Endocrine and metabolic determinants of cardiometabolic risk in mild autonomous cortisol secretion
Prete, Alessandro Abdi, Lida Canducci, Marco van den Brandhof, Elina L Albors-Zumel, Ariadna Jenkinson, Carl Gilligan, Lorna C Zhang, Yuanqing Visser, Ludger Chortis, Vasileios
Prete, Alessandro
Abdi, Lida
Canducci, Marco
van den Brandhof, Elina L
Albors-Zumel, Ariadna
Jenkinson, Carl
Gilligan, Lorna C
Zhang, Yuanqing
Visser, Ludger
Chortis, Vasileios
Affiliation
University of Birmingham; Birmingham Health Partners; University Hospitals Birmingham NHS Foundation Trust; Medical Research Council Laboratory of Medical Sciences; University of Groningen; University Medical Center Groningen; University of Trento; Evangelismos Hospital; Medical University of Warsaw; Mayo Clinic; University Hospital Centre Zagreb; University of Turin; University Clinical Centre of Serbia; University of Belgrade; University of Würzburg; University Hospital Würzburg; Royal College of Surgeons in Ireland; Technische Universität Dresden; Endocrinology in Charlottenburg; Haukeland University Hospital; University Hospital Galway; Universitäts-Spital Zürich; Universität Zürich; Ludwig-Maximilians-Universität München; The LOOP Zurich - Medical Research Center; Centre Hospitalier Universitaire Haut Leveque; European Reference Network on Rare Endocrine Conditions; University of Liverpool; Imperial College London
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Publication date
2026-01-22
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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.
Citation
Prete A, Abdi L, Canducci M, van den Brandhof EL, Albors-Zumel A, Jenkinson C, Gilligan LC, Zhang Y, Visser L, Chortis V, Najdekr L, Jankevics A, Lloyd GR, Winder CL, Tsagarakis S, Lang K, Macech M, Fell V, Vodanovic ID, Reimondo G, Marina LV, Deutschbein T, Balomenaki M, O'Reilly MW, Bednarczuk T, Dusek T, Diamantopoulos A, Asia M, Kondracka A, Yu K, Masjkur JR, Quinkler M, Ueland GÅ, Dennedy MC, Beuschlein F, Tabarin A, Fassnacht M, Ivovic M, Terzolo M, Kastelan D, Young WF Jr, Manolopoulos KN, Ambroziak U, Vassiliadi DA, Bancos I, Sitch AJ, Taylor AE, Tino P, Biehl M, Dunn WB, Arlt W; ENSAT EURINE-ACT Investigators. Endocrine and metabolic determinants of cardiometabolic risk in mild autonomous cortisol secretion. EBioMedicine. 2026 Jan 22;124:106126. doi: 10.1016/j.ebiom.2026.106126. Epub ahead of print.
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Article