Testosterone replacement therapy in metabolic dysfunction-associated steatotic liver disease: a bench-to-bedside narrative review

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with obesity, insulin resistance, and increased cardiovascular risk. Male hypogonadism has emerged as a potentially modifiable risk factor, and testosterone replacement therapy (TRT) has been proposed as a potential adjunctive treatment for MASLD and metabolic dysfunction-associated steatohepatitis (MASH) in hypogonadal men. Cross-sectional and longitudinal studies demonstrate a consistent inverse association between serum testosterone and MASLD prevalence and severity. Interventional evidence from randomized controlled trials (RCTs) and observational cohorts suggests TRT is associated with reductions in hepatic steatosis and improvements in liver-related biomarkers. In selected hypogonadal men, particularly those with metabolically active disease, TRT may contribute to MASH resolution and fibrosis improvement, although histological data remain limited. The most consistent response is observed in men with concurrent type 2 diabetes (T2D), obesity, or obstructive sleep apnea (OSA) and significant baseline steatosis. Preclinical data support convergent mechanisms involving the androgen receptor (AR), adenosine monophosphate-activated protein kinase (AMPK), and antifibrotic pathways. While recently approved therapies such as resmetirom and semaglutide represent significant advances in MASH treatment, their distinct mechanisms suggest that complementary roles alongside TRT are biologically plausible, though this remains entirely hypothetical in the absence of combination trial data. Taken together, TRT may represent a promising adjunctive therapy for reducing hepatic steatosis and improving the histopathological features of MASH in selected hypogonadal men with MASLD, particularly those with obesity or T2D and significant baseline steatosis; however, routine clinical use will require large, well-powered Phase 3 RCTs featuring standardized histological endpoints, extended follow-up, and rigorous cardiovascular and oncologic safety data.

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