Receptor profiling and endocrine interactions of tibolone

• Published in: Steroids 2003, Vol.68 (1), p.21-30
• Main Authors: de Gooyer, Marcel E, Deckers, Godefrides H, Schoonen, Willem G.E.J, Verheul, Herman A.M, Kloosterboer, Helenius J
• Format: Article
• Language: English
• Subjects: Androgen receptor; Animals; Biological and medical sciences; Cell receptors; Cell structures and functions; Dose-Response Relationship, Drug; Endocrine System - drug effects; Endometrium - drug effects; Estrogen receptor; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptor Modulators - metabolism; Estrogen Receptor Modulators - pharmacology; Estrogens - metabolism; Estrogens - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Hormone receptors. Growth factor receptors. Cytokine receptors. Prostaglandin receptors; Humans; Molecular and cellular biology; Norpregnenes - metabolism; Norpregnenes - pharmacology; Progesterone receptor; Progestins - metabolism; Progestins - pharmacology; Rabbits; Rats; Receptors, Estrogen - agonists; Receptors, Estrogen - metabolism; Receptors, Progesterone - agonists; Receptors, Progesterone - metabolism; Receptors, Steroid - drug effects; Receptors, Steroid - metabolism; Steroid; Structure-Activity Relationship; Tibolone; Tissue-specific effects; Tumor Cells, Cultured
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/S0039-128X(02)00112-5

The receptor profiles and in vivo activity of tibolone, and its primary metabolites, Δ 4-isomer, and 3α- and 3β-hydroxytibolone, were studied and compared to those of structurally related compounds. The Δ 4-isomer was the strongest binder and activator of the progesterone receptor (PR); tibolone was 10 times weaker in binding and half as potent in transactivation of PR; 3α- and 3β-hydroxytibolone did not bind or activate PR. In rabbits oral tibolone produced a minor progestagenic effect in the endometrium, whereas co-administration of tibolone and the anti-estrogen ICI 164,384 unmasked tibolone’s progestagenic effect. 3-Hydroxytibolones were the strongest binders and activators of the estrogen receptors (ERs), with greater affinity for ERα than for ERβ. Tibolone showed weaker binding and activation of both ERs and the Δ 4-isomer has a binding and activation activity of less than 0.1% of E2 for ERα or ERβ. Tamoxifen and 4-hydroxytamoxifen showed partial ERα agonistic effects with a maximal response of 12% and raloxifene of 3–5%. Oral administration of 1 mg tibolone to ovariectomized rats induced an estrogenic effect on vaginal epithelium. The Δ 4-isomer was a stronger binder and activator of the androgen receptor (AR) than tibolone; both 3-hydroxytibolones did not bind or activate AR. Introducing a 7α-methyl group decreased progestagenic and increased androgenic activity. We conclude that the progestagenic and androgenic activities of tibolone are mediated by the Δ 4-isomer, and the estrogenic activity, by the 3-hydroxytibolones. The estrogenic activity of the 3-hydroxytibolones masked the progestagenic activity of tibolone in rabbit endometrium. Full estrogenic response was observed in rat vaginal tissue after oral administration of tibolone.