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

Abstract

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: Delta 4-tibolone>3 beta-OH-tibolone congruent with 3 alpha-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.

Estrogenic regulation of skeletal muscle proteome: a study of premenopausal women and postmenopausal MZ cotwins discordant for hormonal therapy

“…The clinical and gynecological characteristics are summarized in Table . Among the HRT using twin sisters, three used HRT medication which contained only estradiol and three a medication which included estradiol and progestogen forming the E 2 ‐HRT group, while another three used tibolone‐containing HRT (Tib‐HRT group), known to possess estrogenic, progestogenic, and androgenic functions (Dubey et al ., ; Hanifi‐Moghaddam et al ., ). As estradiol‐only HRT and estradiol plus progestogen HRT are based on the utilization of estradiol as a main functional hormone, and there were no phenotypic differences between the users (data not shown), these two groups were combined to increase the statistical power of the proteomic analysis.…”

Tibolone Activates Nitric Oxide Synthesis in Human Endothelial Cells

“…Recent data also indicate that tibolone and its estrogenic metabolites inhibit vascular smooth muscle cell growth via regulation of MAPKs (11), therefore reinforcing the concept that a significant part of the cardiovascular actions of this drug is exerted at the vascular level. Indeed, tibolone induces relaxation in selected vascular districts (12)(13)(14)(15), and tibolone administration is associated with increased plasma levels of nitric oxide (NO) metabolites, suggesting a regulation of the synthesis of this potent vasodilatory molecule (16).…”

Influencia de la tibolona en la función sexual y seguridad cardiovascular en la mujer posmenopáusica

“…La tibolona y sus metabolitos estrogénicos inhiben el crecimiento de las células del músculo liso vascular, mediante la regulación de las MAPKs (Mitogen-activated protein kinase) (62), reforzando el concepto de que una parte significativa de las acciones cardiovasculares de este fármaco se ejerce a nivel vascular; e induce vasorelajación al producir aumento de los niveles plasmáticos de metabolitos del óxido nítrico (ON), sugiriendo una regulación de la síntesis de esta potente molécula vasodilatadora (52,63).…”