17-ethinyl-7-alpha-methyl-19-nortestosterone and estrone-sulfate

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), E(1)S (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 E(1)S levels were unchanged with placebo, whereas tibolone significantly increased E(1)S and the E(1)S/(E(1) + E(2)) ratio. In tumors, E(1) and E(2) levels were higher than in serum, and E(1)S levels were lower, with placebo and tibolone administration. The percentage of E(1)S was about 90% in serum and 16% in tissue. Tibolone did not affect tissue levels of endogenous estrogens. Serum levels of estrogenic 3alpha- and 3beta-hydroxytibolone, progestagenic/androgenic Delta(4)-tibolone, and monosulfate metabolites were low. Serum 3alphaS,17betaS-tibolone and 3 betaS,17betaS-tibolone levels were 250 and 52 ng/mL, respectively. Tumor levels of 3alpha- and 3beta-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.

Topics: Aged; Androstenols; Breast; Breast Neoplasms; Chromatography, Liquid; Double-Blind Method; Estradiol; Estrenes; Estrone; Female; Gas Chromatography-Mass Spectrometry; Humans; Middle Aged; Neoplasm Staging; Norpregnenes; Postmenopause; Selective Estrogen Receptor Modulators; Tandem Mass Spectrometry; Tissue Distribution

Tibolone has estrogenic effects on the vagina but not on the uterus. To explain this, levels of tibolone and estradiol and their metabolites were determined in serum, myometrium, and vagina. Thirty-four postmenopausal women with uterine prolapse received either no treatment, tibolone, E(2) or E(2) + medroxyprogesterone acetate (MPA) for 21 days, or a single dose of tibolone. Twenty +/- 6 hours after administration, >98% of the 3-hydroxytibolone metabolites in serum and tissues were disulfated. Of the unconjugated metabolites, the estrogenic 3alpha-hydroxytibolone predominated in serum, whereas the progestagenic/ androgenic Delta(4)-tibolone predominated in myometrium and vagina. Levels of disulfated metabolites in serum and tissues were higher (3- to 5-fold) after multiple dosing than after a single dose. Tissue:serum ratios were <1, except for Delta(4)-tibolone. In all groups, E(2) tissue levels were higher than serum levels; the percentage of serum E(1)S was >90%. Tibolone did not affect endogenous E(1), E(2), or E(1)S levels in serum, but in myometrium and vagina, E(1) levels were significantly higher and E(1)S levels tended to be lower than in controls. Serum and tissue levels of endogenous and exogenous E(1), E(2), and E(1)S were markedly increased 20 hours after E(2) or E(2) + MPA; the percentage of E(1)S and tissue:serum ratios were not affected. MPA had no effect on the degree of sulfation of E(1). Compared with serum, tissue levels of E(2) were high in all groups; absolute E(2) levels in control and tibolone groups were much lower than in the E(2) groups. Tibolone metabolite patterns are different in serum, myometrium, and vagina.

Topics: Aged; Estradiol; Estrone; Female; Humans; Medroxyprogesterone Acetate; Middle Aged; Myometrium; Norpregnenes; Postmenopause; Selective Estrogen Receptor Modulators; Tissue Distribution; Uterine Prolapse; Vagina