Long-term effect of estrogen replacement on plasma nitric oxide levels: results from the estrogen in the prevention of atherosclerosis trial (EPAT)

The estrogen in the prevention of atherosclerosis trial (EPAT) was a 2-year randomized controlled trial in which unopposed 17β-estradiol reduced subclinical atherosclerosis progression, measured as change in carotid intima-media thickness (CIMT). This study was conducted to determine whether long-term 17β-estradiol 1 mg daily increased plasma nitric oxide (NO) levels and whether this accounted for atheroprotection in EPAT. Although the on-trial serum estradiol level was significantly higher in the estradiol-treated group (n = 91 subjects) than the placebo group (n = 89 subjects) (mean (S.D.) = 59.0 (31.7) pg/ml versus 14.3 (10.4) pg/ml, p < 0.0001), there was no significant difference in the on-trial plasma NO levels, 18.5 (8.2) μM versus 20.1 (9.3) μM. Correlation between on-trial estradiol level and NO change was −0.22 (p = 0.003) in the total sample (placebo- and estradiol-treated subjects) and −0.21 (p = 0.049) in the estradiol-treated group. Change in NO levels was inversely correlated to change in LDL-cholesterol in the estradiol group (r = −0.23, p = 0.03). An NO response to 17β-estradiol according to age, time since menopause and baseline CIMT was not found arguing against a possible NO effect in healthy versus diseased endothelium. NO levels were not related to CIMT progression. In this study, we found no evidence for an estrogen-induced effect on plasma total NO levels which unlikely accounted for the mechanism underlying the 17β-estradiol atheroprotective effect on subclinical atherosclerosis progression.