Estrogens and endometrial cancer: responses to arguments and current status of an epidemiologic controversy

From the Departments of Medicine and Epidemiology, Yale University School of Medicine, New Haven, Connecticut. Dr. Horwitz is a Henry J. Kaiser Family Foundation Scholar in General Internal Medicine. This work was supported in part by a grant from the Andrew Mellon Foundation. Requests for reprints should be addressed to Dr. Ralph I. Horwitz, Yale University School of Medicine, Room IE-61 SHM, P.O. Box 3333, New Haven, Connecticut 06510. Manuscript submitted May 6, 1985, and accepted June 19, 1985. Several years ago, we expressed doubts about the methods and interpretation of case-control studies in which replacement estrogen therapy was regarded as having significantly increased the risk of endometrial cancer in postmenopausal women [l]. We proposed instead that a strong association between estrogen use and endometrial cancer might arise if estrogen therapy led to the detection of symptomless endometrial cancers that might otherwise be undiscovered. The “detection bias” could occur in either of two ways: passive or active. The passive effects could be produced by the increased medical surveillance and diagnostic examinations that would be carried out routinely in women receiving estrogen replacement therapy for menopausal symptoms. Since such women would be visiting a physician regularly, routine screening tests would be performed more often and would often be followed by the diagnostic evaluations that uncover otherwise asymptomatic disease. The active effects of detection bias would arise if bleeding, from the endometrial proliferation produced by estrogen therapy, evokes ad hoc diagnostic evaluations that detect co-existing but otherwise symptomless cancers. The co-existence of proliferative and carcinomatous lesions has seldom been reported, because histopathologists who find a carcinoma in endometrial tissue usually concentrate on describing the cancer, and may not report details of any other lesion that is present. Nevertheless, in a recent special “blind” review of specimens [2], proliferative lesions were noted in 63 percent of women who had used estrogens and who had endometrial cancer. Since the source of bleeding is impossible to determine in such women, they might also have had symptomless cancers that were detected only because of the estrogen therapy. If suitable adjustment or compensation is not made for the passive and active sources of “detection bias,” a falsely increased association with antecedent therapy will be produced in any conventional retrospective study of a “case” group of women with endometrial cancer and a “control” group of women without it. To compensate for this bias, we proposed an alternative methodologic design [I] containing two strategies aimed at “equalizing” the intensity of diagnostic surveillance and disease detection in the case-control comparison. First, the case subjects and control subjects would all emerge from a group of women referred for the same pertinent diagnostic procedure: either dilatation and curettage or hysterectomy. Second, the data would be analyzed according to the clinical reason (with bleeding or without bleeding) for the diagnostic procedure. In a case-control study performed with this method, the over-all odds ratio (2.3; 95 percent confidence interval, 1.3 to