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Menopausal Hormone Therapy Does Not Improve CNS Outcomes

HT did not prevent dementia or stroke among older postmenopausal women.

In 3 studies from the Women's Health Initiative (WHI), researchers examined the effects of hormone therapy (HT) on central nervous system function in postmenopausal women who were randomized to receive daily conjugated estrogen (0.625 mg) plus medroxyprogesterone acetate (2.5 mg) or placebo. The WHI estrogen-progestin arm was stopped prematurely in 2002 because overall risks of HT outweighed benefits (Journal Watch Jul 26 2002).

In the WHI Memory Study (WHIMS), 4532 women (age, 65) were tested annually with the Modified Mini-Mental State Examination (3MSE). Probable dementia was diagnosed in 40 women who received HT and in 21 women on placebo (hazard ratio, 2.05) after an average of 4 years of follow-up; diagnoses of mild cognitive impairment did not differ between the groups.

In a related WHIMS study, HT resulted in a slightly smaller improvement in scores on the 3MSE than did placebo -- an effect of little clinical significance. However, 6.7% of women who received HT had decreases of more than 2 standard deviations in their scores on the 3MSE after a mean of 4 years, compared with 4.8% of women on placebo -- a statistically significant difference.

In the third study (of all 16,608 women who were enrolled in the WHI), 151 women who took HT (1.8%) and 107 women on placebo (1.3%) suffered strokes within the mean 5.2-year follow-up -- a significant 31% increased stroke risk for the HT group. A subanalysis showed that HT increased risk only for ischemic stroke.

Comment: As noted by an editorialist, these data reinforce the conclusion from the original analysis of the WHI: HT should not be given to prevent any adverse outcome, including Alzheimer's disease (although the actual risk for dementia that is conferred by HT is very small). HT appears to be warranted only for short-term treatment of menopausal symptoms. However, the fact that these data contradict in vitro and animal studies of estrogens suggests that HT might harm only an as-yet-unidentified subgroup of women and might adversely affect cognitive function only in those who begin therapy at older ages (65). These WHI findings emphasize the need for additional studies on the effects of gonadal steroids.

— Robert W. Rebar, MD

Published in Journal Watch General Medicine June 13, 2003

Citation(s):

Shumaker SA et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenpausal 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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Yaffe K. Hormone therapy and the brain: Déjà vu all over again? JAMA 2003 May 28; 289:2717-9.

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• Medline abstract (Free)