Progestagenic Effects of Tibolone on Human Endometrial Cancer Cells

Author:

Blok L. J.1,De Ruiter P. E.1,Kühne E. C. M.1,Hanekamp E. E.1,Grootegoed J. A.1,Smid-Koopman E.2,Gielen S. C. J. P.2,De Gooyer M. E.3,Kloosterboer H. J.3,Burger C. W.2

Affiliation:

1. Departments of Reproduction and Development (L.J.B., P.E.D.R., E.C.M.K., E.E.H., J.A.G.), 3000 CA Rotterdam, The Netherlands;

2. Gynecology and Obstetrics (E.S.-K., S.C.J.P.G., C.W.B.), Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands;

3. Department of Pharmacology, Research and Development Laboratories, N.V. Organon (M.E.D.G., H.J.K.), 5340 BH Oss, The Netherlands

Abstract

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.

Publisher

The Endocrine Society

Subject

Biochemistry, medical,Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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