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Estrogen and Dementia Risk: Randomized, Controlled Trial Results

Estrogen appears not to protect against dementia, at least in the form of combined hormone therapy.

Estrogen replacement has been actively investigated as a potential preventive and symptomatic treatment for Alzheimer's disease (AD). The Women's Health Initiative (WHI), a randomized, double-blind, placebo-controlled study of estrogen and progestin replacement in women age 65 or older, was halted in July 2002 due to increased risks for breast cancer and vascular disease. Now, in 3 separate articles, WHI researchers report the effects of combination hormone replacement on dementia, cognitive decline, and stroke. These substudies of the WHI included nearly 16,000 women.

Shumaker and colleagues reported that nearly twice as many women in the estrogen-plus-progestin group as in the placebo group developed dementia over an average of 4 years (40 vs. 21 women; hazard ratio, 2.05; 95% confidence interval, 1.21-3.48). Similarly, Rapp and colleagues found that more women in the estrogen-plus-progestin group showed evidence of significant cognitive decline on the modified Mini-Mental State Examination compared with the placebo group (6.7% vs. 4.8%; P=0.008). Moreover, Wassertheil-Smoller and colleagues reported that treatment was associated with an increased incidence of ischemic stroke, a known comorbidity of AD and risk factor for dementia (HR, 1.31; 95% CI, 1.02-1.68). (Previous studies have had similar findings; see Journal Watch Neurology Dec 6 2002, and Journal Watch Neurology Dec 6 2001.)

In a fourth article, from the Rotterdam study (a large, population-based, prospective cohort study), researchers also found that among 508 untreated postmenopausal women, those with relatively higher levels of endogenous estradiol had increased risks for AD (HR, 1.24; 95% CI, 0.87-1.76) and vascular dementia (HR, 2.19; 95% CI, 1.22-3.92) compared with similar women with lower levels.

Comment: Results from several retrospective epidemiologic studies and elegant in vitro experiments have suggested that estrogen plays a protective role against the pathophysiologic process of AD. Nonetheless, these prospective results suggest that women who are treated with estrogen and progestin or who have relatively higher endogenous levels of estrogen may be at increased risk for both AD and cerebrovascular disease. It remains possible that there is some critical period in the early postmenopausal years during which hormone replacement reduces dementia risk or that unopposed estrogen replacement or alternative estrogen-progestin preparations yield more favorable results; these hypotheses are still being investigated. But given the current evidence, the risks of hormone replacement appear to outweigh any benefits in preventing dementia.

— Reisa Sperling, MD

Dr. Sperling is Director of Clinical Research, Memory Disorders Unit, Brigham and Women's Hospital, Boston.

Published in Journal Watch Neurology July 24, 2003

Citation(s):

Shumaker SA et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women's Health Initiative Memory Study: A randomized controlled trial. JAMA 2003 May 28; 289:2651-62.

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Rapp SR et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: The Women's Health Initiative Memory Study: A randomized controlled trial. JAMA 2003 May 28; 289:2663-72.

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Wassertheil-Smoller S et al. Effect of estrogen plus progestin on stroke in postmenopausal women: The Women's Health Initiative: A randomized trial. JAMA 2003 May 28; 289:2673-84.

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Geerlings MI et al. Endogenous estradiol and risk of dementia in women and men: The Rotterdam Study. Ann Neurol 2003 May; 53:607-15.

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