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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 3. The Women's Health Initiative: unopposed estrogen


Background Studies from the Women's Health Initiative have reported an increased risk of breast cancer in users of estrogen plus progestogen. Among users of estrogen alone an increased risk was not observed.

Objective To evaluate the evidence for unopposed estrogen.

Methods In a related article (Part 2) the authors apply generally accepted causal criteria to the findings for estrogen plus progestogen. Here (Part 3) the authors apply the criteria to the findings for unopposed estrogen, as reported in a clinical trial, and in combined data from the trial and an observational study.

Results In the clinical trial, after 7.1 years of follow-up the relative risk (RR) of invasive breast cancer for women assigned to estrogen was 0.77 in an ‘intention-to-treat’ analysis (95% CI 0.59–1.01) and 0.67 (95% CI 0.47–0.97) in an ‘as treated’ analysis; after 10.7 years the risk reduction persisted. Time order was correctly specified; detection bias was minimal; in the ‘as treated’ analysis confounding was unlikely; duration-response and internal consistency could be evaluated only to a limited extent because of scanty data; the findings were discordant with increased risks observed in the Collaborative Reanalysis and the Million Women Study; biological plausibility could not be assessed.

In the combined analysis, among women who had previously used estrogen soon after the menopause there was no clear evidence of either a reduction or an increase in the risk of breast cancer among women assigned to estrogen during the trial, or among women who were using estrogen in the observational study when follow-up commenced. The combined analysis did not satisfy the criteria of time order, bias, confounding, statistical stability and strength of association, duration-response, and internal consistency; biological plausibility could not be assessed.

Conclusions The evidence from the clinical trial suggests that unopposed estrogen does not increase the risk of breast cancer, and may even reduce it. The latter possibility, however, is based on statistically borderline evidence.

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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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