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Postmenopausal hormone therapy: new questions and the case for new clinical trials

Manson, JoAnn E MD, DrPH1; Bassuk, Shari S ScD1; Harman, S Mitchell MD, PhD2; Brinton, Eliot A MD3; Cedars, Marcelle I MD4; Lobo, Rogerio MD5; Merriam, George R MD6; Miller, Virginia M PhD7; Naftolin, Frederick MD, PhD8; Santoro, Nanette MD9

Personal Perspective

Observational studies suggest that postmenopausal hormone therapy (HT) prevents coronary heart disease, whereas randomized clinical trials have not confirmed a cardioprotective effect. Although observational studies may have overestimated the coronary benefit conferred by postmenopausal hormone use, there are other plausible explanations for the apparent discrepancy between previous results and the less favorable findings from clinical trials such as the large Women's Health Initiative. There is now a critical mass of data to support the hypothesis that age or time since menopause may importantly influence the benefit-risk ratio associated with HT, especially with respect to cardiovascular outcomes, and that the method of administration, dose, and formulation of exogenous hormones may also be relevant. Although the weight of the evidence indicates that older women and those with subclinical or overt coronary heart disease should not take HT, estrogen remains the most effective treatment currently available for vasomotor symptoms, and its effects on the development of coronary disease in newly postmenopausal women remain unclear. Moreover, effects of HT on quality of life and cognitive function in recently postmenopausal women merit further study. These unresolved clinical issues provide the rationale for the design of the Kronos Early Estrogen Prevention Study, a 5-year randomized trial that will evaluate the effectiveness of low-dose oral estrogen and transdermal estradiol in preventing progression of atherosclerosis in recently postmenopausal women.

Observational studies suggest that menopause hormone therapy prevents coronary heart disease, whereas randomized clinical trials have not confirmed a cardioprotective effect. This commentary addresses possible methodologic and biologic explanations for the discrepancy and describes a new trial (the Kronos Early Estrogen Prevention Study) designed to address several of the unresolved questions.

From the 1Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; the 2Kronos Longevity Research Institute, Phoenix, AZ; 3Metabolism Section, Cardiovascular Genetics, University of Utah, Salt Lake City, UT; the 4Department of Obstetrics and Gynecology, University of California at San Francisco, San Francisco, CA; the 5Department of Obstetrics and Gynecology, Columbia University, College of Physicians and Surgeons, New York, NY; 6DVA Puget Sound Health Care System and the Departments of Medicine and of Obstetrics and Gynecology, University of Washington, Tacoma and Seattle, WA; the 7Departments of Surgery and Physiology and Bioengineering, Mayo Clinic College of Medicine, Rochester, MN; the 8Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT; and the 9Department of Obstetrics, Gynecology, and Women's Health, Albert Einstein College of Medicine, Bronx, NY.

Received May 31, 2005; revised and accepted June 30, 2005.

©2006The North American Menopause Society