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.
Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, et al.;
Commented by , 19 Jun 2003
Aim of the study
To evaluate the effect of estrogen plus progestin on the incidence of dementia and mild cognitive impairment (MCI) compared to placebo.
Method
Randomized double-blind placebo-controlled clinical trial enrolling 4532 participants from 4894 eligible participants from the Women’s Health Initiative (WHI); post-menopausal women free of probable dementia, aged 65 years or older. 0.625 mg of conjugated equine estrogen plus 2.5mg of medroxyprogesterone acetate (N: 2229) compared to a matching placebo (N: 2303).
Primary outcome incidence of probable dementia as defined by DSM-IV criteria and secondary outcome of MCI defined as poor performance on modified CERAD tests in at least one area of cognition, a report of some functional impairment reported by an informant although not in basic activities of daily living, and no evidence of a psychiatric or medical condition that could account for the decline in cognition.
Hazard ratios and nominal 95% confidence intervals (CI) from unadjusted Cox proportional hazard model were compared between the treatment and placebo groups.
Results
The mean time (SD) between the date of randomization into the WHI and the last cognitive assessment using the Modified Mini-Mental State Examination was 4.05 (1.19) years. Overall, 61 women were diagnosed with probable dementia, 40 (66%) in the estrogen plus progestin group compared to 21 (34%) in the placebo group.
The hazard ratio for probable dementia was 2.05 (95% CI 1.21-3.48; 45 versus 22 per 10,000 person-years; P=.01). This increased risk would result in an additional 23 cases of dementia per 10,000 women per year. Alzheimer’s disease (AD) was the most common cause of dementia in both study groups. Treatment effects on MCI did not differ between groups.
Discussion
The authors conclude that estrogen plus progestin therapy increase the risk of probable dementia in postmenopausal women aged 65 years or older, and did not prevent MCI in these women. A proposed explanation would be an increased risk of silent brain infarcts.
An accompanying editorial by Kristine Yaffe (JAMA 2003; 289: 2717- 2719) reviews the rationale for the potential benefit of estrogen therapy for prevention of dementia and the hard facts from this study along with other publications from the WHI, and concludes that hormone therapy should be prescribed only for temporary use to treat menopausal symptoms.
It should be noted that the operational definition of MCI used in this clinical trial differs significantly from the amnestic MCI used in ongoing studies aiming at delaying conversion to AD using cholinesterase inhibitors and potentially disease modifying agents such as tocopherol.
The negative results of the WHIMS illustrate the need to test all hypothesis related to prevention of AD in well designed prospective clinical trials.