A relative L‐arginine deficiency contributes to endothelial dysfunction across the stages of the menopausal transition

Vascular endothelial function declines across the menopause transition in women. We tested the hypothesis that reduced availability of the endothelial nitric oxide synthase [eNOS] substrate L‐arginine is an underlying mechanism to vascular endothelial dysfunction across menopause stages. Endothelial function (brachial artery flow‐mediated dilation [FMD]) and plasma markers of L‐arginine metabolism (citrulline, N(G)‐mono‐methyl‐ւ‐arginine [L‐NMMA] asymmetric dimethylarginine [ADMA] and N(G)‐N(′G)‐dimethyl‐l‐arginine [SDMA]), were measured in 129 women: 36 premenopausal (33 ± 7 years), 16 early‐ (49 ± 3 years) or 21 late‐ (50 ± 4 years) perimenopausal, and 21 early‐ (55 ± 3 years) or 35 late‐ (61 ± 4 years) postmenopausal. FMD was progressively reduced across menopause stages (P < 0.001). Menopause stage was associated with L‐arginine concentrations (P = 0.012), with higher levels in early postmenopausal compared to early and late perimenopausal women (P < 0.05). The methylarginine and eNOS inhibitor L‐NMMA was higher in early and late postmenopausal women compared to premenopausal and early and late perimenopausal women (all P < 0.001), and was inversely correlated with FMD (r = −0.30, P = 0.001). The L‐arginine/L‐NMMA ratio, a potential biomarker of relative L‐arginine levels, was lower in postmenopausal compared to either premenopausal or perimenopausal women (both P < 0.001), and was positively correlated with FMD (r = 0.33, P < 0.001). There were no differences in plasma citrulline, ADMA or SDMA across groups. These data suggest that a relative L‐arginine deficiency may be a mechanism underlying the decline in endothelial function with the menopause transition in women. The relative L‐arginine deficiency may be related to elevated levels of the methylarginine L‐NMMA, which would compete with L‐arginine for eNOS and for intracellular transport, reducing NO biosynthesis.