American Journal of Epidemiology Advance Access published online on July 23, 2007
American Journal of Epidemiology, doi:10.1093/aje/kwm214
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Hormones and Heart Disease in Women: The Timing Hypothesis
From the Division of Epidemiology, Department of Family and Preventive Medicine, School of Medicine, University of California, San Diego, CA
Correspondence to Dr. Elizabeth Barrett-Connor, Division of Epidemiology, Department of Family and Preventive Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, MC 0607, La Jolla, CA 92093-0607 (e-mail: ebarrettconnor{at}ucsd.edu).
Received for publication September 28, 2006. Accepted for publication December 21, 2006.
Largely on the basis of results from meta-analyses of observational studies, postmenopausal estrogen was widely prescribed to prevent coronary heart disease. However, epidemiologic studies, no matter how consistent and coherent, are not sufficient to recommend mass preventive therapy to healthy women. In fact, all three large clinical trials failed to confirm estrogen's expected cardiac protection. The most persistent explanatory hypothesis for the "trial failure" was the age of the participants, based on the thesis that estrogen in recently menopausal women could prevent the development of coronary artery plaque but, given to older women with vulnerable plaque, would have a null or even harmful effect. The timing hypothesis is plausible, but the prespecified subgroup analyses in both Women's Health Initiative trials showed no significant interaction with age or years since menopause. The best opportunity to test the timing hypothesis was lost when 1,000 Women's Health Initiative women younger than 60 years had coronary artery calcium scans to evaluate the effect of estrogen on plaque burden, but no women 60 years or over were similarly examined. Therefore, this ancillary study can examine the effect of estrogen treatment on coronary calcium in women younger than 60 years but will not be able to determine if the effect is different in older women. In the meantime, publicized statements in multiple venues have promoted the timing hypothesis as fact, confusing patients and physicians who do not realize that the hypothesis is stronger than the evidence.
coronary disease; estrogen replacement therapy; health planning guidelines; hormones; women
Abbreviations: CHD, coronary heart disease; CI, confidence interval; HERS, Heart and Estrogen/progestin Replacement Study; WHI, Women's Health Initiative
Editor's note: An invited commentary on this commentary appears on page 000.
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