Effects of testosterone undecanoate as add-on therapy in obese hypogonadal men that are late responders to tirzepatide: a pilot study.

Abstract

Background: Male obesity-associated hypogonadism promotes a vicious cycle of sarcopenic obesity and increased cardiometabolic risk. Although tirzepatide is highly effective for weight loss, a subset of "late responders" has been reported, and treatment-induced lean body mass (LBM) depletion remains a significant clinical concern. This pilot study evaluated the efficacy of adding testosterone undecanoate (TRT) to tirzepatide in this specific population.

Methods: We enrolled 10 obese men (age range: 35-44 years; Body Mass Index [BMI] = 35.8±2.1 kg/m²) with functional secondary hypogonadism after ≥3 months of treatment with tirzepatide and <5% total body weight loss (late responders). Patients were then allocated to group A (tirzepatide monotherapy, N.=5) or group B (combined tirzepatide plus testosterone undecanoate 1000 mg/im, N.=5) and re-evaluated after 6 months. DXA-derived body composition, hormonal and metabolic profiles, sexual function (International Index of Erectile Function-5, IIEF-5), and physical activity levels (Global Physical Activity Questionnaire) were evaluated.

Results: At 6 months, group B demonstrated significantly greater body weight and fat mass reduction compared to group A (P<0.05). Notably, while group A experienced progressive LBM loss, group B achieved significant LBM recovery (66.1±3.1 kg vs. 63.4±3.0 kg in group A, P<0.01). group B showed restored testosterone levels, leading to superior improvements in insulin sensitivity (HOMA-IR: 2.9±0.6 vs. 3.8±0.7, P<0.01) and sexual health (IIEF-5: 23.2±2.1 vs. 18.0±1.5, P<0.001). Additionally, group B exhibited nearly doubled physical activity levels (P<0.001), suggesting a synergy between hormonal restoration and increased exercise motivation.

Conclusions: Our preliminary findings suggest that adding TRT to tirzepatide in late tirzepatide responders who are hypogonadal may optimize weight loss quality, prevent muscle depletion, and restore sexual and metabolic health. This dual pharmacological approach represents a promising precision medicine strategy for managing complex phenotypes of male obesity-associated hypogonadism.