Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have redefined the management of obesity and type 2 diabetes mellitus, producing sustained and clinically meaningful reductions in total body weight alongside significant cardiometabolic benefits. However, weight loss achieved through pharmacologic energy deficit includes reductions in both adipose tissue and fat-free mass. Although some degree of lean mass decline is physiologically expected, its clinical relevance may vary according to age, baseline muscle reserve, physical activity, nutritional intake, and endocrine status. Testosterone is a key regulator of skeletal muscle mass and metabolic homeostasis. In men with low testosterone levels, testosterone replacement therapy (TRT) consistently increases lean body mass and favorably modifies body composition. Notably, obesity and metabolic disease are frequently associated with reduced circulating testosterone concentrations, creating a subset of patients with diminished anabolic reserve who may be particularly vulnerable to clinically meaningful muscle loss during sustained weight reduction. This structured narrative review examines the physiological and clinical evidence linking GLP-1 RA-induced weight loss, body composition changes, and androgen signaling. While mechanistic and clinical data independently support the anabolic role of testosterone and the predictable lean mass changes accompanying pharmacologic weight loss, no randomized trials have directly evaluated the combined effects of GLP-1 RAs and TRT on body composition outcomes. The available evidence suggests a biologically plausible interaction but does not support routine combined therapy. Testosterone replacement should be beneficial in men with low testosterone levels according to current guidelines; assessment of androgen status, including individuals with low or borderline testosterone levels frequently observed in obesity, may be clinically relevant when evaluating patients experiencing substantial weight loss with GLP-1-based therapies. Future prospective studies incorporating standardized body composition assessment and functional endpoints are required to determine whether androgen status modifies musculoskeletal responses to GLP-1-based pharmacotherapy.
Velasco et al. (Mon,) studied this question.