Effect of medroxyprogesterone acetate and norethisterone on serum-stimulated and estradiol-inhibited proliferation of human coronary artery smooth muscle cells

Objective: The addition of progestogen to estrogen replacement therapy is t hought to antagonize, at least in part, the beneficial effects of estrogens on the vasculature. The aim of this study was to investigate the effect of two progestogens mostly used in clinical practice on the proliferation of vascular smooth muscle cells, which has been demonstrated to be a crucial s tep in the development of atherosclerosis. Material and Methods: The effect of medroxyprogesterone acetate (MPA) and n orethisterone (NET), which represent the two different classes of C21- and C19-progestogens, respectively, was investigated on proliferation of smooth muscle cells from human coronary artery in vitro. The steroids were tested in the concentration range 10(-8) to 10(-5) M, which is in the upper range of that reached during hormonal replacement therapy, and compared with con trol values. Results: Estradiol significantly inhibited serum-stimulated cell growth at the concentrations 10(-6) and 10(5) M by 18% and 34%, respectively. MPA sig nificantly enhanced serum-stimulated growth at the concentrations 10(-6) an d 10(-5) M by 29% and 47%, respectively. In equimolar combinations of MPA a nd estradiol, proliferation of the cells was significantly stimulated at th e concentrations 10(-6) and 10(-5) M by 26% and 44%, respectively. In contr ast, NET had no significant effect on serum-stimulated cell growth and had no impact on the estradiol-inhibited proliferation. Conclusions: These data suggest that MPA may antagonize beneficial antiathe rosclerotic estradiol effects on the vasculature, whereas NET may be neutra l in this respect. However, these effects occurred at supraphysiological co ncentrations. Because these concentrations might be reached in the target t issues, the clinical relevance for treatment of patients with cardiovascula r risk cannot be excluded.