Effect of Hormone Replacement Therapy on Plasma Levels of the Cardiovascular Risk Factor Asymmetric Dimethylarginine: A Randomized, Placebo-Controlled 12-Week Study in Healthy Early Postmenopausal Women

In a prospective, randomized, placebo-controlled 12-wk study, we investigated the effect of oral hormone replacement therapy on asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), and an independent risk factor for coronary heart disease. The effects on arginine and symmetric dimethylarginine were also investigated. Sixty healthy early postmenopausal women received daily placebo (n 16) or oral 17-estradiol 2 mg, either unopposed (E2 ;n 16) or sequentially combined with dydrogesterone 10 mg (E2D; n 14) or trimegestone 0.5 mg (E2T; n 14). ADMA levels reduced in all active treatment groups. Compared with baseline and placebo, the largest reduction in ADMA levels was observed in the E2T group [18.7% (95% confidence interval [CI], 25.4 to 11.9%) and 21.1% (95% CI, 26.2 to 16.1%), at 4 and 12 wk, respectively]. At 4 and 12 wk in the E2T group, arginine levels were significantly reduced as well [30.9% (95% CI, 41.1 to 20.7%) and 36.3% (95% CI, 43.1 to 29.5%), respectively], whereas symmetric dimethylarginine levels were significantly lower in the E2D group after 12 wk [11.6% (95% CI, 19.9 to 3.3%)]. In conclusion, unopposed oral estradiol and estradiol combined with dydrogesterone or trimegestone reduced plasma levels of the NOS inhibitor ADMA. Whether the reduction of the NOS substrate arginine in the E2T group counteracts the potentially beneficial effect of ADMA reduction or reflects increased NO production remains to be investigated. (J Clin Endocrinol Metab 88: 4221– 4226, 2003)