Biological and endocrinological 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 several meta-analyses over a five-decade period, there is no consensus about the answer. At present, the majority of ivestigators agree that short-term or medium-term therapy (less than 10 years) poses no measurable risk; some, but not all, investigators feel that there is a modest risk with long-term therapy (more than 15 years). Even this semi-consensus is clouded by the startling and clear-cut-finding of the largest ever epidemiological study, the Nurses Surveillance Study, that a small increase in risk with estrogen therapy occurred only in women who also ingested alcohol, itself a known risk factor for breast cancer; wpmen who did not ingest alchol were at no increased risk. Because virtuallu none of the other epidemiological studies has contolled for alcohol 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 Lacassagne et al. on the induction of breast cancer in mice by estrogens were 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 induced; 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 administraion. Because (in animal terms) humans are a low-incidence goup, it is to be expected that any increase in breast cancer incidence with estrogen therpay would be modest and would require prolonged administration. This is approximately what is actually ovserved, but several factors may confound the picture: (1) the role of alcohol ingestion may ge important; (2) genetic variability in the capacity to 16α-hydroxylate may be important, because increased 16α-hydroxylation has been found to be a risk factor for breast cancer; (3) the specific estrogen administered may be important, because different estrogens vary in their ability to be 16α-hydroxylated; (4) the presence of atypical duct-cell hyperplasia may increase the risk; (5) a personal history of breat cancer or of premenopausal breast cancer in a mother or sister may increase the risk. In view of the overwhelming benefits of menopausal estrogen replacement therapy (diminished coronary disease, diminished osteoporosis, and prolongation of life-span, as well as relief of menopausal symptoms), it is concluded that all postmenopausal women should receive it unless they themselves have had breast cancer or a mother or sister has had premenopausal breast cancer.