| Source: |
Prete, A, Abdi, L, Canducci, M, van den Brandhof, E L, Albors-Zumel, A, Jenkinson, C, Gilligan, L C, Zhang, Y, Visser, L, Chortis, V, Najdekr, L, Jankevics, A, Lloyd, G R, Winder, C L, Tsagarakis, S, Lang, K, Macech, M, Fell, V, Vodanovic, I D, Reimondo, G, Marina, L V, Deutschbein, T, Balomenaki, M, O'Reilly, M W, Bednarczuk, T, Dusek, T, Diamantopoulos, A, Asia, M, Kondracka, A, Yu, K, Masjkur, J R, Quinkler, M, Ueland, G Å, Dennedy, M C, Beuschlein, F, Tabarin, A, Fassnacht, M, Ivovic, M, Terzolo, M, Kastelan, D, Young, W F, Manolopoulos, K N, Ambroziak, .... |
| Description: |
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. |