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

The Timing Hypothesis

Among the many controversies surrounding the generally negative or at best null clinical trial results, the most prominent is related to the notion that women in the trials were too old to benefit. If women already have predementia due to Alzheimer's disease, small strokes, or both (a common combination), then estrogen started in older postmenopausal women might be too late -- even harmful given the known excess risk of clotting and stroke associated with estrogen. On the other hand, estrogen begun soon after menopause might not show benefit, because women are still cognitively intact, and there is no reason to expect that estrogen will improve normal cognitive function.

The latter situation may explain the entirely null results in the observational study reported from the Melbourne Women's Midlife Health Project. In this cross-sectional study, 326 women ages 52 to 63 years were tested using a 10-word delayed recall three times at one visit. Memory was similar regardless of menopausal status, number of years postmenopause, current or prior use of estrogen, or duration of hormone treatment, and was also unrelated to blood estradiol levels.[18]

A Swedish study[24] examined the association of menopause status on performance on 15 cognitive function tests in 129 premenopausal, 58 perimenopausal, and 55 postmenopausal women. There was no association between any cognitive function test and menopause status or endogenous estradiol (measured using an assay with sensitivity to detect 10.6 pmol/L).

In contrast, a follow-up study of recently postmenopausal women who had been randomly assigned to estrogen or placebo in one of four 2- to 3-year estrogen therapy trials found that women assigned to estrogen in early postmenopause who completed the trial, then discontinued hormone therapy, and returned for cognitive function evaluation 5, l0, or 15 years later showed a decreased risk of cognitive impairment (OR, 0.36; 95% CI, 0.15 to 0.90) compared with that of the placebo group.[47] Although these results are compatible with the thesis that short-term estrogen therapy in the early phase of menopause provides long-term cognitive protection, the results are difficult to interpret because the main analysis was not based on an intention-to-treat analysis, and women who did not complete the trial and return for follow-up were excluded from these analyses.

A large epidemiologic study directly relevant to the timing hypothesis was reported by Petitti et al in 2008.[48] In this study, 2906 postmenopausal women aged 75 years or older (who were members of a health plan) provided an estrogen use history, performed cognitive function tests by telephone, and were followed for dementia for 4 years. The number of incident dementia cases in this study (n = 283) was much larger than prior prospective cohort studies[36,49] allowing a more comprehensive assessment of the effect of timing. Dementia rates were similar in past or current hormone users whether they began estrogen within 10 years of menopause or later, and whether they used estrogen alone or with a progestin.

Long-term benefit for women who initiate hormones at menopause and continue them to age 80 years, when cognitive impairment is common, is unlikely to be addressed with clinical trials. Only long-term prospective epidemiologic studies are available, and these results are mainly negative.


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