Estrogen and tibolone metabolite levels in blood and breast tissue of postmenopausal women recently diagnosed with early-stage breast cancer and treated with tibolone or placebo for 14 days

Unlike estrogens plus progestagens, tibolone, a selective tissue estrogenic activity regulator, does not increase breast tenderness and mammographic density. To elucidate this, serum and breast levels of tibolone and estrogenic metabolites are measured. Postmenopausal women (n = 102) with early-stage, ER+ve, primary breast cancer received tibolone or placebo for 14 days in an exploratory, double-blind, randomized trial (STEM carcinoma tissue). Baseline and presurgery sera were collected; tumor tissues were obtained at surgery. E-1 (estrone), E-2 (estradiol), E1S (estrone-sulfate), tibolone-its nonsulfated, monosulfated, and disulfated 3-hydroxymetabolites-and Delta(4)-tibolone were measured by validated gas chromatography and mass spectrometry and liquid chromatography with tandem mass spectrometry assays. More than 12 hours after the final dose, serum E-1, E-2, and E1S levels were unchanged with placebo, whereas tibolone significantly increased E1S and the E1S/(E-1 + E-2) ratio. In tumors, E-1 and E-2 levels were higher than in serum, and E1S levels were lower, with placebo and tibolone administration. The percentage of E1S was about 90% in serum and 16% in tissue. Tibolone did not affect tissue levels of endogenous estrogens. Serum levels of estrogenic 3 alpha- and 3 beta-hydroxytibolone, progestagenic/androgenic Delta(4)-tibolone, and monosulfate metabolites were low. Serum 3 alpha S, 17 beta S-tibolone and 3 beta S, 17 beta S-tibolone levels were 250 and 52 ng/mL, respectively. Tumor levels of 3 alpha- and 3 beta-hydroxytibolone and Delta(4)-tibolone were higher than in serum, but disulfate levels were lower. The percentage of sulfated tibolone metabolites was 99% in serum and 96% in tumor. Serum metabolite Patterns Of estradiol and tibolone are different from those in tissues and are compatible with neutral effects of tibolone on breast Ki67 expression.