title: Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: part 3. The Women's Health Initiative: unopposed estrogen.
abstract: 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.
authors.affiliation: Department of Epidemiology, University of Cape Town, Cape Town, South Africa. samshap@mweb.co.za
authors.forename: Samuel
authors.initials: S
authors.lastname: Shapiro
authors.forename: Richard D T
authors.initials: RD
authors.lastname: Farmer
authors.forename: Alfred O
authors.initials: AO
authors.lastname: Mueck
authors.forename: Helen
authors.initials: H
authors.lastname: Seaman
authors.forename: John C
authors.initials: JC
authors.lastname: Stevenson
mesh_terms: D015982:Bias; D001943:Breast Neoplasms / Q000139:chemically induced*; D015984:Causality; D015986:Confounding Factors, Epidemiologic; D004338:Drug Combinations; D015340:Epidemiologic Research Design; D016021:Epidemiologic Studies; D004967:Estrogens / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D020249:Hormone Replacement Therapy / Q000009:adverse effects*; D006801:Humans; D011372:Progestins / Q000009:adverse effects* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment
chemical_list: D004338:Drug Combinations; D004967:Estrogens; D011372:Progestins