The Effects of Testosterone Replacement Therapy in Adult Men with Metabolic Dysfunction associated Steatotic Liver Disease: A Systematic Review and Meta-analysis.

Background: Sex steroids modulate metabolic-dysfunction associated steatotic liver disease (MASLD) pathobiology. We hypothesized that testosterone therapy (TT) modulates progression of MASLD, and performed a systematic review to evaluate the efficacy of TT on liver steatosis and fibrosis.

Methods: We searched PubMed and Embase from inception until November 2023. We screened 1489 studies and identified 9 eligible studies. We assessed risk of bias for randomized trials using RoB-2 "Cochrane risk of bias tool for randomized trials", non-randomized studies using ROBINS-I tool "Risk of Bias in Non-randomized Studies-of Interventions", and Murad's Tool for single-arm studies. We pooled estimates using RevMan 5.

Results: 3 randomized controlled trials (RCTs), 4 non-randomized studies, and 2 single-arm studies were identified. The population of interest comprised men with MASLD. TT was administered at varying doses, routes, and frequencies, with follow-up ranging 12-weeks to 8-years. Liver fibrosis and steatosis were assessed using liver biopsy in 3 studies, CT/MRI in 5, and serum scores in 2. All studies provided evidence of reduction in liver steatosis with TT compared to no TT. In addition, the LiFT (RCT) trial demonstrated a resolution of MASLD / MASH and a regression in liver fibrosis. TT led to decrease in liver enzymes. Studies were heterogenous in terms of population characteristics, treatment modalities, endpoints, and follow-up. Adverse events were comparable between the 2 groups.

Conclusion: TT is a promising treatment option for men with MASLD and low testosterone. It may improve liver steatosis and reduce liver fibrosis. Large, double-blinded randomized placebo-controlled trials are needed.