Utilising untargeted metabolomics as a tool to dissect dysfunctional skeletal muscle lipid metabolism in men with hypogonadism: results from a metabolic phenotyping study

Clare Miller; Leanne Cussen; Tara McDonnell; Mark Sherlock; Marie McIlroy; Amar Agha; Catherine Winder; Warwick Dunn; Jerome Coffey; Oleksandr Boychak; Brian O; Michael W. O

doi:10.1530/endoabs.117.P108

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Endocrine Abstracts (2026) 117 P108 | DOI: 10.1530/endoabs.117.P108

SFEBES2026 Poster Presentations Metabolism, Obesity and Diabetes (68 abstracts)

Utilising untargeted metabolomics as a tool to dissect dysfunctional skeletal muscle lipid metabolism in men with hypogonadism: results from a metabolic phenotyping study

Clare Miller ^1,2 , Leanne Cussen ^1,2 , Tara McDonnell ^1,2 , Mark Sherlock ^1,2 , Marie McIlroy ¹ , Amar Agha ² , Catherine Winder ³ , Warwick Dunn ³ , Jerome Coffey ⁴ , Oleksandr Boychak ⁴ , Brian O’Neill ⁴ & Michael W. O’Reilly ^1,2

Author affiliations

¹Androgens in Health and Disease Research Group, Dublin, Ireland; ²Department of Endocrinology, Beaumont Hospital, Dublin, Ireland; ³Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom; ⁴Department of Radiation Oncology, St Lukes Radiation Oncology Centre, Dublin, Ireland

Hypogonadism in men is linked to an adverse metabolic phenotype that improves with testosterone replacement therapy (TRT), however tissue-specific molecular mechanisms remain incompletely defined. Skeletal muscle (SkM) is the principal site of peripheral glucose uptake and fatty acid oxidation and is therefore a potential site of androgen-mediated metabolic remodelling. Here we performed clinical phenotyping and untargeted metabolomic profiling in two independent clinical cohorts before and after pharmacological intervention. Men with prostate cancer (n = 15) underwent blood sampling, anthropometric assessment, bioimpedance analysis and SkM biopsies at baseline and after three months of androgen deprivation therapy (ADT). The protocol was replicated in men with hypogonadism (n = 15) before and after six months of TRT. Plasma and SkM metabolomic profiling was performed using ultra-high performance liquid chromatography–mass spectrometry. ADT significantly increased total body fat (P = 0.01) and trunk fat % (P = 0.0003), with reductions in total muscle mass (P = 0.02). Conversely, TRT induced non-significant reductions in fat mass, significant increases in trunk (P = 0.002) and total muscle mass (kg) (P = 0.02), and a significant reduction in HbA1c (P = 0.006). Despite minimal changes in plasma, ADT decreased the concentration of many lipid classes in SkM, notably fatty acids and ceramides with an increase in acylglycerides. Conversely, TRT increased the concentration of most lipid classes in SkM (notably fatty acids, acylglycerides and ceramides) while plasma lipid classes fell, suggesting altered intramuscular lipid handling and redistribution from circulation to tissue. Acylcarnitines declined in both compartments post TRT but increased in SkM following ADT. ADT and TRT exert opposing diametric tissue-specific effects on lipid metabolism. These findings suggest that androgens influence mitochondrial and carnitine dependent fatty acid pathways, although the physiological significance requires further clarification. Ongoing mechanistic work is needed to determine how these adaptations integrate within the broader metabolic response to androgen manipulation.