Effects of intranasal versus oral hormone therapy on asymmetric dimethylarginine in healthy postmenopausal women: A randomized study

Objective Oral estrogens reduce asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, and an independent risk factor for cardiovascular disease. This study was conducted to compare the effect on ADMA between intranasal and oral 17β-estradiol (E2) combined with norethisterone (acetate) (NET(A)) administration in postmenopausal women. Methods In a two-center, randomized, double-blind, comparative study 90 healthy postmenopausal women (age 56.6 ± 4.7 years) received daily continuous combined intranasal E2/NET 175 μg/275 μg (n = 47) or oral E2/NETA 1 mg/0.5 mg (n = 43) for one year. At baseline, week 12 and 52, plasma concentrations of ADMA, arginine and symmetric dimethylarginine (SDMA) were measured by high-performance liquid chromatography. Results Oral E2/NETA reduced ADMA concentrations (−7.4%; 95% confidence interval (CI) −10.4 to −4.4%), while intranasal E2/NET had no effect (−0.8%; 95% CI −3.7 to 2.1%) after 52 weeks. In both groups, arginine was transiently decreased compared to baseline at week 12 (intranasal: −6.1%; 95% CI −9.1 to −3.0%; oral: −6.5%; 95% CI −10.9 to −2.1%). Only oral E2/NETA reduced SDMA concentrations. Conclusions Oral administration of E2/NETA reduced ADMA and SDMA concentrations, whereas intranasal administration did not. Both treatments transiently reduced arginine. The decrease in ADMA by oral estrogens could be a key phenomenon in the modulation of nitric oxide synthesis by postmenopausal hormone therapy.