Estrogen-Progestin Associated With Increased Risk of Stroke and Dementia
Thursday, May 29th 2003
Combination therapy with estrogen and progestin is associated with increased risk of stroke and dementia and no improvement in cognitive function, according to three reports in the May 28 issue of The Journal of the American Medical Association.
Based on these findings from the Women's Health Initiative (WHI) and the Women's Health Initiative Memory Study (WHIMS), the investigators suggest that this combination should be reserved for menopausal symptoms only. The editorialist summarizes the status of our current understanding and points out where evidence is still lacking.
"The combination of estrogen and progestins in older women appears to increase the risk of stroke and all-cause dementia," Victor Henderson, MD, a professor of geriatrics and neurology at the University of Arkansas for Medical Sciences in Little Rock, told Medscape. "These results are in the context of a large, randomized controlled trial, so they have to be taken seriously even if they are different from the results prophesied years ago."
Dr. Henderson is a coauthor of a study of the effect of estrogen and progestin on cognitive function in the WHIMS trial, which began enrolling subjects from the WHI in May 1996. WHIMS is an ancillary study to the two larger WHI trials. The WHI study of estrogen plus progestin was discontinued in July 2002 because of increased health risks in women receiving this hormone combination, including higher risk of invasive breast cancer, myocardial infarction, and venous thrombosis.
"From a methodological viewpoint, all three of these studies meet the gold standard of being large, double-blind, placebo-controlled, randomized clinical trials," says Phyllis M. Wise, PhD, a professor of neurobiology, physiology, and behavior at the University of California, Davis. "As a basic scientist, I would have to say that these results with this hormone combination are not terribly surprising."
Dr. Wise was not involved in any of these studies, but she commented on them for Medscape. "In most tissues, progestins downregulate any protective effects of estrogen, the one exception being breast tissue, where progestin amplifies the effect of estrogen," she explains. "So this probably explains why this combination increases risk of breast cancer while negating any potential beneficial effect of estrogen on cardiovascular risk."
All women in WHIMS were aged 65 years and older, and they were randomized to receive daily doses of 0.625 mg of conjugated equine estrogen with 2.5 mg of medroxyprogesterone acetate or placebo. In a study of dementia risk in the WHIMS trial, 4,532 postmenopausal women, aged 65 years or older without probable dementia, were enrolled between May 1996 and December 1999.
Baseline and annual evaluation included a structured clinical assessment and Modified Mini-Mental State Examination (3MSE) testing temporal and spatial orientation, immediate and delayed recall, executive function, verbal fluency, abstract reasoning, praxis, and visuoconstructional abilities.
Women with follow-up scores suggesting possible cognitive impairment underwent neuropsychological testing for verbal fluency and memory recall and evaluations by physicians experienced in diagnosing dementia. Women thought to have possible dementia also had computed tomography of the brain and blood tests to rule out possible reversible causes of cognitive decline and dementia.
The risk of probable dementia in the estrogen plus progestin group was twice that in the placebo group (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.21 - 3.48; P = .01). Of 61 women diagnosed with probable dementia, 40 (66%) were in the estrogen plus progestin group and 21 (34%) were in the placebo group.
Evidence of increased risk in the estrogen plus progestin group appeared as early as one year after randomization and persisted over five years of follow-up. However, the absolute risk of developing dementia was relatively small: an additional 23 cases of dementia per 10,000 women treated with estrogen plus progestin for one year.
These findings were described as "unexpected and in striking contrast to most of the earlier research on the effects of hormone therapy on Alzheimer's disease (AD) and dementia," according to Sally A. Shumaker, PhD, from Wake Forest University Health Sciences in Winston-Salem, North Carolina, and colleagues.
"The reasons for the differences from results of observational studies may be simply that the observational studies got it wrong because of unrecognized bias, or that there are meaningful differences in hormonal preparations used, age of use, and in duration and timing of use," Dr. Henderson said. "The primary outcome was all-cause dementia rather than AD per se, so it's possible that what we're observing reflects an effect on vascular dementia rather than on AD, although that's somewhat speculative."
The study of cognitive function in WHIMS, coauthored by Dr. Henderson, evaluated 4,381 women who provided at least one valid follow-up score on the 3MSE between June 1995 and July 8, 2002. Mean 3MSE total scores in both groups increased slightly over a mean follow-up of 4.2 years, which the investigators attributed to a learning effect.
Women in the estrogen-progestin group had smaller mean increases in total scores than did women in the placebo group (P = .03), but these differences were not clinically significant. A substantial and clinically important decline of at least two standard deviations in 3MSE occurred in 6.7% of the hormone therapy group and in 4.8% of the placebo group (P = .008).
Excluding women who developed overt dementia, mild cognitive impairment or stroke, or those who did not adhere to the study protocol, did not affect the results, nor did adjustment for prior use of hormone therapy or duration of prior use.
An offshoot of the WHI studied the effect of estrogen plus progestin on ischemic and hemorrhagic stroke. The WHI was a multicenter, double-blind, placebo-controlled, randomized clinical trial enrolling 16,608 women aged 50 to 79 years. Subjects received 0.625 mg of conjugated equine estrogen per day plus 2.5 mg of medroxyprogesterone acetate per day, and average follow-up was 5.6 years.
Strokes occurred in 151 patients (1.8%) in the estrogen plus progestin group and in 107 patients (1.3%) in the placebo group, yielding an overall increased risk of 31% for total stroke (HR, 1.31; 95% CI, 1.02 - 1.68; or HR, 1.50 adjusted for adherence; 95% CI, 1.09 - 1.90). Ischemic strokes accounted for 79.8% of the total, with increased risk of 44% for hormone therapy compared with placebo (HR, 1.44; 95% CI, 1.09 - 1.90). The risk for hemorrhagic stroke was not significantly different between groups.
"The stroke study doesn't really contradict prevailing beliefs in the medical community," Dr. Henderson said. "There was really no strong evidence that hormone therapy would have a beneficial effect in stroke, so most did not expect a dramatic benefit for stroke, even though they did for AD. Hormone therapy may have both positive and negative effects on vascular factors involving inflammation, clotting, and thrombolysis, so the net effect on vascular risk may be more difficult to predict."
Increased stroke risk related to estrogen plus progestin was independent of other risk factors, including age, history of cardiovascular disease, or hypertension. There was no interaction between estrogen plus progestin exposure and other risk factors that could identify a subgroup of women at highest risk of stroke with estrogen plus progestin.
"Not only was this a huge study population, but it also showed increased stroke risk across the board," Dr. Wise said. "One might have predicted that women in their seventies, some of whom never had hormone therapy before entering this trial and who therefore were unexposed to estrogen and progestin for two decades, might have reacted differently than women who recently entered menopause. But the increased risk was observed at all ages."
So what is the take-home message for clinicians concerning prescription of hormone therapy? In an accompanying editorial, Kristine Yaffe, MD, an assistant professor in psychiatry and neurology at the University of California, San Francisco, points out that the effect of unopposed estrogen on dementia risk will be evaluated with the ongoing estrogen arm of WHIMS.
She notes that progestins, especially medroxyprogesterone, have been reported to modify the beneficial effects of estrogen and possibly increase the risk of thromboembolic events. Timing of use and mode of delivery of estrogen may turn out to be critical factors influencing dementia risk.
"Not much is known about the relative roles of progestins and estrogens in contributing to the negative central nervous system effects of the combination," she told Medscape, adding that discrepancies between the WHI findings and those of earlier studies may be explained by the observational rather than controlled design of previous studies.
Based on these findings and on her own experience, she recommended that hormone therapy be given "only for menopausal symptoms at this point, but more research is needed."
"In terms of management, these studies don't really change things much," Dr. Henderson agreed. "The WHI study from July of 2002 showed no net benefit from use of estrogen plus progestin when certain diseases were considered in terms of outcome. So this study reinforces our earlier conclusions that this combination should be given only for climacteric symptoms."
In animal models, Dr. Wise is testing the effects of unopposed, low-dose estradiol-17-beta, which most closely resembles endogenously secreted estrogen. Although many commercial preparations used in hormone therapy involve a mixture of estrogens, usually in combination with progestin, she recommends clinical trials of low-dose, unopposed estradiol.
"Both as a middle-aged woman and as a scientist, I am very hopeful that results with low-dose estrogen alone might be better," she said. "Especially in older women for whom contraception is not an issue, we should be testing whether low-dose estradiol given alone affords protection against heart disease and stroke.
"Some investigators may be debating whether they should change the estrogen arm in ongoing trials to low-dose unopposed estradiol, but it's difficult to introduce this type of confounding when you're in the middle of a study. These studies amplify those from the WHI last year, and their findings present a significant contraindication to using this particular preparation of estrogen plus progestin," Dr. Wise concluded.
Dr. Henderson is a consultant for and has received honoraria from Wyeth, and over the past five years he has received grant funding from Wyeth and consulting fees from Lilly. Dr. Wise has received grants from Wyeth in the past but is not presently.
These studies were funded in part by the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services. Wyeth Pharmaceuticals helped fund the WHIMS and provided the study drug and placebo to the WHI trial.
Authors of these three studies have various financial arrangements with Wyeth, Pfizer, Duramed, Eli Lilly, GlaxoSmithKline, Merck, Proctor & Gamble, Ortho-McNeil, Bristol Myers Squibb, 3M, Organon, TAP, Abbott, Astra-Zeneca, MSD, Boehringer Ingelheim, Novartis, and/or MGI Pharma.
Laurie Barclay, MD
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