A potent liver-mediated mechanism for loss of muscle mass during androgen deprivation therapy

Context: Androgen deprivation therapy (ADT) in prostate cancer results in muscular atrophy, due to loss of the anabolic actions of testosterone. Recently we discovered that testosterone acts on the hepatic urea cycle to reduce amino acid nitrogen elimination. We hypothesize that ADT enhances protein oxidative losses by increasing hepatic urea production, resulting in muscle catabolism. We also investigated whether progressive resistance training (PRT) can offset ADT-induced changes in protein metabolism. Objective: To investigate the effect of ADT on whole body protein metabolism and hepatic urea production with and without a home-based PRT program. Design: A randomised controlled trial. Patients and Intervention: Twenty-four prostate cancer patients were studied before and after 6 weeks of ADT. Patients were randomised to usual care (UC) (n = 11) or PRT (n = 13) starting immediately after ADT. Main Outcome Measures: Rate of hepatic urea production was measured by the urea turnover technique using 15N2-Urea. Whole-body leucine turnover was measured, and leucine rate of appearance (LRa), an index of protein breakdown and leucine oxidation (Lox), a measure of irreversible protein loss, was calculated. Results: ADT resulted in a significant mean increase in hepatic urea production (from 427.6 ± 18.8 to 486.5 ± 21.3; p<0.01) regardless of PRT. Net protein loss measured by Lox/LRa increased by 12.6 ± 4.9% (p<0.05). PRT preserved lean body mass without affecting hepatic urea production. Conclusion: As early as 6 weeks after initiation of ADT, testosterone suppression increases protein loss through elevated hepatic urea production. Short-term PRT had no effect on protein metabolism during profound testosterone deficiency.