Research ArticleTestosterone therapy increases muscle mass in men with cirrhosis and low testosterone: A randomised controlled trial
Graphical abstract
Introduction
Serum testosterone is reduced in up to 90% of men with cirrhosis [1], [2]. Sarcopenia is similarly common in cirrhosis, with an estimated prevalence of 40–70%. This prevalence appears to be greater in men, at 50–70%, as compared to 20% in women [3], [4], [5]. Both low testosterone and sarcopenia have been associated with increased mortality in men with cirrhosis, independent of the Model for End-stage Liver Disease (MELD) score [5]. Reversal of sarcopenia in an observational cohort has been associated with improved survival [6], and thus it is logical to anticipate a mortality-benefit if we can treat sarcopenia in cirrhosis. However, there are currently no interventions supported by randomised controlled data to increase muscle mass in this population. Testosterone is known to increase muscle mass and reduce body fat in both hypogonadal and eugonadal men [7], [8], but it cannot be assumed that the same is true in cirrhosis, due to multiple other factors contributing to the pathogenesis of sarcopenia in this population [9].
Previous studies investigating the potential therapeutic effects of testosterone therapy in men with cirrhosis have been limited by such issues as inclusion of women and eugonadal men, variable follow-up durations, and inappropriate drug delivery such as oral administration, with inconclusive findings [10], [11], [12], [13]. A Cochrane review of testosterone therapy in men with liver disease included a high proportion of non-cirrhotic subjects with alcoholic hepatitis who ceased alcohol ingestion during the study period, and thus the failure to identify benefit is uninterpretable [14]. Previous studies have not examined effects on muscle mass, which has only relatively recently been identified as an important prognostic factor in cirrhosis.
We hypothesised that testosterone treatment can improve muscle mass in men with cirrhosis and low testosterone levels, and therefore conducted a randomised placebo-controlled trial of appropriately delivered intramuscular testosterone confined to men with established cirrhosis and low testosterone levels, to examine the effects of testosterone in this population.
Section snippets
Patients and methods
This was a randomised, double-blinded, placebo-controlled clinical trial of testosterone undecanoate in men with cirrhosis and low baseline testosterone conducted between May 2013 and November 2015 at a single tertiary referral centre. All patients provided signed informed consent. The trial was approved by the Austin Hospital Human Research Ethics Unit and registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12614000526673) after enrolment of the first patient due to a
Results
Patients receiving testosterone and placebo were well matched with no significant differences at trial commencement including MELD score and muscle mass (Table 1). Median age was 55.0 years [51.0; 60.0] and most men were caucasian (91.1%). The median MELD score was 14 [10; 17]. 19.8% of patients were classified as Child-Pugh A, 35.6% Child-Pugh B and 44.6% Child-Pugh C. At baseline, 52.5% of patients overall had suffered recent (within 3 months) moderate or severe hepatic encephalopathy (56% of
Discussion
Sarcopenia is now recognised as an important independent predictor of adverse outcome in patients with liver cirrhosis [5], [6], [7]. We have shown for the first time that in cirrhotic men with low testosterone levels, testosterone therapy significantly increased muscle mass as assessed by quantification of both appendicular and total lean body mass. We also demonstrated reduced fat mass and increased bone density. Remarkably, these anabolic effects of treatment on muscle and bone were observed
Financial support
The completion of this work was assisted by an Australian Postgraduate Award from the University of Melbourne and a Research Scholarship from Avant Mutual group awarded to MS. MG was supported by a NHMRC Career Development Fellowship (#1024139).
Bayer Pharma AG (Berlin, Germany) provided study drug and financial support to conduct investigations, but had no role in trial design, data analysis, manuscript preparation or the decision to submit the manuscript for publication.
Conflict of interest
Mathis Grossmann has received research funding from Bayer Schering, Novartis, Weight Watchers, Lilly and speaker’s honoraria from Besins Healthcare. Marie Sinclair, Paul Gow, Peter Angus and Rudolf Hoermann have no conflicts of interest to declare pertaining to this work.
Authors’ contributions
Marie Sinclair, Mathis Grossmann, Peter Angus and Paul Gow contributed to planning of the trial, drafting and finalising of the manuscript. Day-to-day trial proceedings were conducted by Marie Sinclair. Dr Rudolf Hoermann provided statistical support
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These authors share senior authorship.