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.