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No Benefit of Menopausal Hormone Therapy (HT) on CNS Outcomes in Older Women

April 19 , 2007
by: ASRM
Published in ASRM Announcement

Comments from the American Society for Reproductive Medicine

One of the presumed benefits of administering estrogen to older women is the prevention of Alzheimer's disease and preservation of other central nervous system (CNS) functions. Numerous molecular, in vitro, and animal studies have documented beneficial effects of estrogen on neurons and the brain. However, findings from clinical studies have been contradictory and inconclusive.

Three studies from the Women's Health Initiative (WHI), the largest randomized controlled trial on the effects of menopausal hormone therapy (HT) conducted to date, examined the effects of daily treatment with 0.625 mg of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate or placebo on CNS function. The WHI estrogen-progestin arm was stopped prematurely in 2002 because the overall risks of therapy outweighed the benefits. In the WHI Memory Study (WHIMS), 40 of 2229 women receiving HT and 21 of 2303 women on placebo aged 65 or older were diagnosed as having probable dementia for a significant hazard ratio (HR) of 2.05 after an average of 4.05 years of follow-up. Effects of therapy on mild cognitive impairment did not differ between the groups. In a related WHIMS study, scores on the Modified Mini-Mental State Examination (3MSE), the cognitive test used to screen for dementia, tended to improve with time, probably as an effect of learning. However, the improvement of women on HT improved slightly less than that of women on placebo, an effect of little clinical significance. However, 6.7% of women receiving HT had a decrease of more than 2 standard deviations in their scores on the 3MSE compared to only 4.8% of women on placebo. The third study found that 151 of 8506 (1.8%) women taking HT and 107 of 8102 (1.3%) women on placebo had strokes, representing a 31% increased risk of combined ischemic and hemorrhagic stroke among users of HT. HT increased risk only of ischemic stroke. The number of strokes was increased in women on HT of all ages, including those aged 50 to 59.

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As noted by an editorialist, these data reinforce the conclusion from the original analysis of the WHI that HT should not be given to prevent any outcome, including Alzheimer's disease. However, it should be noted that the actual increased risk of developing dementia with HT is very low, approximately 0.2%, with 23 additional cases of dementia anticipated for every 10,000 women using HT in a given year.  Still, at this time HT appears warranted only for the short-term treatment of menopausal symptoms. What is confusing about these newly published data, however, is that they are contrary to what we would have predicted based on in vitro and animal studies involving estrogens. Is it possible that HT is harmful to a subgroup of women that remains to be identified? For example, some experts have suggested that the effects of estrogen on the vascular system, promoting inflammation, may account for the effects on the CNS. Moreover, with regard to cognitive function, these data may apply only to those beginning therapy at age 65 or later. This large randomized trial only emphasizes the need for additional studies on the effects of gonadal steroids: the presumption that data from the WHI apply to all women and to all regimens of HT remains to be established.

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;289:2651-2662.

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 trail. JAMA 2003 May 28;289:2663-2672.

Wassertheil-Smoller S et al. Effect of estrogen plus progestin on stroke in postmenopausal women. The Women's Health Initiative: A randomized controlled trial. JAMA 2003 May 28;289:2673-2684.

Yaffe K. Hormone therapy and the brain. Déjà vu all over again? JAMA 2003 May 28;289:2717-2719.  


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