Estrogens, Progestins, and Heart Disease

oronary atherosclerosis is a prevalent, preventable, but slow disease.Demonstrating the clinical effect of an intervention requires at least 3 to 5 years, even in high-risk populations.Despite considerable supportive observational data, the value of hormone replacement therapy in the treatment of coronary heart disease in postmenopausal women remains uncertain.[1][2][3][4] It is therefore very attractive to look for intermediate biological outcomes that may more quickly predict the results of event trials.One intermediate biological outcome, the anatomic progression of coronary atherosclerosis, has been shown to correlate with the incidence of cardiovascular events.5 Changes in angiographic disease progression, however, even with clinically successful interventions such as cholesterol lowering, do not occur in less than 1 to 2 years.6 The endothelium is thought to play an important role in the genesis of atherosclerosis, and changes in endothelial function have been reported within an hour of either estrogen administration or cholesterol lowering.[7][8][9] If changes in endothelial function were found to predict the clinical benefit of interventions, then drug and lifestyle changes could be evaluated more rapidly.In this issue, Sorensen and coworkers 10 report that cyclical estradiol and norethisterone hormone replacement therapy administered for 2.9Ϯ0.5 years did not improve endothelial function, measured as brachial artery flow-mediated vasodilation.The authors conclude that the addition of a progestin in a hormone replacement regimen may counteract the beneficial effects of estrogen alone on cardiovascular disease.If confirmed by other investigations, this study suggests that clinical trials of combined hormone replacement therapy will not find a beneficial effect on events and/or that endothelial function is not an appropriate intermediate biological outcome for assessing coronary heart disease therapy.Either finding would be an important observation.