Metabolism of tibolone and its metabolites in uterine and vaginal tissue of rat and human origin

Abstract In postmenopausal women, tibolone shows clear tissue differences in its stimulatory effects on the vagina and uterus. In rats, however, it has stimulatory effects on both tissues, with a different, more estrogenic, effect on the uterus than in humans. This may be due to differences in local metabolism. Therefore, in the present study, the metabolism of tibolone was analyzed in incubations of uterine and vaginal tissue from postmenopausal women and ovariectomized rats using radiolabeled tibolone in order to understand the tissue- and species-specific metabolism. In the rat, tibolone (50 nM) was mainly 3α-reduced to the estrogenic 3α-OH-tibolone in the uterus and vagina. The 3β-OH tibolone can be isomerized to 3α-OH-tibolone with tibolone as intermediate. In contrast, in the same tissues from postmenopausal women, the progestagenic Δ 4 -isomer and estrogenic 3β-OH-tibolone were the major metabolites of tibolone. The formation of the Δ 4 -isomer was higher in uterine tissue. The 3β-hydroxysteroid dehydrogenase (HSD) inhibitor epostane had no effect on tibolone metabolism in human uterine and vaginal tissue microsomes and HEK293 cells expressing the human 3β-HSD types 1 and 2 isoforms did not metabolize tibolone. Moreover, the 3β-reduction of tibolone to 3β-OH-tibolone was NADPH dependent, while the isomerization of tibolone to the Δ 4 -isomer did not require a cofactor. It was therefore concluded that human 3β-HSD isoforms are not involved in the metabolism of tibolone, and that the 3β-reduction and the Δ 5–10 to Δ 4 isomerization may be catalyzed by different enzymes. In conclusion, we showed that, in hormone therapy target tissues of the rat as compared with the human, different metabolic pathways for tibolone exist and therefore result in metabolites with different pharmacological properties. The rat is therefore a poor model to predict the effects of tibolone on the uterus in postmenopausal women.