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Progestagenic Effects of Tibolone on Human Endometrial Cancer Cells

Departments of Reproduction and Development (L.J.B., P.E.D.R., E.C.M.K., E.E.H., J.A.G.) and Gynecology and Obstetrics (E.S.-K., S.C.J.P.G., C.W.B.), Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands; and Department of Pharmacology, Research and Development Laboratories, N.V. Organon (M.E.D.G., H.J.K.), 5340 BH Oss, The Netherlands

Address all correspondence and requests for reprints to: Leen J. Blok, Ph.D., Department of Reproduction and Development, Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: Blok{at}endov.fgg.eur.nl.

Tibolone, a synthetic steroid acting in a tissue-specific manner and used in hormone replacement therapy, is converted into three active metabolites: a ⁴ isomer (exerting progestagenic and androgenic effects) and two hydroxy metabolites, 3-hydroxytibolone (3-OH-tibolone) and 3ß-OH-tibolone (exerting estrogenic effects). In the present study an endometrial carcinoma cell line (Ishikawa PRAB-36) was used to investigate the progestagenic properties of tibolone and its metabolites. This cell line contains progesterone receptors A and B, but lacks estrogen and androgen receptors.

When tibolone was added to the cells, complete conversion into the progestagenic/androgenic ⁴ isomer was observed within 6 d. Furthermore, when cells were cultured with tibolone or when the ⁴ isomer or the established progestagen medroxyprogesterone acetate was added to the medium, marked inhibition of growth was observed. Interestingly, 3ß-OH-tibolone also induces some inhibition of growth. These growth inhibitions were not observed in progesterone receptor-negative parental Ishikawa cells, and progestagen-induced growth inhibition of PRAB-36 cells could readily be reversed using the antiprogestagen Org-31489. Upon measuring the expression of two progesterone-regulated genes (fibronectin and IGF-binding protein-3), tibolone, the ⁴ isomer and medroxyprogesterone acetate showed similar gene expression regulation.

These results indicate that tibolone, the ⁴ metabolite, and to some extent 3ß-OH-tibolone exert progestagenic effects. Tibolone and most likely 3ß-OH-tibolone are converted into the ⁴ metabolite.

This work was supported by grants from The Netherlands Organization for Scientific Research (NWO 903-46-169 and 903-46-182) and Erasmus Medical Center (Beleidsruimte Subsidie).

Abbreviations: DCC-FBS, Dextran-charcoal-treated fetal bovine serum; FBS, fetal bovine serum; hPRA, human progesterone receptor-A; 3ßHSD, 3-hydroxysteroid dehydrogenase; IGFBP-3, IGF-binding protein-3; MPA, medroxyprogesterone acetate; 3-OH-tibolone, 3-hydroxytibolone.

¹ Smid-Koopman, E., E. C. M. Kühne, E. E. Hanekamp, S. C. J. P. Gielen, P. E. De Ruiter, J. A. Grootegoed, T. J. M. Helmerhorst, C. W. Burger, A. O. Brinkmann, F. J. Huikeshoven, and L. J. Blok, submitted for publication.

² Hanekamp, E. E., S. C. J. P. Gielen, E. Smid-Koopman, E. C. M. Kühne, P. E. De Ruiter, S. Chadha-Ajwani, A. O. Brinkmann, J. A. Grootegoed, C. W. Burger, F. J. Huikeshoven, and L. J. Blok, submitted for publication.

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