Q&A

Estrogen plus progestin may increase incidence of dementia

J Fam Pract. 2003 October;52(10):747-769
By
Nicole S. Culhane, PharmD, BCPS
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  • BACKGROUND: Lower endogenous estrogen levels in post-menopausal women is a potential reason why women have a higher risk of developing Alzheimer disease than men. However, the results of previous trials evaluating the effects of estrogen on Alzheimer disease have been inconsistent. In addition, the role of progestin in Alzheimer disease is unclear. To date, the Women’s Health Initiative Memory Study is the largest randomized controlled trial evaluating the effects of estrogen plus progestin on dementia.
  • POPULATION STUDIED: The Women’s Health Initiative Memory Study, a substudy of the Women’s Heath Initiative, included 4532 of the 4894 postmenopausal women in the Women’s Heath Initiative aged 65 years or older without probable dementia. Participants of the study were subject to the same exclusion criteria published in the Women’s Health Initiative.
  • STUDY DESIGN AND VALIDITY: This randomized, double-blind, placebo-controlled study evaluated the effects of estrogen plus progestin (n=2229) compared with placebo (n=2303) on the incidence of dementia and mild cognitive impairment. Participants were randomly assigned to estrogen 0.625 mg/d plus medroxyprogesterone acetate 2.5 mg/d or matching placebo. They were followed for a mean duration of 4 years.
  • OUTCOMES MEASURED: The outcomes of this study were to determine the effect of estrogen plus progestin on allcause dementia (primary outcome), mild cognitive impairment (secondary outcome), and global cognitive functioning1 in elderly post-menopausal women.
  • RESULTS: Sixty-one participants were diagnosed with probable dementia: 40 (66%) in the estrogen plus progestin group and 21 (34%) in the placebo group (hazard ratio [HR]=2.05; 95% confidence interval [CI], 1.21–3.48; P=0.01). This risk translates into an additional 23 cases of dementia per 10,000 women per year taking estrogen plus progestin compared with placebo. After excluding participants at higher risk of developing dementia at baseline, a higher rate of probable dementia in the estrogen plus progestin group was still seen when compared with placebo (HR=2.64; 95% CI, 1.26–5.53).
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PRACTICE RECOMMENDATIONS

Estrogen plus progestin does not decrease— and may actually increase—the incidence of dementia, mild cognitive impairment, and cognitive dysfunction in elderly postmenopausal women. The effect of unopposed estrogen on these outcomes is still unknown. With these new findings and the recently reported results of the Women’s Health Initiative, for most women the benefits of estrogen plus progestin do not outweigh the risks.

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