Can testosterone replacement therapy (TRT) cause hyperbilirubinemia in males?

Testosterone Replacement Therapy and Hyperbilirubinemia

Testosterone replacement therapy using intramuscular injections or transdermal preparations does not cause hyperbilirubinemia and does not require routine liver function monitoring, while oral testosterone preparations (which are strongly discouraged in the United States) are associated with hepatotoxicity. 1

Hepatic Effects by Formulation Type

Intramuscular and Transdermal Testosterone (Safe)

• Intramuscular injections and transdermal preparations do not appear to be associated with hepatic dysfunction, eliminating the need for routine liver function tests in men receiving these forms of testosterone supplementation 1
• Long-term testosterone undecanoate (intramuscular) therapy actually decreased bilirubin levels in hypogonadal men from 1.64 ± 4.13 to 1.21 ± 1.89 mg/dL over 12 years, along with improvements in other liver parameters 2
• The FDA label for intramuscular testosterone lists cholestatic jaundice and alterations in liver function tests as possible adverse reactions, but these are rare and primarily associated with oral formulations 3

Oral Testosterone Preparations (Hepatotoxic - Avoid)

• Oral preparations of testosterone have been reported to lead to hepatotoxic effects and neoplasia, including benign and malignant tumors 1
• The use of oral forms of testosterone in the United States is strongly discouraged because of the associated hepatotoxicity 1
• Testosterone undecanoate is an oral preparation that does not appear to have appreciable hepatotoxicity, but it is not available in the United States 1

Clinical Evidence Supporting Hepatic Safety

Improvements in Liver Function

• In a 12-year prospective registry study of 321 hypogonadal men receiving testosterone undecanoate, patients exhibited decreased γ-GT (39.31 ± 11.62 to 28.95 ± 7.57 U/L) and improved fatty liver index (83.6 ± 12.08 to 66.91 ± 19.38) 2
• These improvements in liver function may have contributed to reduced cardiovascular-related mortality in the testosterone-treated group 2

Monitoring Recommendations

No Routine Liver Monitoring Required

• Routine monitoring with liver-function tests is unnecessary for men receiving intramuscular or transdermal testosterone supplementation 1
• Baseline monitoring should focus on PSA, hematocrit/hemoglobin, and digital rectal examination, with optional lipid evaluation 1

Follow-up Schedule

• First follow-up visit at 1-2 months to assess efficacy and consider dose escalation if needed 1
• Subsequent monitoring visits at 3-6 month intervals for the first year, then yearly thereafter 1

Important Clinical Caveat

The critical distinction is formulation-dependent: oral testosterone preparations carry hepatotoxic risk and can cause cholestatic jaundice, while modern intramuscular and transdermal formulations used in clinical practice do not cause hyperbilirubinemia and may actually improve liver parameters in men with underlying hepatic steatosis 1, 2. This makes the route of administration the determining factor for hepatic safety.