ABNORMAL PRODUCTION OF ANDROGENS IN WOMEN WITH BREAST-CANCER

Two long and broad streams of medical literature, from the 1950's to d ate, have established the existence of two unrelated abnormalities of androgen production in women with breast cancer. One is the geneticall y determined presence of subnormal production of adrenal androgens (i. e. DHEA and DHEAS) in women with premenopausal breast cancer and their sisters, who are at increased risk for breast cancer. The other is ex cessive production of testosterone, of ovarian origin, in subsets of w omen with either premenopausal or postmenopausal breast cancer and wom en with atypical breast-duct hyperplasia, who are at increased risk fo r breast cancer; along with the hypertestosteronism, there is frequent ly chronic anovulation in the premenopausal patients. The combination of ovarian hypertestosteronism and chronic anovulation is characterist ic of the polycystic ovary syndrome and is also frequently seen in wom en with abdominal (''android'') obesity; both PCOS and abdominal obesi ty me known to be characterized by high risk for postmenopausal cancer . The elevated testosterone levels and the increased levels of insulin , IGF-I, and IGF-II that are seen in PCOS and abdominal obesity could favor the development of breast cancer in several ways, all of which h ave been demonstrated experimentally: binding of testosterone to cance r cells bearing testosterone receptors, with direct stimulation; intra tissular aromatization of testosterone to estradiol, with stimulation of estrogen-sensitive cells; stimulation of the production of epitheli al growth factor (EGF) by testosterone, with direct mitogenic effect o f EGF on cancer cells; stimulation of aromatase by insulin and IGF-I; direct mitogenic stimulation of cancer cells by insulin, IGF-I, and IG F-II; and stimulation by IGF-I and IGF-II of the intratissular reducti on of estrone to estradiol. Since PCOS is probably largely genetically determined, and abdominal obesity may also be, the hypertestosteronis m of these conditions may represent a second genetically determined ho rmonal risk factor for breast cancer.