Treatment strategies for functional hypogonadism in obese men: a systematic review and network meta-analysis

Obesity-related functional hypogonadism (FH) is a potentially reversible condition associated with sexual dysfunction, metabolic disorders, altered body composition, and impaired quality of life. Although several treatment strategies are available, their comparative benefits and safety remain uncertain. This systematic review and network meta-analysis aimed to characterize their outcome-specific effects and the confidence of the comparative evidence in adult men with obesity-related FH.

PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to April 2026 for randomized controlled trials evaluating structured lifestyle therapy (SLT), testosterone replacement therapy (TRT), endogenous testosterone restoration (ETR) therapy, glucagon-like peptide-1 receptor agonist-based therapy, or TRT plus SLT. Frequentist network meta-analyses were performed. Risk of bias was assessed using RoB 2, and confidence in the evidence was evaluated using CINeMA. Sensitivity and direct-evidence analyses were conducted to examine the robustness of the principal findings.

Twenty-three randomized controlled trials involving 1899 participants were included. Compared with usual care/placebo, TRT plus SLT showed the largest estimated increase in total testosterone (MD 7.19, 95% CI, 1.18-13.21), followed by ETR therapy (MD 4.14, 95% CI, 0.74-7.54) and TRT (MD 2.53, 95% CI, 0.26-4.81). Testosterone replacement therapy plus SLT significantly improved International Index of Erectile Function scores (MD 1.29, 95% CI, 0.07-2.50). No intervention significantly reduced glycated hemoglobin compared with usual care/placebo. Testosterone replacement therapy reduced waist circumference and increased lean mass but also increased hematocrit; ETR therapy and TRT plus SLT also increased lean mass. No significant differences in adverse events were detected. Sensitivity and direct-evidence analyses generally supported the direction of the principal findings.

Available treatments showed distinct outcome-specific effects, but no single strategy was consistently superior across all outcomes. Confidence in many comparisons was low or very low, and the included trials differed in participant characteristics, treatment protocols, and follow-up duration. These findings should inform individualized treatment decisions rather than a definitive treatment ranking, and require confirmation in longer-term head-to-head trials.