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The objective of a recently published analysis of the Women’s Health Initiative (WHI) data on coronary heart disease (CHD) was to estimate the effect of therapy with continuous conjugated equine estrogens (CEE) + medroxyprogesterone acetate (MPA) on risk for coronary heart disease (CHD) over time and stratified by years since menopause [1]. The investigators intended to test the ‘timing hypothesis’ by questioning whether there is an early increased risk of CHD for treated, younger, postmenopausal women and whether such a risk would ever disappear. To demonstrate the effect of treatment, they used adherence-adjusted hazard ratios (HRs) and ‘CHD-free survival curves’. The HRs for CEE + MPA therapy in women within 10 years after menopause, as compared to untreated, younger, postmenopausal women were 1.29 (95% confidence interval (CI) 0.52–3.18) for the first 2 years and 0.64 (95% CI 0.21–1.99) for the first 8 years. The authors conclude that, in women who initiated therapy within 10 years of menopause, there was no suggestion of a decreased risk for CHD within the first 2 years of treatment, and that a possible cardioprotective effect became apparent only after 6 years of use, as shown in the ‘CHD-free survival curves’ of users and non-users of hormone therapy (95% CI 2–10 years).


  • Ewald Boschitsch
    Head of the KLIMAX Menopause Clinic, Vienna, Austria
  • Robert D. Langer
    Principal Scientist and Medical Director, Jackson Hole Center for Preventive Medicine; Adjunct Scholar in Epidemiology, University of Pennsylvania Center for Clinical Epidemiology & Biostatistics; Professor of Family and Preventive Medicine, University of California San Diego (retired)


  1. Toh S, Hernández-Díaz S, Logan R, Rossouw JE, Hernán MA. Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: does the increased risk ever disappear? A randomized trial. Ann Intern Med 2010;152:211-17. Published February 16, 2010.
  2. Manson JE, Hsia J, Johnson KC, et al.; Womens Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523-34.
  3. Rossouw JE, Anderson GL, Prentice RL, et al.; Writing Group for the Womens Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Womens Health Initiative randomized controlled trial. JAMA 2002;288:321-33.
  4. Robins JM, Hernn MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology 2000;11:550-60.
  5. Hernn MA, Alonso A, Logan R, et al. Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease. Epidemiology 2008;19:766-79.
  6. Summaries for patients: The effect of estrogen plus progestin on coronary heart disease. Ann Intern Med 2010;152:I-40. Original report in Ann Intern Med 2010;152:211-17.
  7. WHI Protocol for clinical trial and observational study components, page 28.
  8. Langer RD. Re: Estrogen plus progestin therapy and breast cancer in recently postmenopausal women. Am J Epidemiol 2009;169:784-5; author reply 785-6.

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