Associations between asymmetric dimethylarginine (ADMA), nitrite-dependent renal carbonic anhydrase activity, and plasma testosterone levels in hypogonadal men

Background: Circulating inorganic nitrite (NO₂^-) is an abundant nitric oxide (NO) reservoir. Renal carbonic anhydrase (CA) mediates the absorption of urinary nitrite. The urinary nitrate-to-nitrite molar ratio U_NOxR is a measure of nitrite-dependent renal CA activity. The CA family is also involved in the bioactivation of nitrite to S-nitrosothiols and NO. Thus, CA isoforms may combat atherosclerosis.

Methods: In the plasma and urine of 10 hypogonadal men, we measured the major NO metabolites nitrite and nitrate and the endogenous inhibitor of NO synthase (NOS), i.e., asymmetric dimethylarginine (ADMA), before and after a 24-week testosterone treatment to normalize plasma testosterone levels. We tested potential correlations between plasma testosterone, ADMA, and U_NOxR.

Results: Baseline U_NOxR levels were low, indicating impaired nitrite-dependent renal CA activity. Baseline plasma testosterone levels were inversely correlated with creatinine-corrected urinary nitrite excretion (r = -0.74, P = 0.036) and positively with U_NOxR (r = 0.72, P = 0.044). Plasma testosterone level normalization deteriorated these correlations. At baseline, U_NOxR correlated inversely with urinary excretion of ADMA (r = -0.75, P = 0.013). Plasma testosterone levels normalization did not affect U_NOxR. Men with secondary and primary hypogonadal hypogonadism differed with respect to baseline biomarker levels and the testosterone effects.

Conclusions: Impaired testosterone synthesis in hypogonadal men favors inflammatory processes, elevates inducible NOS-mediated NO formation, and impairs CA-dependent nitrite reabsorption. Normalization of plasma testosterone reverses these processes. Pharmacological testosterone may combat atherosclerosis in hypogonadal hypogonadism.