Public Release: 

Use of estrogen does not reduce risk of dementia in older women

The JAMA Network Journals

Contrary to findings in several previous studies, estrogen therapy does not decrease, but may increase, the risk for dementia in older, postmenopausal women, according to a study in the June 23/30 issue of The Journal of the American Medical Association (JAMA).

Dementia is an age-associated illness that imposes severe functional impairment on individuals, according to background information in the article. In the year 2000, more than 4 million people in the United States had Alzheimer disease (AD), and that number is expected to increase to 13 million by 2050. Milder cognitive impairment affects between one-fifth and one-third of older adults and strongly predicts dementia and subsequent institutionalization. Previous studies have reported an association between lower risk of dementia and postmenopausal estrogen use.

In this study, Sally A. Shumaker, Ph.D., of the Wake Forest University School of Medicine, Winston-Salem, N.C., with investigators from the Women's Health Initiative Memory Study (WHIMS) sought to determine whether conjugated equine estrogens (CEE) alone decreased an older woman's risk for dementia or mild cognitive impairment (MCI). The WHIMS previously found an increased risk for dementia and no effect on MCI in women treated with CEE plus medroxyprogesterone acetate (MPA).

The WHIMS is an ancillary study to the larger Women's Health Initiative (WHI) randomized clinical trials of hormone therapy that include a geographically diverse group of approximately 27,000 women. The estrogen plus progestin trial of the WHI was terminated in July 2002 due to significantly more noncognitive adverse events associated with CEE plus MPA compared with placebo. The WHI estrogen-alone trial was terminated on February 29, 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 WHIMS consisted of randomized, double-blind, placebo-controlled clinical trials of CEE or CEE plus MPA (estrogen plus progestin trial) in community-dwelling women aged 65 to 79 years, conducted from June 1995 to July 8, 2002 (estrogen plus progestin; n=4,532), or to February 29, 2004 (estrogen-alone; n=2,947) in 39 of the 40 WHI clinical centers. Participants in the estrogen-alone trial received either 1 daily tablet containing 0.625 mg/d of CEE or matching placebo; in the estrogen plus progestin trial, they received either 1 daily tablet containing CEE (0.625 mg/d) plus MPA (2.5 mg/d) or matching placebos.

The researchers found that in the estrogen-alone trial, 47 participants were diagnosed with probable dementia, of whom 28 were assigned to receive CEE and 19 to receive matching placebo. During follow-up, the incidence of probable dementia was 49 percent higher among women assigned to receive CEE 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 2 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 a nonsignificant 77 percent in the estrogen-alone trial and a significant 2.19 times in the pooled trials.

The risk of being diagnosed with MCI in the CEE group was increased a nonsignificant 34 percent compared with the placebo group. In the combined trials, the risk was similar. The women assigned to CEE had a significant 38 percent increased risk of having either MCI or probable dementia at some time during the trial, compared to the women assigned to placebo.

"Use of hormone therapy to prevent dementia or MCI in women 65 years of age or older is not recommended," the authors conclude. (JAMA. 2004; 291:2947-2958. Available post-embargo at


Editor's Note: For funding and disclosure information, please see the JAMA article.


Additional results from the WHIMS indicate that women aged 65 years and older who took hormone therapy had a greater decline in cognitive function than women taking placebo.

Mark A. Espeland, Ph.D., from Wake Forest University School of Medicine, Winston-Salem, N.C., and investigators with the WHIMS evaluated the effect of postmenopausal hormone therapy on global (overall) cognition in the estrogen-alone trial and in the pooled estrogen-alone and estrogen plus progestin cohorts. The cognitive areas measured included temporal and spatial orientation, immediate and delayed recall, naming, verbal fluency, abstract reasoning (similarities), praxis (obeying command, sentence writing), writing, and visuoconstructional abilities (copying).

Of the 2,947 women enrolled in WHIMS, analyses were conducted on the 2,808 women with a baseline and at least 1 follow-up measure of global cognitive function before the trial's termination.

"We found that women aged 65 years or older assigned to CEE therapy had a slightly but significantly lower average cognitive function compared with women assigned to placebo, as measured ... during 5 to 7 years of follow-up," the authors write. "These differences appeared to emerge 1 to 2 years after initiation of therapy and persisted throughout the trial."

"Our results suggest that neither CEE nor CEE plus MPA should be initiated in older women for the purpose of protecting cognitive function. Furthermore, at least 1 subgroup of women was at particularly high risk for the adverse effects of hormone therapy on cognition--women with relatively low baseline cognitive function," the researchers conclude. (JAMA. 2004; 291:2959-2968. Available post-embargo at

Editor's Note: For funding and disclosure information, please see the JAMA article.


In an accompanying editorial, Lon S. Schneider, M.D., from the University of Southern California, Los Angeles, writes 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 2 or 3 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 AD cases around age 75 years."

"The WHIMS results do not prove that estrogen therapy has no effect on AD or dementia, but they do clearly indicate that women older than 65 years should not be treated with CEE with or without MPA to attempt to prevent dementia or enhance cognition. Whether with different populations, lower doses of CEE, 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 WHI and WHIMS trials will make further development of and research with estrogen therapy a daunting task," writes Dr. Schneider. (JAMA. 2004; 291:3005-3007. Available post-embargo at

Editor's Note: For Dr. Schneider's financial disclosure, please see the JAMA editorial.

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