Context: Testosterone is a major anabolic hormone that reduces protein and nitrogen loss. As the hepatic urea cycle is a rate limiting step for amino acid nitrogen elimination, the rate of urea synthesis is a true indicator of whole body protein catabolism. The effect of testosterone on hepatic urea cycle in humans has not been studied. We hypothesize that testosterone down-regulates the hepatic urea cycle, thereby preventing systemic protein loss.
Objective: To investigate the effect of testosterone on hepatic urea production.
Design: In this open label study, testosterone replacement was initiated in hypogonadal men, and its effects on hepatic urea production and whole-body protein metabolism were studied.
Patients and Intervention: Eight hypogonadal men were studied at baseline, and after two weeks of testosterone replacement (Testogel, 100 mg/day).
Main Outcomes Measures: The rate of hepatic urea synthesis was measured by a recently developed urea turnover technique using stable isotope methodology, with 15N2-Urea as tracer. Whole-body leucine turnover was measured, from which leucine rate of appearance (LRa), an index of protein breakdown and leucine oxidation (Lox), a measure of irreversible protein loss, were calculated.
Results: At baseline, there was a significant association between Lox and the rate of urea synthesis. Testosterone administration significantly reduced the rate of hepatic urea production (from 544.4 ± 71.8 to 431.7 ± 68.3 µmol/min; p < 0.01), which was paralleled by a significant reduction in serum urea concentration. Testosterone treatment significantly reduced Lox by 18.1 ± 6.9% (p < 0.05). Net protein loss, as measured by percent Lox/LRa, was reduced by 19.3 ± 5.8 % (p < 0.05).
Conclusion: Testosterone replacement reduces protein loss and hepatic urea synthesis. We conclude that testosterone may regulate protein metabolism and muscle mass via suppressing the urea cycle.