DOES POSTMENOPAUSAL ESTROGEN ADMINISTRATION INCREASE THE RISK OF BREAST-CANCER - CONTRIBUTIONS OF ANIMAL, BIOCHEMICAL, AND CLINICAL INVESTIGATIVE STUDIES TO A RESOLUTION OF THE CONTROVERSY

Despite nearly six decades of epidemiological studies, meta-analyses, and reviews, there is still considerable controversy in the literature about the question, does postmenopausal estrogen administration incre ase the risk of breast cancer? In an effort to resolve the controversy , a number of animal, biochemical, and clinical investigative studies in this field have been reviewed. The following summary formulation is proposed: 1. Administration of estrogen is inherently capable of prom oting the growth of breast cancer, and therefore of increasing the inc idence of clinical breast cancer. 2. Human response to estrogen is lik e that of the low-cancer-incidence strains of mice studied by Lacassag ne, in that large doses and prolonged administration are required to i nduce clinical breast cancer. 3. The blood levels of estradiol produce d by the usual doses of postmenopausal estrogen are relatively low, eq uivalent to those of the follicular phase of the menstrual cycle. Thes e levels may be near the threshold for producing breast-cancer-promoti ng effects; therefore, the tumor response will vary greatly in differe nt populations, depending on genetic susceptibility factors: a. The pr evalence of a family history of premenopausal breast cancer in a first -degree relative. b. The prevalence of abnormal BRCA1, BRCA2, and p53 genes. c. The prevalence of increased 16 alpha-hydroxylation of estrad iol. d. The prevalence of smokers who are slow acetylators. 4. Consump tion of alcohol (5 grams or more daily) along with the postmenopausal estrogen administration results in elevation of blood estradiol levels to values equivalent to those of the periovulatory peak of the menstr ual cycle, which may be well above the threshold for producing breast- cancer-promoting effects in all women. The risk for cancer will theref ore be uniformly increased in women who use alcohol and take estrogen. 5. Increased risk of breast cancer from postmenopausal estrogen admin istration can be eliminated by taking two synergistic steps: a. Elimin ating alcohol consumption, or at least keeping it well below an averag e of 5 grams daily (equivalent to 2/3 ounce of whiskey or 3 ounces of wine). b. Diminishing the capacity to 16 alpha-hydroxylate estradiol, either through pharmacological agents such as indole-3-carbinol or thr ough increased consumption of cruciferous vegetables.