods (those that extract and separate the estrogens prior to assay) lack sufficient sensitivity to measure estradiol in up to 25% of postmenopausal women. (Measurement of estrone, the primary circulating estrogen after menopause, is less problematic, with 2 to 4 times higher blood levels than that of estradiol.) Another source of concern is that most studies are based on single blood samples, not always drawn fasting or in the early morning. Although single measurements of most hormones have been shown to reliably characterize average levels over a 2- to 3-year period; estradiol levels are less reproducible.[8] Finally, ~37% of estradiol in older women circulates bound to sex hormone binding globulin (SHBG), and only the non-SHBG-bound fraction (commonly termed bioavailable estradiol) or the free fraction is thought to cross the blood-brain barrier.[9] Given these caveats, the inconsistency of the literature should not be surprising.

In this review, studies of populations (not patients) that include at least 100 women are preferentially reviewed. In the first large population-based study (532 women 65 years or older from the Study of Osteoporotic Fractures), women with the highest estrone levels had significantly poorer performance on one (Digit Symbol) of three cognitive function tests at baseline and a greater reduction in scores on another (Trails B) over 5 years compared with that of women with lower estrone levels.[10] Total estradiol levels were not related to cognitive performance, and neither estrogen predicted performance on the modified Mini-Mental Status Exam (mMMSE), a measure of global cognitive function. These early results did not support the hypothesis that estrogen preserves brain function, however a later report from the Study of Osteoporotic Fractures showed that women with high concentrations of (measured) free and bioavailable estradiol were less likely to develop cognitive impairment (decrease of 3+ points on the mMMSE after 6 years) than were women with low concentrations.[11] Free and bioavailable estradiol levels were not related to baseline cognitive function test scores in this study.

The Rancho Bernardo Study also failed to identify any consistent cross-sectional association of estrone or total and bioavailable estradiol with performance on 12 cognitive function tests in postmenopausal women.[12] By contrast, a cross-sectional analysis of data from the Rotterdam Scan Study found that women with higher (calculated) bioavailable estradiol levels had significantly poorer memory performance (delayed recall).[13] Another large cross-sectional Dutch study found the opposite: women in the highest quintile of either estradiol or estrone were 40% less likely to be cognitively impaired (MMSE < 27) compared with women in the lowest quintile.[14] There is no obvious reason for these divergent findings of null, harmful, and protective associations. Differences in populations studied, estrogen assays, or cognitive assessment tools are possible explanations, but none seem universal or satisfactory.

Results from case-control studies comparing estrogen levels in women with and without Alzheimer's disease also have been inconsistent; differences were attributed by the authors of a review of 10 such studies to assay sensitivity.[15] Lower levels could reflect lower estrogen levels secondary to the weight loss that often precedes clinical dementia. The Rotterdam study is the only large single-population-based study to report whether endogenous estrogens predict future dementia in older nondemented women. Higher levels of total estradiol were associated with an increased 6-year risk of dementia (age-adjusted hazard ratio per standard deviation increase, 1.38; 95% CI, 1.04 to 1.84); results were similar for (calculated) bioavailable estradiol. The association seemed to be mainly for vascular dementia.[16] This single study provides no evidence that endogenous estrogen protects against dementia and raises the possibility of harm.


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