Background: Tibolone (Org-OD14) is the active substance of Livial (R), a synthetic steroid with the structure 7 alpha,17 alpha- 17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one, possessing weak tissue-specific estrogenic, progestogenic, and androgenic properties, used to treat menopausal complaints. After oral administration, tibolone is extensively metabolized into the 3 alpha-(Org-4904) and 3 beta-(Org-30126) hydroxy derivatives with estrogenic properties, its 4-ene (Org-OM38) isomer with progestogenic/androgenic activities, and the 3 alpha-sulfate (Org-34322) derivative, a major biologically inactive circulating form. We compared the dose response of tibolone and its metabolites on estrone sulfatase activity [conversion of estrone sulfate (E1S) to estrone (E-1)] in normal and cancerous human breast tissues. Materials and methods: Tissue minces were incubated with physiological concentrations of [H-3]-E1S (5x10(-9) M) alone or in the presence of tibolone and its metabolites (concentration range: 5x10(-7) to 5x10(-5)M) for 4h. Tritiated E-1, estradiol (E-2), and E1S were separated and evaluated quantitatively by thinlayer chromatography. Results: The sulfatase activity was significantly higher in cancerous breast but strongly inhibited by tibolone and the different metabolites, whereas 3 alpha- and 3 beta-hydroxy derivatives were the most potent inhibitors. Conclusion: This very significant inhibitory effect of tibolone and its principal metabolites on the enzyme involved in E-2 biosynthesis in the human breast provides interesting perspectives to study the biological responses of these compounds in trials with breast cancer patients.
