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Tibolone and Its Metabolites Induce Antimitogenesis in Human Coronary Artery Smooth Muscle Cells: Role of Estrogen, Progesterone, and Androgen Receptors

Department of Medicine (R.K.D., D.G.G., B.I.), Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213; Department of Obstetrics and Gynecology (R.K.D., M.G., B.I.), Clinic for Endocrinology, University Hospital Zurich, 8091 Zurich, Switzerland; and Research and Development Laboratories (H.J.K.), NV Organon, 5340 BH Oss, The Netherlands

Address all correspondence and requests for reprints to: Dr. Raghvendra K. Dubey, Clinic for Endocrinology (D217, NORD-1), Department of Obstetrics and Gynecology, University Hospital Zurich, Frauenklinikstrasse 10, 8091 Zurich, Switzerland. E-mail: raghvendra.dubey{at}usz.ch.

Tibolone, a hormone replacement drug, protects postmenopausal women against osteoporosis and climacteric symptoms without inducing adverse effects on the endometrium and breast. Compared with other estrogens, little is known about the cardiovascular effects of tibolone. Because abnormal growth of smooth muscle cells (SMCs) is a prerequisite for coronary artery disease, here we investigated the effects of tibolone on SMC growth.

We examined the effects of tibolone and its metabolites on human arterial SMC growth (DNA synthesis, cellular proliferation, cell migration, collagen synthesis) and MAPK expression. Fetal calf serum-induced SMC growth, phosphorylated MAPK expression, and platelet-derived growth factor-induced SMC-migration were concentration-dependently inhibited by tibolone and its endogenous estrogenic and progestogenic/androgenic metabolites in the following order of potency: 4-tibolone>3ß-OH-tibolone 3-OH-tibolone. The antimitogenic effects of tibolone were partially blocked by ER antagonist (ICI182780), progesterone receptor antagonist (RU486) but not by the androgen receptor antagonist (flutamide); moreover, RU486 was more potent than ICI182780. The antimitogenic effects of tibolone were completely blocked by RU486 plus ICI182780. In addition, the inhibitory effects of equimolar concentrations of the three tibolone metabolites summed up to the inhibitory effects of tibolone.

In conclusion, tibolone inhibits SMC growth and MAPK phosphorylation via both its estrogenic and progestogenic metabolites, and these inhibitory effects involve both progesterone and ERs. Hence, tibolone may induce antivasoocclusive actions and protect women against coronary artery disease.

This work was supported by the Swiss National Science Foundation Grant 32-64040.00 and in part from an educational grant from N.V. Organon (Oss, The Netherlands).

Abbreviations: AR, Androgen receptor; ER, estrogen receptor; FCS, fetal calf serum; HDL, high-density lipoprotein; PDGF, platelet-derived growth factor; PR, progesterone receptor; SMC, smooth muscle cell.

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