What are the considerations for testosterone replacement therapy in males with hepatic (liver) cirrhosis?

Testosterone Replacement Therapy in Males with Hepatic Cirrhosis

Testosterone replacement therapy may be considered in select men with cirrhosis and documented low testosterone levels to improve muscle mass, bone density, and potentially reduce mortality, but only after careful risk stratification and exclusion of hepatocellular carcinoma, other malignancies, and thrombotic history. 1

Baseline Assessment Requirements

Before initiating testosterone therapy in cirrhotic men, the following must be completed:

• Check baseline testosterone levels (total testosterone <12 nmol/L or free testosterone <230 pmol/L indicates hypogonadism requiring treatment consideration) 1, 2
• Screen for hepatocellular carcinoma using abdominal imaging (ultrasound and/or MRI) to exclude active HCC 3
• Assess for contraindications: personal or family history of HCC, other malignancies (particularly prostate cancer), and history of thrombophilia or prior thrombotic events 1, 4
• Evaluate bone mineral density via DEXA scan if osteoporosis is a concern 1

Clinical Benefits Supported by Evidence

The most recent high-quality randomized controlled trial demonstrates substantial benefits:

• Increased appendicular lean mass by +1.69 kg at 12 months (p=0.021) 2
• Increased total lean mass by +4.74 kg with corresponding fat mass reduction of -4.34 kg (p<0.001) 2
• Improved bone mineral density at the femoral neck and increased total bone mass 2
• Increased hemoglobin by +10.2 g/L, addressing anemia common in cirrhosis 2
• Reduced HbA1c by -0.35%, improving glucose metabolism 2
• Lower mortality risk in a 2025 emulated trial (subdistribution hazard ratio 0.92,95% CI 0.85-0.99) 5
• Reduced decompensation events, particularly ascites requiring paracentesis (sHR 0.82) and variceal hemorrhage (sHR 0.67) 5

These benefits directly address sarcopenia, which is a predictor of mortality in cirrhosis. 1

Formulation Selection

Transdermal testosterone (gel or patch) is strongly preferred over oral formulations to avoid hepatic first-pass metabolism and minimize hepatotoxicity risk. 1, 4, 3

• Testosterone gel 50 mg/day has been shown safe and effective in cirrhotic men, raising free testosterone without supraphysiological levels 3
• Intramuscular testosterone undecanoate is an alternative that has demonstrated efficacy in the largest RCT 2

Safety Considerations and Monitoring

The theoretical risk of hepatocellular carcinoma with testosterone has been overstated in older literature, with more recent data suggesting this concern is not evidence-based. 6 However, caution remains warranted:

• Relative contraindications include history of HCC, other malignancy, or thrombosis 1
• Mandatory monitoring includes: hematocrit for polycythemia, liver function tests, signs of thromboembolism, serum testosterone levels, and lipid profile 4
• Transient liver enzyme elevations may occur but are usually self-limited 1
• No increase in adverse events was observed in the 12-month RCT compared to placebo 2

Addressing the HCC Concern

While older guidelines from 2002 emphasized discussing "theoretical risks of hepatocellular carcinoma" before initiating testosterone 1, the most recent 2025 evidence shows no increased risk of HCC (sHR 1.09,95% CI 0.91-1.3, not statistically significant). 5 The 2021 AASLD guidance acknowledges this concern but notes testosterone may still be used in select patients without HCC history. 1

Clinical Decision Algorithm

1. Document hypogonadism with testosterone levels below threshold (<12 nmol/L total or <230 pmol/L free) 2
2. Exclude absolute contraindications: active or history of HCC, recent thrombotic event, active malignancy 1, 4
3. Assess degree of hepatic decompensation: testosterone has been studied safely even in decompensated cirrhosis 1
4. Identify treatment goals: sarcopenia, osteoporosis, anemia, or metabolic dysfunction 1, 2
5. Initiate transdermal testosterone with close monitoring 4, 3
6. Reassess at 3-6 months for clinical response and adverse effects 3

Special Populations

In males with hemochromatosis and hypogonadism, testosterone supplementation combined with venesection is considered effective and appropriate. 1, 4

Common Pitfalls to Avoid

• Do not withhold testosterone solely due to cirrhosis diagnosis if hypogonadism is documented and no contraindications exist 1, 2
• Do not use oral testosterone formulations in cirrhotic patients due to hepatotoxicity concerns 4, 3
• Do not assume HCC risk is prohibitive based on outdated literature; recent evidence does not support increased HCC risk 5
• Do not forget to supplement calcium (1,000-1,500 mg/day) and vitamin D (400-800 IU/day) if osteoporosis is present 1

Divergent Evidence

While the 2002 Gut guidelines emphasized caution regarding HCC risk 1, the 2021 AASLD guidelines 1 and 2025 research 5 demonstrate a more favorable risk-benefit profile. The most recent and highest quality evidence (2025 emulated trial and 2016 RCT) shows mortality benefit and no HCC signal, supporting a more liberal approach to testosterone replacement in appropriately selected cirrhotic men. 2, 5