CHICAGO—Estrogen plus progestin therapy increases older women's risk for probable dementia and does not protect against mild cognitive impairment, according to a new study in the May 28 issue of The Journal of the American Medical Association (JAMA).

Sally A. Shumaker, Ph.D., from Wake Forest University Health Sciences, Winston-Salem, N.C., and the investigators from the Women's Health Initiative Memory Study (WHIMS) report their findings in this issue of JAMA, which also includes another study from WHIMS on global cognitive function in postmenopausal women taking combined hormone therapy, and a study on the effect of combined hormone therapy on stroke from the Women's Health Initiative (WHI).

Background information provided in the article states that approximately ten percent of persons older than 65 years and about 50 percent of those older than 85 years have Alzheimer disease (AD). "At present, this represents approximately 4 million persons in the United States, and that number is projected to increase to 14 million by the year 2040. Postmenopausal women may have a greater risk of developing AD than men, perhaps due to lower endogenous estrogen levels following menopause."

The researchers set out to determine whether estrogen supplementation (either estrogen alone or estrogen plus progestin) reduces the risk of all-cause dementia and mild cognitive impairment in healthy women aged 65 years or older. WHIMS is an ancillary study to the two larger Women's Health Initiative hormone therapy trials. The WHI study of estrogen plus progestin came to an early end last year because of increased health risks in women receiving the combined hormone therapy, so these study results are from the combined hormone therapy versus placebo portion of the study. The discontinuation of the WHI trial resulted in the "early, unplanned examination of this same component within WHIMS." The WHI estrogen-only hormone therapy trial, which enrolled women with a prior hysterectomy, continues, as does the WHIMS component of the estrogen-only hormone therapy trial.

In this study, the researchers enrolled 4,532 postmenopausal women, aged 65 years or older and free of probable dementia who were participating in the WHI trial. The participants were enrolled in the WHIMS trial between May 1996 and December 1999. The participants received either one daily tablet of 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate (n = 2,229), or a matching placebo (n = 2,303). The WHIMS participants were asked to name a friend or family member who could provide information regarding the participant's cognitive and behavioral functioning. The participants were tested at baseline and annually thereafter with a standard mental state examination. Individuals with scores suggesting possible cognitive impairment were administered neuro-psychological testing for verbal fluency and memory recall, plus evaluations by physicians experienced in diagnosing dementia. If dementia was suspected based on this additional testing, a computed tomography scan of the brain and laboratory blood tests were ordered to rule out possible reversible causes of cognitive decline and dementia.

"Of the 4,532 participants in the estrogen plus progestin component of the WHIMS trial, 61 were diagnosed with probable dementia; 40 (66 percent) in the estrogen plus progestin group compared with 21 (34 percent) in the placebo group," the researchers report. "Overall, the risk of probable dementia for women in the estrogen plus progestin group was twice that of women in the placebo group, and evidence of an increased risk began to appear as early as one year after randomization, with differences persisting over five years of follow-up." The researchers state that their results are "unexpected and in striking contrast to most of the earlier research on the effects of hormone therapy on AD and dementia."

"Despite the significant negative effect of estrogen plus progestin on risk for developing probable dementia, our findings need to be kept in perspective," the authors note. "Although participants assigned to active therapy were at twice the risk for dementia, the absolute risk is relatively small. That is, for every 10,000 postmenopausal women aged 65 years or older with risk factor profiles similar to those of WHIMS participants who took estrogen plus progestin for one year, 45 would be diagnosed with probable dementia versus 22 women taking placebo. This increased risk would result in an additional 23 cases of dementia per 10,000 women per year."

CHICAGO—Estrogen plus progestin does not improve cognitive function and may even result in cognitive decline for some postmenopausal women, according to a study in the May 28 issue of The Journal of the American Medical Association (JAMA).

Stephen R. Rapp, Ph.D., from Wake Forest University School of Medicine, Winston-Salem, N.C, and investigators from the Women's Health Initiative Memory Study (WHIMS), an ancillary study of the Women's Health Initiative (WHI) hormone therapy trials, analyzed data from the 4,381 women in the WHIMS trial who provided at least one valid follow-up cognitive function score between June 1995 and July 8, 2002. A total of 4,532 women aged 65 years and older were enrolled in WHIMS.

"Declining cognitive function is a growing public health concern for older adults, given the well-documented pattern of age-associated decrements in many areas of cognitive performance and the increasing proportion of elderly individuals in the U.S. population," the authors provide as background information in the article. "The prevalence of age-associated memory impairment is estimated to be between 17 percent and 34 percent."

The participants received either one daily tablet containing 0.625 mg of conjugated equine estrogen with 2.5 mg of medroxyprogesterone acetate (n = 2,145) or matching placebo (n = 2,236). The main outcome in this analysis is global cognitive function measured longitudinally with the Modified Mini-Mental State Examination (3MSE). "The 3MSE's 15 parts comprise 46 items that contribute to a total score that can range from 0 to 100, with a higher score reflecting better cognitive functioning," the authors explain. "The test items measure temporal and spatial orientation, immediate and delayed recall, executive function (mental reversal, 3-stage command), naming, verbal fluency, abstract reasoning (similarities), praxis (obeying command, sentence writing), writing, and visuoconstructional abilities (copying)." The authors add the 3MSE has demonstrated reliability in detecting cognitive impairment and dementia. The 3MSE was administered at a screening visit and then annually to the participants by a trained technician. This analysis was not part of the original trial plan but was conducted when an increased risk of dementia was found among women taking estrogen plus progestin.

"The Modified Mini-Mental State Examination mean (average) total scores in both groups increased slightly over time (mean follow-up of 4.2 years)," the researchers report. "Women in the estrogen plus progestin group had smaller average increases in total scores compared with women receiving placebo, but these differences were not clinically important." The researchers note that these increases may be attributed to a learning effect known to result from repeated administrations of cognitive tests. "More women in the estrogen plus progestin group had a substantial and clinically important decline in Modified Mini-Mental State Examination total score (6.7 percent) compared with the placebo group (4.8 percent)."

CHICAGO—Healthy postmenopausal women who take the combination hormone replacement therapy of estrogen plus progestin are at increased risk for stroke, according to a study in the May 28 issue of The Journal of the American Medical Association (JAMA).

According to background information in the article, stroke is a major health issue for women and cerebrovascular disease is the third leading cause of death in the United States and the leading cause of adult disability. The Women's Health Initiative (WHI) clinical trial, which began in the early 1990s, was designed to examine a number of factors affecting the health of postmenopausal women. One study within the WHI, the clinical trial of estrogen plus progestin was terminated three years before its planned completion date because the harmful effects of hormone therapy outweighed the benefits.

In this study, Sylvia Wassertheil-Smoller, Ph.D., of the Albert Einstein College of Medicine, Bronx, N.Y., and WHI Investigators, assessed the effect of estrogen plus progestin on ischemic and hemorrhagic stroke and in subgroups of participants in WHI. The study was a multicenter double-blind, placebo-controlled, randomized clinical trial involving 16,608 women aged 50-79 years with an average follow-up of 5.6 years. Participants received conjugated equine estrogen 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d (n=8,506) or placebo (n=8,102).

The researchers found that 151 (1.8 percent) patients in the estrogen plus progestin group and 107 (1.3 percent) in the placebo group had strokes, an overall increased risk of 31 percent for total stroke. Overall 79.8 percent of strokes were ischemic, with the hormone therapy group having a 44 percent increased risk for ischemic stroke, compared to those taking placebo. The risk for hemorrhagic stroke was not significantly different in the hormone therapy vs. placebo groups.

"The increase [in stroke risk] was unrelated to a number of other risk factors, including age and a prior history of cardiovascular disease, hormone use, or hypertension. Furthermore, no interaction was observed between estrogen plus progestin and any stroke risk factor that might allow identification of women at the highest risk of stroke when taking estrogen plus progestin. The increase in risk did not appear until after the first year of treatment. The results extend those published in the first WHI report ...," the authors write.

CHICAGO—Patients with moderate to severe heart failure experience improved functional status, exercise capacity, and quality of life with implantable devices that combine cardiac resynchronization therapy (CRT, a pacemaker-based technology that improves heart function) and cardioverter defibrillator (ICD) function (that corrects dangerous, abnormal heart rhythms), according to a study in the May 28 issue of The Journal of the American Medical Association (JAMA).

James B. Young, M.D., of the Cleveland Clinic Foundation, Cleveland, and The Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD) trial investigators examined the efficacy and safety of combined CRT and ICD therapy in patients with advanced congestive heart failure. The study was a randomized, double-blind trial conducted from October 1999 to August 2001 of 369 patients at high risk of life-threatening ventricular arrhythmias and with New York Heart Association (NYHA) class III (moderate) (n = 328) or IV (severe) (n = 41) heart failure (HF) despite optimized medical treatment.

Of 369 randomized patients who received devices with combined CRT and ICD capabilities, 182 were controls (ICD activated, CRT off) and 187 were in the CRT group (ICD activated, CRT on).

The researchers found that at six months, patients assigned to CRT had a greater improvement in average quality of life score and functional class than controls but were no different in the change in distance walked in 6 minutes. There was a greater increase in peak oxygen consumption in the CRT group than in controls. No significant differences were observed in changes in left ventricular size or function, overall heart failure status, survival, and rates of hospitalization. The capability to terminate an abnormal heart rhythm was not impaired.

COMBINED HORMONE THERAPY INCREASES RISK OF DEMENTIA IN ELDERLY WOMEN