Estradiol 17β and weaker uterotropic metabolites oxidized on C2, C6, and C16 (“impeded” estrogens) mutually compete for cytoplasmic proteins of uterus, vagina, and breast, which appear implicated in the initial concentration of C18 steroids, activating target tissues. Experimental and human endemiologic evidence suggests that the relative concentrations of estradiol 17β and of estriol, the principal human “impeded” estrogen, sustained chronically in the vicinity of breast tissues may influence the risk of mammary carcinogenesis. Impeded estrogens have not yet been proven to be carcinogenic in any species. Estriol has failed to induce breast tumors in 30 Sprague‐Dawley female rats over 250 days of observation in our experience. Estriol, along with progesterone, is one of the 2 major hormones produced and excreted in pregnancy. It inhibits several of the tissue tropic actions of estradiol 17β, presumably by displacing the latter from receptor proteins of the cytoplasm and nucleus, which has been demonstrated for uterine, vaginal, and mammary tissues. Several investigations by different analytic methods indicate a relative deficiency of estriol production and excretion from adrenocortical and gonadal sources in about one quarter of healthy, nonpregnant Caucasian premenopausal women; two thirds of patients with fibrocystic disease of the breast and with untreated breast cancer may excrete subnormal estriol concentrations. In induced rat mammary cancers, estriol can inhibit estradiol binding to homogenates. The hypothesis is advanced that estriol plays a significant anticarcinogenic role in the human female, accounting in part for the reduced expectancy of mammary cancer in Japanese women, in whom low estriol excretion has not yet been reported, and in women with multiple pregnancies in their early child‐bearing years, or after early castration. Estriol should be an effective form of endocrine therapy for hormone‐dependent breast cancer, since it retains much of its capacity to bind to estrogen receptor proteins in tissues, substituting for estradiol 17β.
