Does Tamoxifen Enhance Endothelial Function by Lowering the Plasma Levels of Homocysteine?

To the Editor:In their interesting study, Clarke et al 1 showed that treatment with tamoxifen (40 mg/d) for 56 days caused an increase in endothelium-dependent flow-mediated dilatation (ED-FMD) of the brachial artery in men with angiographically proven coronary artery disease (CAD) and in men with angina-like symptoms but normal coronary arteries (as shown by angiography).In contrast, tamoxifen did not affect endothelium-independent FMD in the same subjects.The ED-FMD response to tamoxifen was unlikely to have been caused by the associated increase in plasma estradiol or a reduction in plasma cholesterol levels. 1 A possible mechanism for the observed enhanced endothelial function in men treated with tamoxifen could be the reduction in plasma total homocysteine (tHcy) levels.High tHcy levels are associated with increased risk for CAD and other atherothrombotic diseases.2 Compelling evidence indicates that both long-and shortterm (induced by oral methionine loading) increases in the plasma levels of tHcy impair the ED-FMD of the brachial artery without affecting endothelium-independent FMD.Two studies showed that the oral administration of folic acid, alone 3 or in combination with vitamin B 12 , 4 improved the ED-FMD in patients with CAD.The improvement in ED-FMD correlated with the reduction in total 3 or free Hcy levels 4 caused by vitamin treatment.Tamoxifen, at oral doses ranging between 20 and 30 mg/d, reduces tHcy levels not only in patients with advanced breast cancer, 2 but also in healthy women, 5 indicating that its lowering effect is not only due to its antitumoral activity, but also to its direct effect on estrogenregulated targets.The reduction of tHcy levels by tamoxifen (20 mg/d) was seen in women with moderate hyperhomocystinemia and in women with normal tHcy levels.5 On the basis of these considerations, it seems reasonable to hypothesize that the improvement of vascular endothelial function after treatment with tamoxifen, as described by Clarke et al, 1 can be attributed, at least in part, to the lowering effect of the drug on plasma tHcy levels.