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 clinical trials 2

Safety Considerations and Monitoring

The theoretical risk of hepatocellular carcinoma with testosterone has been a longstanding concern, but recent evidence suggests this risk has been overstated. 6 However, caution remains warranted:

• HCC risk: While older guidelines emphasized theoretical HCC risk 1, the 2025 emulated trial found no increased HCC risk (sHR 1.09,95% CI 0.91-1.3) 5
• Thrombotic events: Testosterone may be associated with myocardial infarction or stroke risk 1
• Liver enzyme elevations: Transient, usually self-limited elevations may occur 1

Mandatory Monitoring Protocol

• Hematocrit levels for polycythemia 4
• Liver function tests for hepatotoxicity 4
• Signs of thromboembolism (clinical assessment) 4
• Serum testosterone concentrations to ensure therapeutic range 4
• Lipid profile 4

Degree of Hepatic Decompensation Matters

While testosterone has shown benefits even in decompensated cirrhosis 1, the degree of liver dysfunction should guide decision-making:

• Compensated cirrhosis (Child-Pugh A): Testosterone therapy is most appropriate with documented hypogonadism 1
• Decompensated cirrhosis (Child-Pugh B or C): Exercise greater caution, though benefits on muscle and bone mass have been demonstrated even in advanced disease 1

Special Populations

Men with hemochromatosis and hypogonadism: Testosterone supplementation combined with venesection is considered effective and appropriate. 1, 4

Common Pitfalls to Avoid

• Do not use oral testosterone formulations in cirrhotic patients due to hepatotoxicity concerns 4, 3
• Do not initiate therapy without baseline HCC screening, as this is an absolute contraindication 1, 4, 3
• Do not assume all hypogonadism requires treatment—document biochemical hypogonadism with appropriate testosterone thresholds 2
• Do not overlook thrombotic risk factors in patients with cirrhosis who may already have altered coagulation profiles 1, 4

Informed Consent Discussion

Patients must be counseled about the theoretical risks of HCC despite reassuring recent data, as well as cardiovascular and thrombotic risks. 1 The discussion should emphasize that testosterone therapy represents the first evidence-based therapy for sarcopenia in cirrhosis. 2