BIOLOGICAL AND ENDOCRINOLOGIC INSIGHTS INTO THE POSSIBLE BREAST-CANCER RISK FROM MENOPAUSAL ESTROGEN REPLACEMENT THERAPY

The question of whether estrogen therapy increases the risk of breast cancer is reviewed. Despite more than 60 epidemiological studies and s everal meta-analyses over a five-decade period, there is no consensus about the answer. At present, the majority of investigators agree that short-term or medium-term therapy (less than 10 years) poses no measu rable risk; some, but not all, investigators feel that there is a mode st risk with long-term therapy (more than 15 years). Even this semi-co nsensus is clouded by the startling and clear-cut finding of the large st ever epidemiological study, the Nurses Surveillance Study, that a s mall increase in risk with estrogen therapy occurred only in women who also ingested alcohol, itself a known risk factor for breast cancer; women who did not ingest alcohol were at no increased risk. Because vi rtually none of the other epidemiological studies has controlled for a lcohol ingestion, the conclusions of all of them are placed in doubt. To try to shed light on this problem, the 60-year-old studies of Lacas sagne et al. on the induction of breast cancer in mice by estrogens we re reviewed. They found that the magnitude and timing of the inducing effect of estrogen depended on the spontaneous breast cancer incidence in the mouse strain studied: in no-incidence strains, no cancer was i nduced; in high-incidence strains, induction was rapid and universal; in low-incidence strains, only a low percentage of animals had cancer induced, and it required prolonged estrogen administration. Because (i n animal terms) humans are a low-incidence group, it is to be expected that any increase in breast cancer incidence with estrogen therapy wo uld be modest and would require prolonged administration. This is appr oximately what is actually observed, but several factors may confound the picture: (1) the role of alcohol ingestion may be important; (2) g enetic variability in the capacity to 16alpha-hydroxylate may be impor tant, because increased 16alpha-hydroxylation has been found to be a r isk factor for breast cancer; (3) the specific estrogen administered m ay be important, because different estrogens vary in their ability to be 16alpha-hydroxylated; (4) the presence of atypical duct-cell hyperp lasia may increase the risk; (5) a personal history of breast cancer o r of premenopausal breast cancer in a mother or sister may increase th e risk. In view of the overwhelming benefits of menopausal estrogen re placement therapy (diminished coronary disease, diminished osteoporosi s, and prolongation of life-span, as well as relief of menopausal symp toms), it is concluded that all postmenopausal women should receive it unless they themselves have had breast cancer or a mother or sister h as had premenopausal breast cancer.