Tibolone is a tissue-specific compound used for treatment of climacteric complaints and prevention of osteoporosis. It is converted by steroid metabolizing enzymes in the liver and intestine into three active metabolites: delta-4-isomer (exerting progestagenic and androgenic effects) and two hydroxy-metabolites: 3α-OH-tibolone and 3β-OH-tibolone (exerting estrogenic effects). Depending on which metabolites are formed, tibolone acquires the capacity to exert estrogenic, progestogenic and/or androgenic effects. The aim of the current study is to characterize the transcription profile that reflects the cellular response to the progestagenic and estrogenic actions of tibolone separately in vitro in cell lines, and combined in vitro in cell lines and in vivo in patients. For the in vitro experiments, the specific progestagenic properties of tibolone were investigated in the progesterone responsive Ishikawa PRAB-36 cell line and the specific estrogenic properties of tibolone were investigated in the estrogen responsive ECC1 cell line. Gene expression profiling was performed for both cell lines treated with tibolone for 6, 24 and 48h. For the in vivo study, healthy post-menopausal uterine prolapsed women requiring a hysterectomy are currently being recruited and distributed into different treatment groups. Tissues are being collected of all treatment groups for genomic (microarrays) and biochemical analyses (hormone levels). Both cell lines are derived from well-differentiated human endometrial tumors and, cultured in the absence of hormones, display 99.5% similarity in mRNA expression profile. Gene expression profiling of these cell lines, treated by tibolone, revealed 570 regulated genes. Functional classification and genetic network analyses showed that the progestogenic (via PRAB-36 cells) and estrogenic (via ECC1 cells) effects of tibolone act on the same biological/cellular processes and genetic networks, but do so via their own distinct set of regulated genes. The balance between the growth-inhibiting properties of the progestagenic metabolites of tibolone and the growth-inducing properties of the estrogenic metabolites of tibolone have been investigated in an endometrial cancer cell line expressing both PRA/B and ERα/β. In these cells growth induction is now effectively inhibited by tibolones progestagenic properties. In conclusion, using the cell lines it was observed that the balance between the progestagenic properties and the estrogenic properties of tibolone may take effect through a different set of genes acting in the same genetic network.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]