Elsevier

Journal of Hepatology

Volume 65, Issue 5, November 2016, Pages 906-913
Journal of Hepatology

Research Article
Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: A randomised controlled trial

https://doi.org/10.1016/j.jhep.2016.06.007Get rights and content

Background & Aims

Low testosterone and sarcopenia are common in men with cirrhosis and both are associated with increased mortality. Whether testosterone therapy in cirrhosis improves muscle mass and other outcomes is unknown.

Methods

We conducted a 12-month, double-blinded, placebo-controlled trial of intramuscular testosterone undecanoate in 101 men with established cirrhosis and low serum testosterone (total testosterone <12 nmol/L or free testosterone <230 pmol/L) in a single tertiary centre. Body composition was assessed using dual-energy X-ray absorptiometry at baseline, 6 and 12 months.

Results

At study completion, appendicular lean mass was significant higher in testosterone-treated subjects, with a mean adjusted difference (MAD) of +1.69 kg, (CI +0.40; +2.97 kg, p = 0.021). Secondary outcomes included a substantially higher total lean mass in the active group (MAD +4.74 kg, CI +1.75; +7.74 kg, p = 0.008), matched by reduced fat mass (MAD −4.34 kg, CI −6.65; −2.04, p <0.001). Total bone mass increased (MAD +0.08 kg, CI +0.01; +0.15 kg, p = 0.009) as did bone mineral density at the femoral neck (MAD +0.287 points, CI +0.140; +0.434, p <0.001). Haemoglobin was higher with testosterone therapy (MAD +10.2 g/L, CI +1.50; +18.9 g/L, p = 0.041) and percentage glycosylated haemoglobin (HbA1c) lower (MAD −0.35%, CI −0.05; −0.54, p = 0.028). Mortality was non-significantly lower in testosterone-treated patients (16% vs. 25.5%, p = 0.352). There was no increase in adverse events in testosterone-treated subjects.

Conclusion

Testosterone therapy in men with cirrhosis and low serum testosterone safely increases muscle mass, bone mass and haemoglobin, and reduces fat mass and HbA1c. This is the first evidence-based therapy for sarcopenia in cirrhosis and thus requires larger-scale investigation into its potential impact on mortality.

Lay summary

Both low testosterone and muscle wasting are associated with increased risk of death in men with severe liver disease. Administering testosterone to men with liver disease who have low testosterone levels significantly increases their muscle mass. In addition, testosterone has non-muscle beneficial effects which may be able to increase survival in this population.

Clinical trial number

Australian New Zealand Clinical Trials Registry trial number ACTRN 12614000526673.

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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