Liver Effects of Oral Testosterone Therapy
Oral testosterone therapy may cause transient elevations in liver enzymes that are usually self-limited, but 17-alpha-alkylated oral testosterone (methyltestosterone) should be avoided due to significant risk of hepatotoxicity including peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice. 1, 2
Types of Oral Testosterone and Their Hepatic Impact
17-Alpha-Alkylated Testosterone (Methyltestosterone)
- Significant hepatotoxicity risk - Associated with serious adverse liver effects including:
- Peliosis hepatis (potentially life-threatening)
- Hepatic neoplasms
- Cholestatic hepatitis
- Jaundice 2
- The American Urological Association strongly recommends against prescribing alkylated oral testosterone due to these liver toxicity concerns 1
Newer Testosterone Undecanoate Formulations
- Improved safety profile - Generally not associated with clinically significant liver toxicity 3
- No clinically significant liver toxicities were noted in clinical trials of oral testosterone undecanoate 3
- Provides a safer oral administration option compared to older formulations
Liver Effects in Different Patient Populations
Patients with Normal Liver Function
- Transient elevations in liver enzymes may occur but are usually self-limited 1
- Regular monitoring of liver function is recommended during treatment
Patients with Liver Disease
- Altered testosterone metabolism - Patients with liver cirrhosis show decreased hepatic extraction of testosterone 4
- Bioavailability of oral testosterone is significantly higher in patients with cirrhosis and portocaval shunts due to decreased metabolism and portosystemic shunting 5
- Long-term oral testosterone treatment (200 mg TID) did not significantly affect liver morphology in men with alcoholic cirrhosis in a controlled study 6
- Testosterone replacement may be used in hypogonadal men with chronic liver disease 1
- Testosterone therapy in men with cirrhosis has shown benefits including significant increases in muscle and bone mass, with a trend toward lowering mortality 1
Monitoring Recommendations
Initial Assessment
- Baseline liver function tests before starting therapy
- Identify patients with pre-existing liver conditions
Follow-up Monitoring
- Regular assessment of liver function during treatment
- First follow-up at 1-2 months to assess efficacy and safety 7
- Subsequent visits at 3-6 month intervals for the first year, then yearly 7
- Patients should be instructed to report any signs or symptoms of hepatic dysfunction (e.g., jaundice) 2
Clinical Considerations and Precautions
Alternative Formulations
- Non-oral formulations (transdermal, intramuscular, subcutaneous pellets) bypass first-pass liver metabolism and may be preferred in patients with liver concerns
- Target testosterone levels should be in the mid-normal range (450-600 ng/dL) 7
Special Populations
- Female-to-male transgender patients should be screened for liver abnormalities before initiation of high-dose androgen therapy 1
- Patients with advanced liver disease may benefit from testosterone therapy for sarcopenia, but require close monitoring 1
Mechanism of Hepatic Effects
- Oral testosterone undergoes first-pass metabolism in the liver
- 17-alpha-alkylation (in methyltestosterone) prevents hepatic degradation but increases hepatotoxicity 2
- Newer formulations like testosterone undecanoate are absorbed via the lymphatic system, partially bypassing first-pass metabolism 3
- Testosterone has direct hepatic actions in the regulation of protein, lipid, and glucose metabolism 8
In conclusion, while older 17-alpha-alkylated oral testosterone formulations carry significant hepatotoxicity risks, newer oral testosterone undecanoate formulations appear to have a better liver safety profile. Regular monitoring of liver function is still recommended, and non-oral formulations may be preferred in patients with pre-existing liver concerns.