Alessandro Prete, Lida Abdi, Marco Canducci, Elina Laura 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 Dora Vodanović, Giuseppe Reimondo, Ljiljana V. Marina, Timo Deutschbein, Maria Balomenaki, Michael O'Reilly, Tomasz Bednarczuk, Tina Dušek, 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 Ivović, Massimo Terzolo, Darko Kastelan, William F. Young, Konstantinos Manolopoulos, Urszula Ambroziak, Dimitra A. Vassiliadi, Irina Bancos, Alice J. Sitch, Angela E. Taylor, Peter Tiňo, Michael Biehl, Warwick B. Dunn, Wiebke Arlt
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.