Endocrine and metabolic determinants of cardiometabolic risk in mild autonomous cortisol secretion
Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Benign adrenal tumours, found in 1-7% of adults, can be non-functioning (NFAT) or show mild autonomous cortisol secretion (MACS), i.e., biochemical cortisol excess without manifestations of Cushing's syndrome (CS). MACS occurs in 20-50% of cases and is linked to increased cardiometabolic burden. METHODS: In a cross-sectional study, we analysed the 24-h urinary steroid metabolome of 1305 prospectively recruited patients (649 NFAT, 591 MACS, 65 adrenal CS) by tandem mass spectrometry. A sub-group (104 NFAT, 140 MACS, 47 adrenal CS) underwent untargeted serum metabolome analysis by mass spectrometry. Data were analysed using linear regression and supervised machine learning. FINDINGS: Alongside the expected increase in glucocorticoid excretion from NFAT over MACS to adrenal CS, steroid analysis revealed decreased classic androgen metabolite excretion. By contrast, adrenal-derived 11-oxygenated androgen metabolites remained unchanged. Both glucocorticoid metabolites and the major 11-oxygenated androgen metabolite 11β-hydroxyandrosterone correlated with a higher risk of hypertension and type 2 diabetes. Untargeted metabolome analysis revealed gradual changes towards a lipotoxic phenotype from NFAT over MACS to adrenal CS, with perturbations in glycerophospholipids, lysoglycerophospholipids, triacylglycerides, ceramides, sphingolipids, and acylcarnitines. INTERPRETATION: MACS represents a metabolic continuum between NFAT and adrenal CS. Increased activity of the adrenal enzyme 11β-hydroxylase (CYP11B1), which catalyses key steps in cortisol and 11-oxygenated androgen biosynthesis, may contribute to steroid excess and cardiometabolic morbidity in MACS. These findings suggest that CYP11B1 may be a potential therapeutic target to ameliorate metabolic dysfunction in MACS. FUNDING: NIHR Birmingham Biomedical Research Centre; Diabetes UK; Wellcome Trust; European Commission; Medical Research Council.
Source: EBioMedicine
Authors: Alessandro Prete, Lida Abdi, Marco Canducci, Elina L. van den Brandhof, Ariadna Albors-Zumel, Carl Jenkinson, Lorna C. Gilligan, Yuanqing Zhang, Ludger Visser, Vasileios Chortis, Lukáš Najdekr, Andris Jankevics, Gavin R. Lloyd, Catherine L. Winder, Stylianos Tsagarakis, Katharina Lang, Magdalena Macech, Vanessa Fell, Ivana D. Vodanovic, Giuseppe Reimondo, Ljiljana V. Marina, Timo Deutschbein, Maria Balomenaki, Michael W. O'Reilly, Tomasz Bednarczuk, Tina Dusek, Aristidis Diamantopoulos, Miriam Asia, Agnieszka Kondracka, Kai Yu, Jimmy R. Masjkur, Marcus Quinkler, Grethe Å. Ueland, M. Conall Dennedy, Felix Beuschlein, Antoine Tabarin, Martin Fassnacht, Miomira Ivovic, Massimo Terzolo, Darko Kastelan, William F. Young, Konstantinos N. Manolopoulos, Urszula Ambroziak, Dimitra A. Vassiliadi, Irina Bancos, Alice J. Sitch, Angela E. Taylor, Peter Tino, Michael Biehl, Warwick B. Dunn, Wiebke Arlt
Institutions: University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Medical Research Council, University Medical Center Groningen, University of Groningen, University of Trento, Evangelismos Hospital, Medical University of Warsaw, Mayo Clinic, University Hospital Centre Zagreb, University of Turin, University of Belgrade, Univerzitetski Klinički Centar Srbije, University of Würzburg, Universitätsklinikum Würzburg, Royal College of Surgeons in Ireland, Technische Universität Dresden, Haukeland University Hospital, University Hospital Galway, University of Zurich, University Hospital Zurich, Ludwig-Maximilians-Universität München, Endo-ERN, National Institute for Health and Care Research, University of Liverpool, Imperial College London
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,780
Funders: National Institute on Handicapped Research, Mayo Foundation for Medical Education and Research, Wellcome Trust, Alan Turing Institute, UK Research and Innovation, Queen Elizabeth Hospital Birmingham Charity, National Institute for Health and Care Research, Department of Health and Social Care, Diabetes UK, Academy of Medical Sciences, European Commission, Deutsche Forschungsgemeinschaft, National Institutes of Health, Horizon 2020 Framework Programme, Seventh Framework Programme, HORIZON EUROPE Framework Programme, Medical Research Council, Seventh Framework Programme, NIHR Imperial Biomedical Research Centre, Birmingham Biomedical Research Centre, National Institute of Diabetes and Digestive and Kidney Diseases, FP7 Coordination of Research Activities
Awards: G1020156634, G129648101, G149142424, Improving treatment efficacy in hypertension by biomarker-guided personalised decision support, G2397378216, Integrating innovative technologies for genotyping and phenotyping in stratified medicine, TRR 205: Die Nebenniere: Zentrales Relais in Gesundheit und Krankheit, Exploring the metabolic impact of mild autonomous cortisol excess (MACE), an underestimated cause of diabetes, G3207356259, G339059223, G4002980589, G4341039167, European Network for the Study of Adrenal Tumours - Structuring clinical research on adrenal cancers in adults, Dissecting Androgen excess and metabolic dysfunction – an Integrated SYstems approach to PolyCystic Ovary Syndrome (DAISY-PCOS), Application of omics-based strategies for improved diagnosis and treatment of endocrine hypertension, G600920662, G6715304073, G6839890769, G8544719433, G9000064846
OpenAlex ID: W7125429891