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

Abstract

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. E₁ (estrone), E₂ (estradiol), E₁S (estrone-sulfate), tibolone—its nonsulfated, monosulfated, and disulfated 3-hydroxymetabolites—and Δ 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 E₁, E ₂, and E₁S levels were unchanged with placebo, whereas tibolone significantly increased E₁S and the E₁S/(E₁ + E₂) ratio. In tumors, E₁ and E₂ 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 3α- and 3β-hydroxytibolone, progestagenic/androgenic Δ ⁴-tibolone, and monosulfate metabolites were low. Serum 3αS,17βS-tibolone and 3 βS,17βS-tibolone levels were 250 and 52 ng/mL, respectively. Tumor levels of 3α- and 3β-hydroxytibolone and Δ 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.