Progestagenic Effects of Tibolone on Human Endometrial Cancer Cells

Tibolone, a synthetic steroid acting in a tissue-specific manner and used in hormone replacement therapy, is converted into three active metabolites: a Δ4 isomer (exerting progestagenic and androgenic effects) and two hydroxy metabolites, 3α-hydroxytibolone (3α-OH-tibolone) and 3β-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 Δ4 isomer was observed within 6 d. Furthermore, when cells were cultured with tibolone or when the Δ4 isomer or the established progestagen medroxyprogesterone acetate was added to the medium, marked inhibition of growth was observed. Interestingly, 3β-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 Δ4 isomer and medroxyprogesterone acetate showed similar gene expression regulation. These results indicate that tibolone, the Δ4 metabolite, and to some extent 3β-OH-tibolone exert progestagenic effects. Tibolone and most likely 3β-OH-tibolone are converted into the Δ4 metabolite.