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WHI Findings Another Blow to Hormone Replacement Therapy

Kate Traynor

For the second time in less than a year, an analysis of data from the Women's Health Initiative (WHI) indicates that the risks of estrogen–progestin combination therapy for disease prevention outweigh the benefits.

A report released in May concluded that, instead of preventing the development of dementia in postmenopausal women, the combination hormone replacement therapy (HRT) regimen doubled the risk for dementia.1 In all, 40 of 2229 women assigned to the combination therapy group and 21 of 2303 women in the placebo group were diagnosed with probable dementia over a five-year period. The increased dementia risk was evident after the first year of treatment and persisted throughout the duration of the trial.

These latest WHI results are reminiscent of the study's initial findings, released last July,2 that estrogen-and-progestin combination therapy puts postmenopausal women at increased risk for stroke, myocardial infarction, and breast cancer. Epidemiologic and case–control studies conducted before WHI had suggested that HRT can prevent cardiovascular disease in women.

In a statement describing the newest study findings, the National Institute on Aging (NIA) observed that the overall risk of dementia among HRT recipients was small—23 additional cases per 10,000 women who used the regimen.

Nevertheless, NIA Deputy Director Judith A. Salerno said in the statement that "combination hormone therapy should not be prescribed at this time for older, postmenopausal women to maintain or improve cognitive function."

WHI is a 15-year, National Institutes of Health-sponsored program that examines cardiovascular disease, cancer, and osteoporosis in postmenopausal women. The combination HRT component of WHI was halted in June 2002, three years ahead of schedule, when the cardiovascular and breast cancer risks of the therapy became apparent. A separate WHI study examining the effects of unopposed estrogen therapy in women who have had a hysterectomy is ongoing.

Approximately 16,000 women ages 50–79 years with an intact uterus had enrolled in the combination HRT study. Participants in the dementia clinical trial, dubbed the WHI Memory Study (WHIMS), were a subset of women 65 years or older who had enrolled in the larger HRT trial and had no symptoms of dementia at baseline.

Each WHIMS participant was randomly assigned to receive either a placebo or a single tablet containing 0.625 mg of conjugated equine estrogens and 2.5 mg of medroxyprogesterone acetate daily. The placebo and HRT tablets were identical in appearance, and neither the study participants nor the clinical staff at the 39 participating study sites knew which tablets contained active drug or placebo.

WHIMS enrollees were screened at baseline and at yearly intervals for signs of dementia. Women whose score on a standard mental function test suggested the possibility of dementia underwent additional neuropsychological testing. A computed tomography scan of the brain was ordered for each woman suspected of suffering from dementia.

Half of the dementia cases in the HRT group and 57% in the placebo group were classified as Alzheimer's disease. Approximately 13% of the dementia cases in the HRT group and 5% in the placebo group were described as vascular dementia. The report's authors suggested that the higher frequency of vascular dementia cases among HRT recipients may be tied to the increased risk of stroke in this treatment group.

Mild cognitive impairment, which can precede the onset of dementia, affected 56 women in the HRT group and 55 in the placebo group, indicating that HRT does not ward off the condition.

1. Shumaker SA, Legault C, Thal L 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; 289:2651-62.

2. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002; 288:321-33.