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

Physiol Rep. 2017 Sep;5(17):e13409. doi: 10.14814/phy2.13409.


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, NG-mono-methyl-ւ-arginine [L-NMMA] asymmetric dimethylarginine [ADMA] and NG-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.

Keywords: Aging; endothelial function; estrogen; methylarginines; nitric oxide.

MeSH terms

  • Adult
  • Aged
  • Arginine / analogs & derivatives
  • Arginine / blood*
  • Arginine / deficiency
  • Endothelium, Vascular / growth & development
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / physiopathology
  • Female
  • Humans
  • Menopause / blood*
  • Menopause / physiology
  • Middle Aged
  • Nitric Oxide / metabolism
  • Vasodilation


  • Nitric Oxide
  • Arginine