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Testosterone Helps Diet and Exercise
Improve Sarcopenia in Men With Cirrhosis
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AASLD The Liver Meeting Digital Experience, November 13-16, 2020
Mark Mascolini
Adding monthly testosterone injections to structured diet and exercise for men with cirrhosis improved sarcopenia and frailty in a 102-man randomized trial in India [1]. Men getting testosterone also had significantly fewer hospital admissions and spent less time in the hospital than men relying only on diet and exercise to stymie sarcopenia (age-related muscle loss).
Researchers from New Delhi's Institute of Liver and Biliary Sciences who conducted this study noted that serum testosterone drops up to 90% in men with cirrhosis, whose sarcopenia prevalence may range from 40% to 70%. Reversing sarcopenia has been linked to improved survival. Research shows that testosterone increases muscle mass in men, but therapeutic testosterone remains poorly studied in men with cirrhosis.
Current treatment of sarcopenia relies on nutrition therapy (adequate calories, high protein) and structured physical activity and resistance and endurance exercise. Prior research showed that testosterone is generally safe in cirrhotic men with low testosterone, boosts muscle mass, bone mass, and hemoglobin, and cuts fat mass and HbA1c, the diabetes metric [2]. But normal testosterone levels remain unestablished in men with cirrhosis, testosterone has not been well studied in combination with diet and exercise, and its impact on muscle function and frailty is poorly understood.
To address these issues, the New Delhi team conducted a randomized controlled trial with several secondary endpoints and one primary endpoint: proportion of participants achieving more than a 10% gain in appendicular muscle mass [3]. The study included 18- to 60-year-old men with cirrhosis from any cause, with a Child-Turcotte-Pugh (CTP) score of 6 to 12, and with sarcopenia defined as an appendicular skeletal muscle index below 7 kg/m2. The trial excluded men with hepatocellular carcinoma or other malignancy, CTP above 12, acute liver injury, prostate disease, chronic kidney disease, and a few other clinical or lab signals of poor prognosis.
The trial randomized men to nutrition, exercise, and testosterone (NExT) or to nutrition and exercise alone (NEx). Nutritionists relied on ESPEN guidelines to formulate individual plans for each participant. A structured exercise program included endurance exercise, weight training, and strength training. Testosterone recipients received 1000 mg of deep intramuscular testosterone undecanoate at weeks 0, 6, 12, 16, and 20. The trial randomized 64 men to NExT and 63 to NEx. Researchers analyzed an as-treated group of 50 NExT men and 52 NEx men who reached week 24. Five men in the NExT group and 4 in the NEx group died; respective numbers who missed study visits or did not adhere to study regimens were 9 and 7.
Age averaged 46.9 years in the NExT group and 47.3 years in the NEx group. Body mass index averaged 23.4 kg/m2 with NExT and 23.3 kg/m2 with NEx. Respective CTPs averaged 9.14 and 9.4, and Model for End-Stage Liver Disease (MELD) scores were 23.8 and 23.1. Similar proportions of NExT men and NEx men were prefrail (58% and 63.5%) or frail (36% and 30.1%).
In the NExT group average serum testosterone level rose from 3.08 ng/dL at baseline to 8.3 ng/dL at week 12 and to 11.5 ng/dL at week 24 (P = 0.03 vs control group at week 24). Respective levels in the NEx group were 3.08 ng/dL, 3.12 ng/dL, and 3.3 ng/dL. The researchers noted that some men reached above-normal testosterone levels, though they saw no major side effects. The investigators did not present a detailed analysis of adverse events.
After 24 weeks, 33 men in the NExT group and 13 in the NEx group had more than a 10% increase in appendicular lean muscle index, the primary endpoint (66% vs 25%, P = 0.04, odds ratio 5.8, 95% confidence interval 2.47 to 13.74).
The NExT group also did significantly better in all but one major secondary endpoint: at least 10% improvement in hand grip (92% vs 67.3%, P = 0.002), 6-minute walk (82% vs 63.5%, P = 0.046), fat-free mass (36% vs 5.7%, P = 0.005), fat mass (38% vs 7.7%, P = 0.001), muscle mass (34.7% vs 7.7%, P = 0.001), bone mass (18% vs 5.8%, P = 0.053, not significant), serum ammonia level (64% vs 25%, P = 0.01), and TNF-alpha level (88% vs 40.4%, P = 0.01).
Nine men in the NExT group (18%) and 18 in the NEx group (34.6%) got admitted to the hospital. Cumulative hospital admissions numbered 16 in NExT men and 49 in NEx men (P = 0.03). Respective person-days in the hospital were 108 and 348 (P < 0.001).
The New Delhi team noted that the study is limited by its short duration and lack of biopsies to establish a histologic basis for improvements in the NExT group. But with those limitations in mind, they recommended adding injected testosterone to structured diet and exercise to improve sarcopenia and frailty in men with cirrhosis.
References
1. Singh S, Choudhury AK, Benjamin J, et al. Addition of testosterone therapy to nutrition and structured exercise is superior to nutrition and structured exercise alone in improving sarcopenia in men with cirrhosis: a randomized controlled trial. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 74.
2. Sinclair M, Grossmann M, Hoermann R, Angus PW, Gow PJ. Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: A randomised controlled trial. J Hepatol. 2016;65:906-913. doi: 10.1016/j.jhep.2016.06.007.
3. ClinicalTrial.gov. Efficacy and safety of testosterone therapy in improving sarcopenia in men with cirrhosis. ClinicalTrials.gov identifier NCT03995251.
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