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Levels of Tibolone and Estradiol and their Nonsulfated and Sulfated Metabolites in Serum, Myometrium, and Vagina of Postmenopausal Women Following Treatment for 21 Days With Tibolone, Estradiol, or Estradiol Plus Medroxyprogestrone Acetate

NV Organon, Oss, the Netherlands, herman.verheul{at}organon.com

Leen J. Blok, PhD

Department of Reproduction & Development, Erasmus University Medical Center, Rotterdam, the Netherlands

Curt W. Burger, MD, PhD

Department of Obstetrics & Gynecology (CWB), Erasmus University Medical Center, Rotterdam, the Netherlands

Payman Hanifi-Moghaddam, PhD

Department of Reproduction & Development, Erasmus University Medical Center, Rotterdam, the Netherlands

Helenius J. Kloosterboer, PhD

NV Organon, Oss, the Netherlands

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, E₂ or E₂ + 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 3-hydroxytibolone predominated in serum, whereas the progestagenic/ androgenic 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 ⁴-tibolone. In all groups, E₂ tissue levels were higher than serum levels; the percentage of serum E₁S was >90%. Tibolone did not affect endogenous E₁, E₂, or E₁S levels in serum, but in myometrium and vagina, E₁ levels were significantly higher and E₁S levels tended to be lower than in controls. Serum and tissue levels of endogenous and exogenous E₁, E₂, and E ₁S were markedly increased 20 hours after E₂ or E₂ + MPA; the percentage of E₁S 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 E₂ were high in all groups; absolute E₂ levels in control and tibolone groups were much lower than in the E₂ groups. Tibolone metabolite patterns are different in serum, myometrium, and vagina.

Key Words: Tibolone metabolites • estradiol metabolites • sulfation • tissue distribution • uterus • vagina.

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