The release of new data from the Women’s Health Initiative (WHI) trial of estrogen plus progestin in 16,608 postmenopausal women revealed that combined hormone replacement therapy increased the risk of stroke, dementia, and global cognitive decline, and did not protect against mild cognitive impairment. These findings, published in the May 28 JAMA, follow previous findings that the risks of developing breast cancer and cardiovascular disease outweighed the benefits of combined hormone replacement therapy. For this reason, the estrogen plus progestin arm (0.625 mg/day of conjugated equine estrogen plus 2.5 mg/ day of medroxyprogesterone acetate) of the WHI was prematurely cancelled in July 2002.

REFINING THE RISK OF STROKE

A link between the estrogen plus progestin therapy and stroke risk was found in the WHI investigators’ initial report. The recent findings build off that data but include all the cases of stroke with 5.6 years of follow-up, adjudicated by neurologists, allowing the investigators, led by Sylvia Wassertheil-Smoller, PhD, of the Department of Epidemiology and Social Medicine at Albert Einstein College of Medicine in the Bronx, New York, to analyze the findings by type of stroke.

The researchers found that the 8,506 participants taking hormone therapy had a 31% higher overall risk of stroke than did the 8,102 patients on placebo. Almost 80% of the strokes were ischemic, Dr. Wassertheil-Smoller reported, and the hormone therapy group had a 44% increased risk for ischemic stroke compared with the placebo group. The risk for hemorrhagic stroke did not significantly differ between the two groups.

“Excess risk of all stroke was apparent in all age-groups, in all categories of baseline stroke risk, and in women with and without hypertension, history of cardiovascular disease, use of hormones, statins, or aspirin,” the investigators said. Other risk factors for stroke also did not modify the effect of estrogen plus progestin on stroke risk, they added.

The Women’s Health Initiative Memory Study (WHIMS), a subgroup of the WHI, investigated the incidence of probable dementia and mild cognitive impairment in 4,532 postmenopausal WHI participants 65 and older, who were free of probable dementia at baseline. The Modified Mini-Mental State Examination served as the diagnostic instrument. Overall, after approximately four years of follow-up, 61 women were diagnosed with dementia, said Sally A. Shumaker, PhD, of the Department of Public Health Sciences at Wake Forest University in Winston-Salem. Of these, 40 women (66%) were in the estrogen plus progestin group, yielding a hazard ratio for dementia of 2.05. Alzheimer’s disease was the most common classification of dementia in both study groups, and the hormone therapy did not significantly prevent mild cognitive impairment.

In a second facet of WHIMS, Stephen R. Rapp, PhD, of the Department of Psychiatry and Behavioral Medicine at Wake Forest University, reported that annually recorded Modified Mini-Mental State Examination measures of global cognitive function showed that the mean total score for women in both the hormone therapy and placebo groups increased slightly over four years. “Women in the estrogen plus progestin group had smaller average increases in total scores compared with women receiving placebo,” Dr. Rapp reported. While these differences were not clinically significant, more women in the hormone therapy group “had a substantial and clinically important decline” in total score, compared with placebo. The results do not support the use of estrogen plus progestin to protect cognitive function in older women and imply a degree of associated cognitive decline, the investigators concluded.

A VASCULAR VIEWPOINT

The results from the WHI and WHIMS “provoke a strong sense of déjà vu,” said Kristine Yaffe, MD, in an accompanying editorial. She was referring to the previous WHI findings of the harmful effect of estrogen on coronary disease outcomes. Dr. Yaffe, of the Departments of Psychiatry, Neurology, and Epidemiology at the University of California, San Francisco, noted that the WHI stroke findings and the WHIMS dementia findings might have a shared explanation. Though most dementia in WHIMS was Alzheimer’s type, a higher rate of vascular dementia in hormone-treated women as opposed to women receiving placebo (five cases versus one case) is consistent with the observation that women taking hormone therapy had a twofold higher risk of stroke, she said. This fact is supportive of “an increasing understanding that vascular disease often coexists with Alzheimer’s disease and that silent brain infarcts may markedly increase the risk of developing dementia,” she added.

Dr. Yaffe cautioned that the continued findings of cerebrovascular risks associated with estrogen plus progestin therapy, coupled with the current findings from WHIMS, strongly advocate against recommending hormone therapy “for prevention of any outcome, including Alzheimer’s disease.”

NR

—C. Justin Romano

Suggested Reading
Rapp SR, Espeland MA, Shumaker SA, 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;289:2663-2672.
Shumaker SA, Legault C, Rapp SR, 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;289:2651-2662.
Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA. 2003;289:2673-2684.
Yaffe K. Hormone therapy and the brain: déjà vu all over again? JAMA. 2003;289:2717-2719.

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