In contrast to findings from several previous studies, estrogen therapy does not decrease risk for dementia in older, postmenopausal women and may actually increase it, according to an article in the June 23rd issue of The Journal of the American Medical Association.

In the current study, the Women's Health Initiative Memory Study, Sally A. Shumaker, PhD, and her American colleagues tried to determine whether conjugated equine estrogens alone decreased an older woman's risk for dementia or mild cognitive impairment. The same study group had previously found an increased risk for dementia and no effect on mild cognitive impairment in women treated with estrogens plus medroxyprogesterone acetate.

The study was conducted as an arm of the major US Women's Health Initiative randomized trials of hormone therapy that included approximately 27,000 women. The estrogen plus progestin trial of the major study was terminated early in July 2002 due to significantly more noncognitive adverse events associated with estrogens plus medroxyprogesterone compared with placebo. The estrogen-alone trial was terminated on early in February 2004 because the National Institutes of Health considered the excess risk of stroke in the active hormone group to be unacceptable in healthy women in the absence of benefit for coronary heart disease, the primary outcome.

The memory study arm consisted of randomized, double-blind, placebo-controlled clinical trials of conjugated equine estrogens or estrogens plus progestin in community-dwelling women aged 65 to 79 years, conducted from June 1995 to July 8, 2002 (estrogen plus progestin trial; n=4,532), or to February 29, 2004 (estrogen-alone trial; n=2,947). Participants in the estrogen plus progestin trial received either combination therapy or placebo.

The researchers found that in the estrogen-alone trial, 47 participants were diagnosed with probable dementia, with 28 estrogen patients and 19 placebo patients. During follow-up, the incidence of probable dementia was 49 percent higher among women assigned to estrogen compared with those receiving placebo, but this difference was not significant. Incidence rates for probable dementia in the estrogen-alone trial were statistically similar to those in the estrogen plus progestin trial.

When data from the two trials were pooled, the overall risk for probable dementia was significantly increased, by 76 percent. After excluding participants with certain baseline scores at or below the cut point, suggesting early cognitive decline, risk for probable dementia increased to a significant 2.19 times in the pooled trials.

In the combined trials, the risk was similar. Estrogen patients had a significant 38 percent increased risk of diagnosis for mild cognitive impairment or probable dementia at some time during the trial compared with placebo participants.

"Use of hormone therapy to prevent dementia or mild cognitive impairment in women 65 years of age or older is not recommended," the authors concluded.

In an accompanying editorial, Lon S. Schneider, MD, wrote that some important questions regarding estrogen therapy remain: "Most important is whether short-term use of estrogen over several years in early postmenopause is effective in reducing dementia two or three decades later. This is the crux of the observational data, suggesting that previous hormone therapy during a critical period is protective while recent or current use is not. By initiating hormone therapy at an approximate mean age of 71 years and following up patients to 4 to 5 years, WHIMS is intervening fairly late in life while seeking to identify relatively infrequent earlier-onset Alzheimer’s disease cases around age 75 years."

"The [current] results do not prove that estrogen therapy has no effect on Alzheimer’s disease or dementia, but they do clearly indicate that women older than 65 years should not be treated with estrogens with or without progestin to attempt to prevent dementia or enhance cognition. Whether with different populations, lower doses of conjugated equine estrogens, other forms of estrogen or receptor modulators, or delivered in lower more physiological doses, estrogen therapy could eventually be proven beneficial remains to be seen. However, the harmful to neutral effects of estrogen in [the overall and memory trials] will make further development of and research with estrogen therapy a daunting task," Schneider concluded.