This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Blok, L. J. Articles by Burger, C. W. Search for Related Content PubMed PubMed Citation Articles by Blok, L. J. Articles by Burger, C. W. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB PROGESTERONE

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.

This article has been cited by other articles:

				T. L. McCarthy, R. B. Hochberg, D. C. Labaree, and M. Centrella 3-Ketosteroid Reductase Activity and Expression by Fetal Rat Osteoblasts J. Biol. Chem., November 23, 2007; 282(47): 34003 - 34012. [Abstract] [Full Text] [PDF]

				W. Zhang, J. Mazella, H. J. Kloosterboer, and L. Tseng Progestagenic Effects of Tibolone are Target Gene--Specific In Human Endometrial Cells Reproductive Sciences, September 1, 2006; 13(6): 459 - 465. [Abstract] [PDF]

				S. Steckelbroeck, B. Oyesanmi, Y. Jin, S.-H. Lee, H. J. Kloosterboer, and T. M. Penning Tibolone Metabolism in Human Liver Is Catalyzed by 3{alpha}/3beta-Hydroxysteroid Dehydrogenase Activities of the Four Isoforms of the Aldo-Keto Reductase (AKR)1C Subfamily J. Pharmacol. Exp. Ther., March 1, 2006; 316(3): 1300 - 1309. [Abstract] [Full Text] [PDF]

				S. C.J.P. Gielen, C. W. Burger, L. C.M. Kuhne, P. Hanifi-Moghaddam, and L. J. Blok Analysis off Estrogen Agonism and Antagonism of Tamoxifen, Raloxifene, and ICI182780 in Endometrial Cancer Cells: A Putative Role for the Epidermal Growth Factor Receptor Ligand Amphiregulin Reproductive Sciences, October 1, 2005; 12(7): e55 - e66. [Abstract] [PDF]

				J. K Oosterhoff, J A. Grootegoed, and L. J Blok Expression profiling of androgen-dependent and -independent LNCaP cells: EGF versus androgen signalling Endocr. Relat. Cancer, March 1, 2005; 12(1): 135 - 148. [Abstract] [Full Text] [PDF]

				P. Hanifi-Moghaddam, S. C. J. P. Gielen, H. J. Kloosterboer, M. E. De Gooyer, A. M. Sijbers, A. J. van Gool, M. Smid, M. Moorhouse, F. H. van Wijk, C. W. Burger, et al. Molecular Portrait of the Progestagenic and Estrogenic Actions of Tibolone: Behavior of Cellular Networks in Response to Tibolone J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 973 - 983. [Abstract] [Full Text] [PDF]

				S. C.J.P. Gielen, E. E. Hanekamp, L. J. Blok, F. J. Huikeshoven, and C. W. Burger Steroid-Modulated Proliferation of Human Endometrial Carcinoma Cell Lines: Any Role for Insulin-like Growth Factor Signaling? Reproductive Sciences, January 1, 2005; 12(1): 58 - 64. [Abstract] [PDF]

				E. E Hanekamp, L. M Kuhne, J A. Grootegoed, C. W Burger, and L. J Blok Progesterone receptor A and B expression and progestagen treatment in growth and spread of endometrial cancer cells in nude mice Endocr. Relat. Cancer, December 1, 2004; 11(4): 831 - 841. [Abstract] [Full Text] [PDF]

				S. Steckelbroeck, Y. Jin, B. Oyesanmi, H. J. Kloosterboer, and T. M. Penning Tibolone Is Metabolized by the 3{alpha}/3{beta}-Hydroxysteroid Dehydrogenase Activities of the Four Human Isozymes of the Aldo-Keto Reductase 1C Subfamily: Inversion of Stereospecificity with a {Delta}5(10)-3-Ketosteroid Mol. Pharmacol., December 1, 2004; 66(6): 1702 - 1711. [Abstract] [Full Text] [PDF]

				R. K. Dubey, D. G. Gillespie, M. Grogli, H. J. Kloosterboer, and B. Imthurn Tibolone and Its Metabolites Induce Antimitogenesis in Human Coronary Artery Smooth Muscle Cells: Role of Estrogen, Progesterone, and Androgen Receptors J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 852 - 859. [Abstract] [Full Text] [PDF]