HRT for CV Protection? Still a Balancing Act

Updated:Jun 18,2014
Disclosure: Speakers bureau for Kaneka, Pfizer, and Merck.
Pub Date: Wednesday, March 26, 2008
Authors: Donna M. Polk, MD
Article:  HRT for CV Protection? Still a Balancing Act


1.  Heiss G, Wallace R, Anderson GL, Aragaki A, Beresford SA, Brzyski R, Chlebowski RT, Gass M, LaCroix A, Manson JE, Prentice RL, Rossouw J, Stefanick ML.,  Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin.,  JAMA : the journal of the American Medical Association,  299 (9) 1036-45.

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Article Text

Until recently, epidemiologic evidence supported the protective role of estrogen in the prevention of atherosclerotic disease. Due to effects on lipids, and its antioxidant, antiinflammatory, and vasomotor properties, the biological plausibility of estrogen supported its beneficial effect. Large observational studies of women have suggested an inverse relationship between estrogen and coronary heart disease (CHD). In the Nurses' Health Study [1], the CHD risk observed in estrogen/progestin users was 0.39 versus nonusers. Stampfer and Colditz [2] in a metaanalysis showed a relative risk reduction of 0.56 (0.5-0.61) for estrogen users compared with nonusers. It was not until the publication of the HERS [3] trial that the role of estrogen in the treatment and prevention of CHD was really questioned.

In the HERS [3] trial, 2763 postmenopausal women (mean age, 66.7 years) with known coronary artery disease were randomized in a placebo-controlled fashion to 0.625 mg of conjugated estrogen and 2.5 mg medroxyprogesterone acetate or placebo and followed for an average of 4.1 years. While the women did have potentially beneficial effects on their lipids, with lower low-density lipoprotein cholesterol levels and higher high-density lipoprotein cholesterol levels, there was no difference in the primary outcome, nonfatal myocardial infarction or CHD death. There was, however, a 50% increase in the primary outcome in the first year of the trial. This prompted speculation about the role of estrogen in the atherosclerotic process and, importantly, during the acute event. The prothrombotic effect of estrogen as well as the role of estrogen in the inflammatory process were implicated as potential mechanisms for the increased events within the first year. The major criticism of the study was the advanced age of the subjects, with an average age of greater than 66 years, well past the menopause.

Animal evidence as well as evidence from women who have gone through surgical menopause would suggest that early administration of estrogen prior to the development of atherosclerotic plaque is potentially beneficial. The Women's Health Initiative (WHI) [4] was designed to evaluate strategies for the prevention and control of several disease states affecting postmenopausal women, including CHD. WHI randomized 16,608 women aged 50-79 (mean age, 63 years) with an intact uterus to continuous combined hormone replacement therapy (HRT) (Prempro) between 1993 and 1998. Only a small fraction (7%) of these women had established CHD. The safety monitoring board (DSMB) stopped this arm of the trial after 5.2 years due to adverse increase in breast cancer. Analysis of outcomes also showed a nonsignificant increase in CHD events in women taking combined therapy. The estrogen-only arm continued for an additional 1.5 years and showed no benefit of estrogen therapy in the prevention of CHD.

With these results, guidelines for health care professionals advised against the use of estrogen for the purpose of cardiovascular disease prevention. The risk-benefit ratio of estrogen therapy would have to be weighed against serious menopausal symptoms. The recent longer term follow-up study of the WHI participants by Heiss et al. [5] shows no difference in cardiovascular outcomes after an additional 3 years of follow-up (annualized event rate of 1.97% versus 1.91% for placebo), but a continued increase in the risk of fatal and nonfatal malignancies in those randomized to receive estrogen/progestin therapy. Those participants who received combination therapy had an annualized risk of malignancy of 1.56% versus 1.26% in those receiving placebo.

Overall, the risks of therapy with combination therapy outweigh the benefits of therapy for chronic disease prevention. With these new results, practitioners must carefully weigh the risks and benefits of combined estrogen/progestin therapy in postmenopausal women.



  1. Grodstein F, Stampfer M, Manson J, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. New Engl J Med 1996;335:453-461.
  2. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991;20:47-63.
  3. Hully S, Grady D, Bush T, et al., and the HERS Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-611.
  4. Writing Group for the Women's Health Initiative Investigators. Risk and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-333.
  5. Heiss G, Wallace R, Anderson GL, et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 2008;299:1036-1045.

-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association. -- 

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