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Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies
  1. Samuel Shapiro1,
  2. Richard D T Farmer2,
  3. Alfred O Mueck3,
  4. Helen Seaman4,
  5. John C Stevenson5
  1. 1Visiting Professor of Epidemiology, Department of Epidemiology, University of Cape Town, Cape Town, South Africa
  2. 2Emeritus Professor of Epidemiology, Department of Epidemiology, University of Surrey, Guildford, UK
  3. 3Professor of Clinical Pharmacology and Experimental Endocrinology, Department of Endocrinology, University Women's Hospital, Tübingen, Germany
  4. 4Freelance Medical Writer, Aldershot, UK
  5. 5Consultant Physician and Reader in Metabolic Medicine, National Heart and Lung Institute, Imperial College, London and Royal Brompton Hospital, London, UK
  1. Correspondence to Professor Samuel Shapiro, Department of Public Health and Family Medicine, University of Cape Town Medical School, Anzio Road, Observatory, Cape Town, South Africa; samshap{at}

Part 2. The Women's Health Initiative: estrogen plus progestogen


Background Based principally on findings in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI), and the Million Women Study (MWS), it is claimed that combined hormone replacement therapy (HRT) with estrogen plus progestogen is now an established cause of breast cancer. For unopposed estrogen therapy the evidence in the three studies is conflicting: the CR and MWS have reported increased risks in estrogen users, while the WHI has not. The authors have previously reviewed the findings in the CR (Part 1).

Objective To evaluate the evidence for causality in the WHI studies.

Methods Using generally accepted causal criteria, in this paper (Part 2) the authors evaluate the findings in the WHI for estrogen plus progestogen; in a related paper (Part 3) the authors evaluate the findings for unopposed estrogen. An evaluation of the MWS (Part 4), and of trends in breast cancer incidence following publication of the WHI findings in 2002 (Part 5) will follow.

Results For estrogen plus progestogen the findings did not adequately satisfy the criteria of bias, confounding, statistical stability and strength of association, duration-response, internal consistency, external consistency or biological plausibility.

Conclusion HRT with estrogen plus progestogen may or may not increase the risk of breast cancer, but the WHI did not establish that it does.

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  • Competing interests Samuel Shapiro, Alfred Mueck and John Stevenson presently consult, and in the past have consulted, with manufacturers of products discussed in this article. Richard Farmer has consulted with manufacturers in the past.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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