Tibolone and its metabolites: Pharmacology, tissue specificity and effects in animal models of tumors

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Abstract
Tibolone is a steroid with weak estrogenic, progestogenic and androgenic properties that can be used as an alternative to conventional hormone replacement therapy in postmenopausal women. Tibolone is rapidly metabolized to three active metabolites: a 3α.-OH and a 3β-OH metabolite and a Δ4-isomer, which have different steroid binding affinities and different biological activities. A series of experiments was conducted to study the effects of tibolone and its metabolites on tissue selectivity and in in vitro and in vivo tumor models. In vitro, the Δ4-isomer was found to bind to and to activate progesterone and androgen receptors whereas the 3α-OH and the 3β-OH metabolites bound to and activated estrogen receptors only. Tibolone itself displays only minor affinity and activity for all the various receptors. In vivo, the Δ4-isomer had a higher estrogenic activity than tibolone, due to its conversion to the estrogenic metabolites. Tissue selectivity of tibolone was found in bone where the estrogenic activity restores bone mass and bone quality in ovariectomized rats and the lack of estrogenic activity prevents endometrial proliferation. Tibolone did not stimulate cell proliferation in tumor cell lines and reduced the tumor load in DMBA-induced mammary tumors both in the therapeutic and prophylactic models. Tibolone and each of the three metabolites were shown to significantly reduce the mean tumor load after 10 weeks of treatment. These results show that metabolites may contribute to the final effect of tibolone in In vivo experiments and that metabolism plays a crucial role in the tissue selective effects of tibolone. The tissue-selective action of tibolone may be caused by differences in metabolism in various tissues in combination with the presence of receptor types and their density.