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Publications

Journal Article Ahead of print 3 citations

PubMed: 42413529 DOI: 10.1016/S2213-8587(26)00098-7

Temporal changes in cortisol secretion and their association with long-term outcomes in benign adrenal incidentalomas: a retrospective cohort study.

Lancet Diabetes Endocrinol

Authors: Onnicha Suntornlohanakul, Giuseppe Reimondo, Marco Ghislieri, Luigi Petramala, Kimberly Coscia, Ivana Kraljevic, Anna Perini, Filippo Ceccato, Serena Palmieri, Lakshmi Rengarajan, Malgorzata Bobrowicz, Barbara Altieri, Leili Rahimi, Joanna Matrozova, Maria Elena Aloini, Diego Rivas-Otero, Magnus Löndahl, Ljiljana V Marina, Krystallenia I Alexandraki, Henrik Falhammar, Nuria Valdés Gallego, Valentina Morelli, Anna Angelousi, Grethe Å Ueland, Andrea M Isidori, Duarte Pignatelli, Vittoria Favero, Verena Theiler-Schwetz, Francesco Circosta, Lorenzo Tucci, Mirjana Đukić, Soraya Puglisi, Giulia Bovo, Alessandra Mangone, Cristina L Ronchi, Adrianna Gladka, Mario Detomas, Vladimir Vasilev, Adriana D Servello, Francesca Donnarumma, Cristina Botto, Yasir S Elhassan, Miomira Ivović, Ola Lindgren, Edelmiro Menéndez Torre, Antonio Stigliano, Irina Bancos, Urszula Ambroziak, Giovanna Mantovani, Carla Scaroni … and 8 other authors

Affiliations

  • Department of Metabolism and Systems Science, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK; Endocrinology and Metabolism Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.
  • Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Turin, Italy.
  • Department of Electronics and Telecommunications, Polito(BIO)Med Lab, Politecnico di Torino, Turin, Italy.
  • Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
  • Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.
  • School of Medicine, University of Zagreb, Zagreb, Croatia; Department of Endocrinology, University Hospital Zagreb, Zagreb, Croatia.
  • Department of Medicine DIMED, University of Padova, Padova, Italy; Endocrine Disease Unit, University-Hospital of Padova, Padova, Italy.
  • Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Department of Metabolism and Systems Science, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UK.
  • Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw, Poland.
  • Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Germany.
  • Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA; Division of Endocrinology and Metabolism, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • University Hospital of Endocrinology, Medical University, Sofia, Bulgaria.
  • Endocrinology, Department of Clinical and Molecular Medicine, Sant'Andrea University Hospital - Sapienza University of Rome, Rome, Italy.
  • Servicio de Endocrinología, Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.
  • Eli Lilly and Company, Indianapolis, IN, USA.
  • Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
  • Second Department of Surgery, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
  • Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Endocrinology and Nutrition Department, Diabetes and Endocrine Research Group, Biobizkaia Health Research Institute, Hospital Universitario Cruces, EHU, Endo-ERN, CIBERDEM, CIBERER, Barakaldo, Spain.
  • Department of Endocrine and Metabolic Disease, Istituto Auxologico Italiano, IRCCS, Milan, Italy.
  • First Department of Internal Medicine, Unit of Endocrinology, Laiko Hospital, National and Kapodistrian University of Athens, Greece.
  • Department of Medicine, Haukeland University Hospital, Bergen, Norway.
  • Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
  • Department of Endocrinology, Centro Hospitalar Universitário São João, Porto, Portugal.
  • Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy; Unit of Endocrinology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.
  • Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
  • Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.
  • Department of Metabolism and Systems Science, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UK; Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.
  • Department of Endocrinology and Diabetes, General Hospital Dr Ivo Pedisic, Sisak, Croatia.
  • Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Italy.
  • Department of Metabolism and Systems Science, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK.
  • Department of Endocrinology, Skåne University Hospital, Lund, Sweden; Faculty of Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
  • Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA.

Abstract

BACKGROUND

Mild autonomous cortisol secretion (MACS), the most common hormonal abnormality in adrenal incidentalomas, is associated with increased cardiometabolic risk. MACS is defined by cortisol concentrations higher than 50 nmol/L after a 1-mg overnight dexamethasone suppression test (1-mg DST). The prognostic value of a single test remains uncertain. We examined longitudinal changes in 1-mg DST results, cumulative cortisol exposure, and their associations with cardiometabolic outcomes and mortality.

METHODS

In this retrospective cohort study conducted in 25 adrenal centres that are part of the European Network for the Study of Adrenal Tumours consortium across 14 countries with adults (aged ≥18 years) with benign adrenal incidentalomas diagnosed from Jan 1, 2000, to Dec 1, 2020, two or more 1-mg DSTs, and follow-up of at least 36 months, we used multivariable Cox models to assess associations between longitudinal 1-mg DST results and all-cause mortality and cardiovascular and thrombotic events. Patients with Cushing's syndrome, primary aldosteronism, phaeochromocytoma, or androgen-secreting tumour at baseline; active malignancy within 36 months of incidentaloma diagnosis; or suspicion of unreliable 1-mg DST results were excluded, along with patients taking oral glucocorticoids, strong CYP3A4 modulators, adrenal enzyme inhibitors, oral oestrogen, or selective oestrogen receptor modulators. Cumulative cortisol exposure was estimated from serial 1-mg DSTs. Restricted mean survival time (RMST) quantified differences in event-free time. Data were collected from the electronic health records of all eligible patients at each participating centre.

FINDINGS

Among 2525 patients (median follow-up 80 months [IQR 49-122]), 563 (22·3%) had changes in 1-mg DST results leading to a change in diagnosis, most within 3 years of their baseline 1-mg DST. Patients with persistently abnormal 1-mg DST results (ie, MACS-to-MACS patients; n=839) were older and had a greater cardiometabolic burden than those with persistently normal results (ie, non-functioning adrenal tumours [NFAT]-to-NFAT patients; n=1103). MACS-to-MACS patients had a higher rate of worsening hypertension (adjusted hazard ratio 1·34 [95% CI 1·03-1·73]) and a shorter event-free time for worsening hypertension (10-year RMST 60·4 months [56·8-75·5] vs 86·1 months [79·1-93·4]) than NFAT-to-NFAT patients. In crude analyses, patients with higher baseline post-1-mg DST cortisol, patients with greater cumulative cortisol exposure, and MACS-to-MACS patients had shorter survival and event-free time; however, these associations were not independent of age and baseline cardiometabolic risk factors after multivariable adjustment.

INTERPRETATION

Longitudinal 1-mg DST changes are common. MACS-to-MACS patients had worsening hypertension, but rates of mortality and cardiovascular or thrombotic events were not significantly associated with 1-mg DST trajectories after adjustment for age and cardiovascular risk factors. These findings identify patients with persistently abnormal 1-mg DST results as a group with high cardiometabolic risk that warrants closer attention to modifiable risk factors. Prospective studies are needed to establish the clinical significance of repeated 1-mg DSTs for risk stratification.

FUNDING

National Institute for Health and Care Research Birmingham Biomedical Research Centre, Horizon Europe 2022, and Deutsche Forschungsgemeinschaft.

MeSH

Diabetes Mellitus, Hypertension, Mortality, Incidental Findings, Cohort Studies, Risk Factors, Diagnosis, Hydrocortisone