Tibolone inhibits leukocyte adhesion molecule expression in human endothelial cells

Tibolone is a synthetic steroid with mixed estrogenic and progestogenic/and rogenic activity used for post-menopausal hormone replacement therapy. Sinc e its cardiovascular effects are still not clear, and no data have been pub lished on possible direct actions on the vessel wall, we studied the effect s of tibolone and its metabolites on lipopolysaccharide (LPS)-induced expre ssion of leukocyte adhesion molecules on human endothelial cells. Tibolone and its two estrogenic 3 alpha-OH and 3 beta-OH metabolites, but not the pr ogestogenic/androgenic Delta(4)-isomer, concentration-dependently decreased LPS-induced vascular cell adhesion molecule-1 protein expression. This eff ect was estrogen receptor dependent, since it was completely blocked by the pure estrogen receptor antagonist ICI 182780. Furthermore, only tibolone, the 3 alpha-OH and the 3 beta-OH metabolites decreased endothelial expressi on of E-selectin, while none of the compounds changed the levels of interce llular adhesion molecule-1. These findings were associated with parallel ch anges in mRNA levels for the three adhesion molecules. Our data show that t ibolone and its estrogenic metabolites exert direct actions on the vascular wall, decreasing the expression of endothelial-leukocyte adhesion molecule s, thus producing potentially important direct anti-atherogenic effects. (C ) 2000 Elsevier Science Ireland Ltd. All rights reserved.