title: Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: part 2. The Women's Health Initiative: estrogen plus progestogen.
abstract: 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.
  
  
  CONCLUSIONS
  HRT with estrogen plus progestogen may or may not increase the risk of breast cancer, but the WHI did not establish that it does.
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: D000368:Aged; D001943:Breast Neoplasms / Q000139:chemically induced* / Q000453:epidemiology*; D015984:Causality; D003627:Data Interpretation, Statistical; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D019317:Evidence-Based Medicine; D005260:Female; D006801:Humans; D008875:Middle Aged; D012107:Research Design