Skeletal muscle is a critical site of disrupted lipid metabolism in male hypogonadism: an in vivo interventional study

Context Male hypogonadism is associated with adverse cardiometabolic outcomes, however tissue-specific metabolic mechanisms underlying this phenotype remain poorly characterised. Metabolomic profiling in hypogonadism to date has been confined to plasma, with limited insights into skeletal muscle. Objective To characterise the impact of testosterone replacement therapy (TRT) and androgen deprivation (ADT) on the plasma and skeletal muscle metabolome. Design Parallel prospective interventional studies examined men initiating TRT for organic hypogonadism (n=15) and ADT for prostate cancer (n=15). Participants underwent metabolic phenotyping, plasma sampling and vastus lateralis muscle biopsies pre and post intervention (6 months TRT; 3 months ADT), with untargeted metabolomic profiling of both tissues at each timepoint. Results TRT significantly increased serum testosterone (p<0.001) and muscle mass (p<0.05); ADT significantly reduced serum testosterone (p<0.001) and muscle mass (p<0.05) while simultaneously increasing fat mass (p<0.05). TRT significantly altered a total of 118 plasma metabolites, reflecting predominant suppression of circulating lipid species, whereas ADT altered only two. In skeletal muscle, TRT perturbed 89 metabolites and was characterised by expansion of intramuscular lipid species, while ADT altered 109 metabolites, with predominant depletion of intramuscular lipid classes. Following TRT, eight lipid classes showed divergent responses between plasma and skeletal muscle. In skeletal muscle, nine lipid classes responded differentially to TRT and ADT, including fatty acids, triacylglycerides and ceramides. Conclusion This study provides the first untargeted metabolomic characterisation of skeletal muscle in response to androgen manipulation in humans. Distinct plasma and skeletal muscle responses demonstrate tissue-specific regulation that is incompletely captured by plasma profiling alone. These findings highlight skeletal muscle as a key site of androgen-sensitive metabolic regulation, providing evidence for tissue-specific lipid partitioning that may contribute to the cardiometabolic consequences of hypogonadism.