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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

Research and Development Department, NV Organon, Oss, the Netherlands

Lars Löfgren, MD

Department of Surgery, Capio St Göran Hospital, Stockholm, Sweden

Eva von Schoulz, MD, PhD

Department of Oncology, Karolinska University Hospital, Stockholm, Sweden

Bo von Schoultz, MD, PhD

Department of Obstetrics and Gynecology (BvS), Karolinska University Hospital, Stockholm, Sweden

Herman A. M. Verheul, PhD

Research and Development Department, NV Organon, Oss, the Netherlands, herman.verheul{at}organon.com

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 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 3- and 3ß-hydroxytibolone, progestagenic/androgenic ⁴-tibolone, and monosulfate metabolites were low. Serum 3S,17ßS-tibolone and 3 ßS,17ßS-tibolone levels were 250 and 52 ng/mL, respectively. Tumor levels of 3- and 3ß-hydroxytibolone and 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.

Key Words: Tibolonemetabolites • estrogenmetabolites • tissue level • breast • postmenopausal

Reproductive Sciences, Vol. 14, No. 2, 151-159 (2007)
DOI: 10.1177/1933719106298679


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