The mechanisms by which diabetes obviates the cardiovascular protective effects of female sex hormones in premenopausal women are not well understood. However, data are emerging suggesting potential mechanisms involved in this process. Increased cardiovascular disease in individuals with diabetes mellitus appears to be related to a number of factors. Pathological factors include enhanced platelet aggregation,48,49 relatively greater coagulation and decreased fibrinolytic activity,10,50 lipoprotein abnormalities,51 endothelial dysfunction,10,52- 54 enhanced oxidative stress,10,55 vascular protein glycation,10 and enhanced growth factor stimulation.10,56 Thus, diabetes mellitus, associated hyperglycemia, and other attendant metabolic abnormalities may obviate the cardiovascular protective effects of estradiol through one or more of these mechanisms. One possible mechanism involves the interaction between hyperglycemia and estradiol in regulation of cardiovascular nitric oxide production. It has recently been reported that hyperglycemia decreases estradiol-mediated nitric oxide production from cultured endothelial cells.56 Thus, it appears that hyperglycemia may negate the protective effects of estradiol in part by decreasing vascular and perhaps platelet nitric oxide production. Since nitric oxide production reduces vascular tone, platelet aggregation,23 and vascular growth,21- 23 this hyperglycemia-related abnormality may help explain why premenopausal women with diabetes mellitus have a high prevalence of hypertension, platelet abnormalities, and premature atherosclerosis.