Is it safe for a patient with stage 3 liver fibrosis to continue low-dose testosterone (testosterone) therapy for hypogonadism?

Testosterone Therapy in Stage 3 Liver Fibrosis

Low-dose testosterone therapy can be continued in patients with stage 3 liver fibrosis (advanced fibrosis without cirrhosis) who have documented hypogonadism, provided they do not have a history of hepatocellular carcinoma, other malignancy, or thrombosis. 1

Key Decision Points

Absolute Requirements Before Continuing Therapy

• Confirm hypogonadism with morning total testosterone levels using an accurate assay, as testosterone levels should guide treatment decisions 1
• Screen for hepatocellular carcinoma with abdominal imaging (ultrasound or MRI) before initiating or continuing therapy, as HCC is an absolute contraindication 2
• Assess for thrombotic history, as testosterone increases risk of venous thromboembolic events including deep vein thrombosis and pulmonary embolism 3
• Evaluate for other malignancies, particularly prostate cancer in older men, as these are relative contraindications 1, 3

Stage 3 Fibrosis vs. Cirrhosis: A Critical Distinction

Stage 3 fibrosis represents advanced fibrosis but not yet cirrhosis (which is stage 4/F4). 1 The guidelines specifically address testosterone use in cirrhosis, not pre-cirrhotic fibrosis. 1 This distinction matters because:

• The evidence supporting testosterone safety comes primarily from cirrhotic patients (more advanced disease than stage 3 fibrosis) 2, 4
• If testosterone is safe in cirrhosis, it is reasonable to use in the less severe stage 3 fibrosis, provided contraindications are absent
• The American Association for the Study of Liver Diseases (AASLD) states testosterone may be considered in select men with cirrhosis and low testosterone to improve muscle mass 1

Monitoring Requirements

If continuing testosterone therapy:

• Check liver function tests monthly during the first 6 months, as drug-induced cholestatic hepatitis requires immediate discontinuation 3, 2
• Monitor for signs of hepatic decompensation, including new ascites, variceal bleeding, or hepatic encephalopathy 5
• Assess for edema and fluid retention, which can worsen in patients with hepatic disease due to sodium and water retention 3
• Screen for HCC every 6 months with imaging and alpha-fetoprotein, as prolonged androgen use has been associated with hepatic neoplasms 3
• Evaluate testosterone levels to ensure therapeutic range and avoid supraphysiological dosing 2

Route of Administration Matters

Transdermal testosterone (gel or patch) is preferred over oral formulations in patients with liver disease, as it avoids hepatic first-pass metabolism and appears safer 1, 2 Intramuscular testosterone undecanoate has also been studied safely in cirrhotic patients. 4

Potential Benefits in Advanced Liver Disease

The rationale for continuing therapy includes:

• Testosterone improves muscle mass and reduces sarcopenia, which is associated with increased mortality in liver disease 1, 4
• Increases bone mineral density, addressing osteoporosis common in chronic liver disease 1, 4
• Improves hemoglobin levels and reduces insulin resistance (lower HbA1c) 4
• Low testosterone independently predicts mortality in men with cirrhosis, suggesting correction may improve outcomes 6, 7

Safety Evidence

A 12-month randomized controlled trial in 101 men with cirrhosis demonstrated that testosterone therapy significantly increased muscle mass without increasing adverse events compared to placebo. 4 Additionally, a 6-month study using testosterone gel 50mg/day in cirrhotic men showed no significant adverse effects. 2

Common Pitfalls to Avoid

• Do not use oral testosterone preparations (e.g., methyltestosterone) in liver disease, as these carry higher hepatotoxicity risk 2
• Do not assume normal liver enzymes exclude significant liver disease—stage 3 fibrosis can exist with normal aminotransferases 1
• Do not continue therapy if jaundice develops or liver function tests become abnormal, as this indicates drug-induced hepatitis requiring immediate discontinuation 3
• Do not ignore cardiovascular risk—testosterone has been associated with increased risk of major adverse cardiovascular events in some studies, though data are inconclusive 3

When to Stop Therapy

Discontinue testosterone immediately if:

• Hepatocellular carcinoma is diagnosed 1, 3
• Cholestatic jaundice or abnormal liver function tests develop 3
• Venous thromboembolic event occurs (DVT, PE) 3
• Progression to decompensated cirrhosis with ascites, variceal bleeding, or encephalopathy 3
• Hypercalcemia develops, which may indicate occult malignancy 3