Tibolone, a synthetic steroid acting in a tissue-specific manner and used in hormone replacement therapy, is converted into three active metabolites: a Delta(4) isomer (exerting progestogenic and androgenic effects) and two hydroxy metabolites, 3 alpha-hydroxytibolone (3 alpha-OH-tibolone) and 3beta-OH-tibolone (exerting estrogenic effects). In the present study an endometrial carcinoma cell line (Ishikawa PRAB-36) was used to investigate the progestogenic 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 progestogenic/androgenic Delta(4) isomer was observed within 6 d. Furthermore, when cells were cultured with tibolone or when the Delta(4) isomer or the established progestagen medroxyprogesterone acetate was added to the medium, marked inhibition of growth was observed. Interestingly, 3 beta-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 Delta(4) isomer and medroxyprogesterone acetate showed similar gene expression regulation. These results indicate that tibolone, the Delta(4) metabolite, and to some extent 3 beta-OH-tibolone exert progestogenic effects. Tibolone and most likely 3 beta-OH-tibolone are converted into the Delta(4) metabolite.

Cell Division/drug effects, Endometrial Neoplasms/chemistry/*metabolism/pathology, Female, Fibronectins/genetics, Gene Expression Regulation/drug effects, Humans, Insulin-Like Growth Factor Binding Protein 3/genetics, Medroxyprogesterone 17-Acetate/pharmacology, Norpregnenes/metabolism/*pharmacology, Progesterone/pharmacology, Progestins/antagonists & inhibitors/*metabolism, Receptors, Progesterone/analysis, Research Support, Non-U.S. Gov't, Tumor Cells, Cultured
Journal of Clinical Endocrinology and Metabolism
Erasmus MC: University Medical Center Rotterdam

Blok, L.J, de Ruiter, P.E, Kuhne, E.C, Hanekamp, E.E, Grootegoed, J.A, Smid-Koopman, E, … Burger, C.W. (2003). Progestogenic effects of tibolone on human endometrial cancer cells. Journal of Clinical Endocrinology and Metabolism. Retrieved from http://hdl.handle.net/1765/10130