Estrogen plus progestin and the risk of coronary heart disease

N Engl J Med. 2003 Aug 7;349(6):523-34. doi: 10.1056/NEJMoa030808.


Background: Recent randomized clinical trials have suggested that estrogen plus progestin does not confer cardiac protection and may increase the risk of coronary heart disease (CHD). In this report, we provide the final results with regard to estrogen plus progestin and CHD from the Women's Health Initiative (WHI).

Methods: The WHI included a randomized primary-prevention trial of estrogen plus progestin in 16,608 postmenopausal women who were 50 to 79 years of age at base line. Participants were randomly assigned to receive conjugated equine estrogens (0.625 mg per day) plus medroxyprogesterone acetate (2.5 mg per day) or placebo. The primary efficacy outcome of the trial was CHD (nonfatal myocardial infarction or death due to CHD).

Results: After a mean follow-up of 5.2 years (planned duration, 8.5 years), the data and safety monitoring board recommended terminating the estrogen-plus-progestin trial because the overall risks exceeded the benefits. Combined hormone therapy was associated with a hazard ratio for CHD of 1.24 (nominal 95 percent confidence interval, 1.00 to 1.54; 95 percent confidence interval after adjustment for sequential monitoring, 0.97 to 1.60). The elevation in risk was most apparent at one year (hazard ratio, 1.81 [95 percent confidence interval, 1.09 to 3.01]). Although higher base-line levels of low-density lipoprotein cholesterol were associated with an excess risk of CHD among women who received hormone therapy, higher base-line levels of C-reactive protein, other biomarkers, and other clinical characteristics did not significantly modify the treatment-related risk of CHD.

Conclusions: Estrogen plus progestin does not confer cardiac protection and may increase the risk of CHD among generally healthy postmenopausal women, especially during the first year after the initiation of hormone use. This treatment should not be prescribed for the prevention of cardiovascular disease.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Case-Control Studies
  • Coronary Disease / chemically induced*
  • Coronary Disease / mortality
  • Coronary Disease / prevention & control
  • Double-Blind Method
  • Drug Combinations
  • Estrogens, Conjugated (USP) / adverse effects*
  • Estrogens, Conjugated (USP) / therapeutic use
  • Female
  • Follow-Up Studies
  • Heart Diseases / chemically induced
  • Heart Diseases / epidemiology
  • Hormone Replacement Therapy / adverse effects*
  • Humans
  • Medroxyprogesterone Acetate / adverse effects*
  • Medroxyprogesterone Acetate / therapeutic use
  • Middle Aged
  • Myocardial Infarction / chemically induced
  • Myocardial Infarction / epidemiology
  • Postmenopause
  • Progesterone Congeners / adverse effects*
  • Progesterone Congeners / therapeutic use
  • Proportional Hazards Models
  • Risk Factors
  • Treatment Outcome


  • Drug Combinations
  • Estrogens, Conjugated (USP)
  • Prempro
  • Progesterone Congeners
  • Medroxyprogesterone Acetate