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A Critique of the Statistical Evidence Associating Estrogens with Endometrial Cancer¹

Departments of Medicine and Epidemiology, Yale University School of Medicine, New Haven, Connecticut 06510

The epidemiological problem of detection bias occurs when the evidence needed to diagnose a particular disease is sought more intensively in the group of people exposed to a particular agent than in the comparative group, who did not receive the agent. The bias can occur during community surveillance before hospitalization, during the ordering of diagnostic tests for hospitalized patients, or during the interpretation of the tests.

In postmenopausal women with endometrial cancer, detection bias is produced because of the dilation and curettage (or other diagnostic tests) ordered when bleeding occurs as a side effect of estrogen therapy. In estrogen takers, these diagnostic explorations allow the detection of endometrial cancers that might otherwise be silent and undetected in women who do not take estrogen.

Since this bias occurs before patients are hospitalized, its removal requires special sampling and analytic techniques that have not been used in most epidemiological case-control studies where high risk ratios were found for the association between estrogens and endometrial cancer. When cases and controls have been selected with the use of a diagnostic procedure as the sampling frame, the odds ratios are much closer to 1; with appropriate stratification for the diagnostic stimulus of bleeding, the odds ratios approximate 1.

Other sources of bias for the estrogen-endometrial cancer association can be the "protopathic" prescription of estrogen for women with unrecognized endometrial cancer, the absence of "double-blind" interviewing techniques, and arbitrary definitions of "exposure to estrogens."

The difficulties in interpreting the relationship of estrogens and endometrial cancer indicate the need for development of rigorous scientific standards in the epidemiological methods used for case-control research.

¹ Presented at the John E. Fogarty International Center Conference on Hormones and Cancer, March 29 to 31, 1978, Bethesda, Md.