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c h a p t e r f i v e From Hero to Villain Estrogen and Endometrial Cancer Estrogen turned from hero to villain upon the publication of two studies that presented conclusive evidence that estrogen users were more likely to get endometrial cancer (cancer of the uterine lining) as compared to nonusers. The appearance of these two reports in the prestigious New England Journal of Medicine ensured that they would be taken seriously by the medical profession. The editors of the Journal underscored the gravity of the findings by commissioning two editorials on the subject of estrogen and cancer, published along with the research articles in the same issue on 4 December 1975. The first study compared two groups of older women in the state of Washington , 317 diagnosed with endometrial cancer and 317 diagnosed with other gynecological cancers (such as ovarian or cervical cancer).∞ The investigators found that 152 of those with endometrial cancer, as opposed to 54 of the controls, had used estrogen, which translated to a 4.5 times greater risk for women exposed to prescription estrogen. Upon further refinement of the data, they found that the risk grew with increased duration of estrogen use. The study did not take into account dosages, specific estrogens, or treatment schedules, but it did look at the potentially confounding factors of hypertension and obesity. Surprisingly, women without the predisposing risk factors of hypertension or obesity who took estrogen had the highest likelihood of developing endometrial cancer. The authors stopped short of announcing that estrogen caused the disease; in the circumspect style that had come to characterize scientific prose, they noted a pattern of increasing numbers of endometrial cancers in women without typical physiological predisposition to the disease ‘‘coincident with’’ a pattern of increasing use of prescription estrogen, and they proposed that ‘‘an apparently significant relative risk’’ of developing this type of cancer was ‘‘associated with estrogen administration.’’≤ The other study matched endometrial cancer patients with control subjects 94 The Estrogen Elixir (without cancer) and found that a greater proportion of the cancer group had used conjugated estrogens (e.g., Premarin).≥ Furthermore, it appeared that the longer a woman took conjugated estrogens, the greater her risk of endometrial cancer (up to fourteen times for women who took the hormones for more than seven years). One of the authors, Harry K. Ziel, an obstetrician-gynecologist at the Kaiser Permanente Medical Center in Los Angeles, initiated the study because he had noticed that a significant number of his patients with endometrial cancer took this form of estrogen.∂ Investigators matched the record of each cancer patient with the records of two controls, based on age, area of residence, and duration of membership in the Kaiser Foundation Health Plan. They also controlled for age at menopause, excessive weight, and parity (number of children). When they looked at three other drugs (Valium, thyroid hormone, and reserpine—used to treat high blood pressure ) taken by patients and controls, the risk ratios of developing endometrial cancer associated with these medications were each less than 1.0, compared to the 7.6 risk ratio for estrogen. By working with preexisting medical records and a stringent set of requirements, the researchers claimed to have avoided both information bias (in ascertaining use of estrogen) and selection bias (in choosing patients and controls). They concluded that ‘‘the evidence for a connection between the use of conjugated estrogens and the development of endometrial cancer seems rather persuasive,’’ but they cautioned that further study was needed to confirm their results in other groups of women and for other types of estrogen before any policy decisions could be made.∑ The accompanying editorials attempted to locate the estrogen-cancer studies in a broader frame of reference. The first one acknowledged the legitimacy of the epidemiological findings, especially in light of anecdotal evidence in humans and animal studies that demonstrated estrogen-induced cancer. However, the author played down the five-to-fourteen-fold increase in the risk of endometrial cancer for estrogen users by comparing it to the three-to-nine-fold increase in risk of endometrial cancer for obese women and the seventeen-fold increase in risk of dying from lung cancer for pack-a-day cigarette smokers. ‘‘Although such comparisons may seem specious and falsely comforting,’’ he wrote, ‘‘they are testimony to the hypothesis that one might take estrogens for valid medical indications with a potential risk of cancer comparable to the self-abuse of overeating or...

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