Exploration of Digestive Diseases

Table 1. Clinical studies of TRT in men with MASLD and other metabolically at-risk populations (2012–2025).

Study (Year)	Design/Population	Intervention/Duration	Key hepatic outcomes	Limitations
Hoyos et al. (2012) [55]	RCT; n = 67 men with obesity and severe OSA (54 completed)	IM T undecanoate 1,000 mg at 0, 6, 12 weeks vs. placebo; 18 weeks	Liver fat ↓ 0.09 HU attenuation ratio (95% CI 0.009–0.17, p = 0.03); insulin sensitivity improved (HOMA-IR ↓ 1.14 units, 95% CI –2.27 to –0.01, p < 0.05); lean muscle mass ↑ 1.6 kg (95% CI 0.69–2.5, p = 0.0009); arterial stiffness ↓ 3.2%	OSA-specific population; short duration (18 weeks); concurrent weight loss program; no change in total weight, fat mass, or VAF; ALT/AST unchanged
Ng Tang Fui et al. (2016) [43]	RCT; n = 100 men with obesity (BMI ≥ 30, T ≤ 12 nmol/L); 82 completed	IM T undecanoate 1,000 mg q10w vs. placebo; 10-week VLED followed by 46-week weight maintenance (56 weeks total)	Fat mass ↓ 2.9 kg (MAD –5.7 to –0.2, p = 0.04); visceral fat ↓ 2,678 mm² (p = 0.04); lean mass preserved; weight loss almost exclusively from fat in T group	Men with obesity and without diabetes; no liver fat measurements; body composition focus only; concurrent hypocaloric diet in all participants
Albhaisi et al. (2020) [56] LiFT Trial	Single-arm study; n = 21, hypogonadal males with MRI-proven MASLD (hepatic fat ≥ 8%)	LPCN 1144 (Oral T undecanoate): 450 mg daily. Duration: 16 weeks	Steatosis: 81% (17/21) showed improvement; mean decrease 4.04% in hepatic fat. MASLD resolution: 46.7% (10/21) achieved < 5% fat on MRI. Enzymes: significant reduction in ALT and AST	No control group; very small sample (n = 21); short duration (16 weeks); MRI only (no biopsy)
Khripun et al. (2020) [57]	RCT; 60 men with T2D and hypogonadism (mean age 54 years)	1% transdermal T gel (AndroGel, 50 mg/day) vs. standard hypoglycemic therapy alone; 6 months	TRT group (n = 30) vs. control group (n = 30): ↓ hepatic fat fraction by 1.7 times; ↓ AST by 31%, ↓ ALT by 21%, ↓ GGT by 15.9% (p < 0.05); improved adipose tissue function (↓ leptin by 1.4×, ↓ resistin by 1.5×, ↑ adiponectin by 1.3×, p < 0.01); ↓ visceral obesity, ↓ hyperinsulinemia by 1.5×, ↓ HOMA-IR by 2.2×; ↓ total cholesterol and TG; improved glycemic control (↓ fasting glucose and HbA1c)	Single-center study; specific population (T2D with hypogonadism only); no long-term safety or efficacy data beyond 6 months; adverse events not specifically reported
Yassin et al. (2020) [58]	Prospective controlled registry study; n = 505 hypogonadal men (age 61 ± 10 years, TT ≤ 350 ng/dL); 321 TRT, 184 controls	IM T undecanoate 1,000 mg q12w (following initial 6-week interval); up to 12 years	FLI ↓ from 83.6 ± 12.08 to 66.91 ± 19.38 (vs. ↑ from 69 to 81 in controls); GGT ↓ from 39.31 ± 11.62 to 28.95 ± 7.57 U/L; bilirubin ↓ from 1.64 ± 4.13 to 1.21 ± 1.89 mg/dL; TG ↓ from 252.35 ± 90.99 to 213 ± 65.91 mg/dL; CVD mortality ↓ (7.8% vs. 15.2% in controls)	Non-randomized; observational design; treatment interruption in 147 men for 17 months due to reimbursement issues; surrogate markers (FLI) rather than imaging or biopsy; self-selection bias (controls opted out of treatment)
Al-Qudimat et al. (2021) [59]	Prospective controlled registry study; n = 496 hypogonadal men (age 59 ± 9.5 years, TT ≤ 12.1 nmol/L); 312 TRT, 184 controls	IM T undecanoate 1,000 mg q12w (following initial 6-week interval); 8 years	FLI ↓ from 83.70 ± 12.15 to 67.12 ± 19.21 (vs. stable in controls); bilirubin ↓ from 1.69 ± 4.21 to 1.31 ± 1.91 mg/dL; GGT ↓ from 39.45 ± 11.51 to 29.11 ± 7.68 U/L; TG ↓ from 254.87 ± 92.99 to 213.37 ± 66.91 mg/dL; CVD-related mortality improved	Non-randomized; observational design; surrogate markers (FLI) rather than imaging or biopsy; self-selection bias (controls opted out of treatment); no histological outcomes
Maseroli et al. (2021) [37]	Prospective observational study; 78 men with severe obesity (bariatric surgery candidates): eugonadal (n = 17), untreated hypogonadal (n = 46), treated hypogonadal (n = 15)	T undecanoate 1,000 mg IM q12w; mean 30 weeks	TTh vs. untreated hypogonadal: ↓ NAS and steatosis scores (p < 0.05); ↓ liver TG to eugonadal levels (p < 0.05); ↓ FLI (p = 0.001); ↓ total cholesterol (p = 0.022); improved hepatic gene expression (insulin signaling, lipid metabolism); enhanced preadipocyte mitochondrial function and insulin sensitivity	Observational design: selection bias (symptomatic patients treated); liver biopsies only at surgery (no baseline); short duration; small TTh group (n = 15)
TEREPINS study (2021) [60] LiFT Trial	Single-arm pilot; n = 3. Hypogonadal males with biopsy-proven MASH	LPCN 1144 (Oral T undecanoate): 450 mg daily. Duration: 52 weeks	Steatosis: Fatty liver grade improved from 2 to 1 in all 3 subjects. Fibrosis: Mean change in central fibrosis: 2.75 (improvement in all 3)	Extremely small sample (n = 3); study terminated early; no control group; results only in trial registry (no peer-reviewed publication)
Apostolov et al. (2022) [61] Secondary analysis of Gianatti 2014	Secondary analysis of RCT; n = 39 men with T2D and low T (subset of 88 from parent trial; 20 T, 19 placebo)	IM T undecanoate 1,000 mg at 0, 6, 18, 30 weeks; 40 weeks	Liver fat ↓ 38.3% relative reduction (95% CI 25.4%–49.0%, p < 0.001) by MRI; median absolute reduction 3.5% vs. placebo increase 1.2% (between-group difference 4.7%, p < 0.001); lean mass ↑ 2.1 kg; fat mass ↓ 3.0 kg; no change in ALT, glucose, or HbA1c	Secondary analysis: not all parent trial participants had MRI; MRI IP/OP sequences used (not MRI-PDFF); liver enzymes within normal range (no significant inflammation); T2D-specific population; 40-week duration may be too short for some outcomes
LiFT Trial (2021) [49]	Phase 2 RCT; N = 56 randomized (3 arms); NASH Resolution set n = 37 (Treatment A: n = 13, Treatment B: n = 13, Placebo: n = 11). Biopsy-proven MASH (NAS ≥ 4, F1–F3), hypogonadal or eugonadal men	LPCN 1144 (oral T undecanoate): Treatment A: 225 mg BID; Treatment B: 225 mg BID + d-alpha tocopherol; vs. placebo. Duration: 36 weeks	Steatosis: ↓ up to 9.2% absolute and 46.8% relative vs. placebo (12 weeks, MRI-PDFF). MASH Resolution: 53.8% (7/13) vs. 9.1% (1/11) placebo. Fibrosis: No significant benefit over placebo; requires confirmation. Enzymes: ALT ↓ 23.4 U/L; AST ↓ 13.3 U/L vs. placebo	Small sample (n = 37); wide CIs due to small numbers; 36-week duration may be insufficient for long-term fibrosis assessment
Lee et al. (2024) [62]	RCT (secondary analysis of T Trials); n = 479 (246 TRT, 233 placebo); CT subgroup n = 140; older hypogonadal men (≥ 65 years, T < 275 ng/dL)	AndroGel 1%, 5 g daily titrated to T 400–800 ng/dL: 12 months	No significant differences in NAFLD scores: LAP (P = 0.98), HSI (P = 0.67), MASLD-MS (P = 0.52); or CT measures: liver HU (P = 0.24), LSR (P = 0.74). MASLD prevalence by HU < 40: 24.6% vs. 24.5% at 12 months (P = 0.21); by LSR < 1: 21.2% vs. 30.4% (P = 0.69). Subgroup analysis (MASLD+): no T benefit	Secondary analysis (not powered for MASLD); small CT subgroup; CT less sensitive than MRI-PDFF; no histology; short duration (12 months); excluded severe obesity (BMI > 37) and uncontrolled DM (HbA1c > 8.5%); no fibrosis assessment
Shigehara et al. (2025) [63] EARTH Study	RCT sub-analysis; n = 186 hypogonadal Japanese men (88 TRT, 98 controls); subgroup with FIB-4 ≥ 1.30 at baseline (n = 60; 28 TRT, 32 controls)	IM T enanthate 250 mg q4w; 12 months	Overall cohort: no change in FIB-4; FIB-4 ≥ 1.30 subgroup: FIB-4 ↓ from 1.98 ± 0.52 to 1.87 ± 0.60 in TRT group (p = 0.0277) vs. no change in controls; improvements correlated with ↓ waist circumference, ↓ body fat, ↓ TG	Retrospective sub-analysis; surrogate marker (FIB-4) rather than imaging or biopsy; no direct measurement of liver fat or histology; Japanese population only; modest effect size in FIB-4 reduction
Mahmoud et al. (2025) [36]	Systematic review and meta-analysis; 9 studies (3 RCTs, 4 non-randomized studies, 2 single-arm studies); adult men with MASLD/MASH, mostly hypogonadal (LiFT included hypogonadal and eugonadal men)	Varied TT (oral LPCN 1144/T undecanoate, IM/parenteral T undecanoate/Reandron, and transdermal AndroGel/T gel); follow-up ranged from 12 weeks to 8 years	All studies reported evidence of reduced hepatic steatosis with TT. LiFT showed MASH resolution and fibrosis improvement/regression; Albhaisi et al. [56] reported MASLD resolution by MRI. TT was associated with decreased liver enzymes; adverse events were generally comparable in comparative studies	Significant heterogeneity in populations, interventions/formulations, routes, doses, durations, endpoints, and outcome assessments; small samples/imprecision; observational studies had confounding/selection-bias concerns; larger high-quality double-blinded placebo-controlled RCTs are needed

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Yassin et al. (2020) [58] and Al-Qudimat et al. (2021) [59] are derived from the same patient registry and should not be considered independent datasets. ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI: body mass index; CI: confidence interval; CT: computed tomography; CVD: cardiovascular disease; DM: diabetes mellitus; FIB-4: fibrosis-4 index; FLI: fatty liver index; GGT: gamma-glutamyl transferase; HbA1c: hemoglobin A1c; HOMA-IR: homeostatic model assessment of insulin resistance; HSI: hepatic steatosis index; HU: Hounsfield unit; IM: intramuscular; LAP: lipid accumulation product; LPCN: Lipocine Inc.; LSR: liver-spleen ratio; MAD: mean absolute difference; MASLD: metabolic dysfunction-associated steatotic liver disease; MASLD-MS: MASLD metabolic score; MASH: metabolic dysfunction-associated steatohepatitis; MRI: magnetic resonance imaging; MRI IP/OP: MRI in-phase/opposed-phase; MRI-PDFF: MRI-proton density fat fraction; NAFLD: non-alcoholic fatty liver disease; NAS: NAFLD activity score; OSA: obstructive sleep apnea; q4w: every 4 weeks; q10w: every 10 weeks; q12w: every 12 weeks; RCT: randomized controlled trial; T: testosterone; T2D: type 2 diabetes; TG: triglyceride; TRT: testosterone replacement therapy; TT: total testosterone; TTh: testosterone therapy; VAF: visceral adipose fat; VLED: very low energy diet.

Declarations

Acknowledgments

The diagrams were generated using BioRender.

Author contributions

YL: Conceptualization, Writing—original draft. VP: Conceptualization, Writing—review & editing, Supervision. Both authors read and approved the submitted version.

Conflicts of interest

Vassilios Papadopoulos, who is the Editorial Board Member of Exploration of Digestive Diseases, had no involvement in the decision-making or the review process of this manuscript. Another author declares no conflicts of interest.

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Not applicable.

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Funding

This work was supported by the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences and the John Stauffer Dean’s Chair in Pharmaceutical Sciences at USC (to VP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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