Estrogen therapy may increase the risk for dementia

A new study in the Journal of the American Medical Association (JAMA) suggests that estrogen therapy does not decrease, but may increase, the risk for dementia in older, postmenopausal women.

Dementia is progressive decline in cognitive function due to damage or disease in the brain beyond what might be expected from normal ageing. Particulary affected areas may be memory, attention, language and problem solving, although particularly in the later stages of the condition, affected persons may be disoriented in time (not knowing what day, week, month or year it is), place (not knowing where they are) and person (not knowing who they are).

Today more than 4 million people in the United States had Alzheimer disease, 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.

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