Estrogenic Effects of 5-Androstene-3β,17β-Diol at Physiological Concentrations and Its Possible Implication in the Etiology of Breast Cancer*

Abstract

Previously it has been proposed that (1) dehydroepiandrosterone and dehydroepiandrosterone sulfate secreted by the adrenal may be involved in the etiology of human breast cancer, particularly of the postmenopausal type; and (2) the mechanism may involve the blood-borne metabolite 5-androstene- 3β,17β-diol (ADIOL; which is derived from these steroids) acting as an estrogen. We have now further tested this hypothesis by maintaining physiological concentrations of ADIOL in sexually immature female rats by means of pellet implantation, and examining estrogenic responses in uteri. A blood concentration of about 0.8 ng/ml (∼2.7 nM) was reached after 24 h and was subsequently maintained close to this level for the duration of the experiments (up to 120 h). This approximates the concentration found in the blood of Western women. ADIOL concentrations, measured in the cytosolic fraction, were found to be 5- to 10-fold higher in uteri compared to those in nonestrogen target tissues (kidney, muscle, and heart). Uterine wet weights were significantly increased over control values 5, 24, and 72 h after implantation. Depletion of estrogen receptor (ER) in the cytosol at 5 h was accompanied by an increase in ER in the nucleus. At the longer time intervals of 24 and 72 h, receptor in the cytosol was replenished to values in excess of controls. ER in the nucleus was also increased at these time intervals. Protein in uterine cytosol was increased at 5, 24, and 72 h, while DNA was unaltered at the earlier times, but was increased at 72 h. The above effects are typical of classical estrogens when blood concentrations are maintained by pellet implantation. ADIOL should now be classed as an estrogen, and its presence in comparatively high concentrations in the blood of Western women, particularly where the opposing action of progesterone is absent, may be implicated in the etiology of breast cancer.