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The addition of progestogen to estrogen replacement therapy is thought 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 step in the development of atherosclerosis.The effect of medroxyprogesterone acetate (MPA) and norethisterone (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 control values.Estradiol significantly inhibited serum-stimulated cell growth at the concentrations 10−6 and 105 M by 18% and 34%, respectively. MPA significantly enhanced serum-stimulated growth at the concentrations 10−6 and 10−5 M by 29% and 47%, respectively. In equimolar combinations of MPA and estradiol, proliferation of the cells was significantly stimulated at the concentrations 10−6 and 10−5 M by 26% and 44%, respectively. In contrast, NET had no significant effect on serum-stimulated cell growth and had no impact on the estradiol-inhibited proliferation.These data suggest that MPA may antagonize beneficial antiatherosclerotic estradiol effects on the vasculature, whereas NET may be neutral in this respect. However, these effects occurred at supraphysiological concentrations. Because these concentrations might be reached in the target tissues, the clinical relevance for treatment of patients with cardiovascular risk cannot be excluded.