Nontargeted metabolomics identifies a central role for dysfunctional skeletal muscle lipid metabolism in hypogonadism associated metabolic dysfunction in men

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.115.OC10

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Endocrine Abstracts (2026) 115 OC10 | DOI: 10.1530/endoabs.115.OC10

IES2025 Oral Communications Oral Communications (14 abstracts)

Nontargeted metabolomics identifies a central role for dysfunctional skeletal muscle lipid metabolism in hypogonadism associated metabolic dysfunction in men

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 ² , Oleksandr Boychak ² , Brian O’Neill ² & Michael W. O’Reilly ^1,2

Author affiliations

¹Royal College of Surgeons, Dublin, Ireland; ²Beaumont Hospital, Dublin, Ireland; ³University of Liverpool, Liverpool, UK

Hypogonadism in men is linked to an adverse metabolic phenotype which improves after testosterone replacement therapy (TRT). Underlying molecular mechanisms are incompletely defined, however perturbations in skeletal muscle (SkM) energy metabolism have been hypothesised. Here we performed untargeted metabolomic profiling in two separate clinical cohorts with hypogonadism before and after pharmacological intervention. Men with prostate cancer (n = 15) underwent blood sampling and SkM biopsies at baseline and after three months of androgen deprivation therapy (ADT). This protocol was replicated in men with hypogonadism (n = 15) before and after TRT for six months. Plasma and SkM metabolomic profiling was performed by ultra-high performance liquid chromatography–mass spectrometry. Classes with at least five significantly altered metabolites (P < 0.05 for fold change) are discussed. Despite minimal changes in plasma metabolomic profile, the SkM metabolome after ADT revealed significant perturbations, with predominant downregulation of ceramides/sphingolipids, fatty acids, glycerophospholipids and lysoglycerophospholipids. Conversely, the SkM metabolome after TRT showed predominant upregulation of ceramides/sphingolipids, fatty acids, glycerophospholipids and lysoglycerophospholipids. We observed suppressive changes in lipid-related classes in plasma metabolome after TRT. In both cohorts significant changes were observed in SkM metabolites linked with the Krebs cycle and nucleotide metabolism. Divergent trends in the lipid metabolome after ADT and TRT identify novel associations between testosterone deficiency and impaired SkM lipid metabolism. Distinct responses between the plasma and SkM metabolome highlight the tissue-specific effects of androgens in energy metabolism in men. Further research is required to identify therapeutic targets within these pathways to reduce metabolic risk in hypogonadal men.