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Cushing syndrome

Nature Reviews Disease Primers volume 11, Article number: 4 (2025) Cite this article

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Abstract

Cushing syndrome (CS) is a constellation of signs and symptoms caused by excessive exposure to exogenous or endogenous glucocorticoid hormones. Endogenous CS is caused by increased cortisol production by one or both adrenal glands (adrenal CS) or by elevated adrenocorticotropic hormone (ACTH) secretion from a pituitary tumour (Cushing disease (CD)) or non-pituitary tumour (ectopic ACTH secretion), which stimulates excessive cortisol production. CS is associated with severe multisystem morbidity, including impaired cardiovascular and metabolic function, infections and neuropsychiatric disorders, which notably reduce quality of life. Mortality is increased owing to pulmonary emboli, infection, myocardial infarction and cerebrovascular accidents. The clinical presentation is variable and because some CS signs and symptoms are common in the general population, the diagnosis might not be considered until many features have accumulated. Guidelines recommend screening patients with suspected CS with 24-h urine cortisol, bedtime salivary cortisol and/or 1 mg dexamethasone suppression test. Subsequently, determining the aetiology of CS is important as it affects management. The first-line therapy for all aetiologies of endogenous CS is surgical resection of the causal tissue, including corticotroph adenoma or ectopic tumour for ACTH-dependent CS or unilateral or bilateral adrenalectomy for adrenal CS. Second-line therapies include steroidogenesis inhibitors for any cause of CS, pituitary radiation (with or without steroidogenesis inhibitors) for CD, and bilateral adrenalectomy for ACTH-dependent causes of CS.

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Fig. 1: Aetiologies of CS and clinical signs associated with the most severe presentations.
Fig. 2: Pathophysiology of CS.
Fig. 3: Incidence of CS in various countries/regions.
Fig. 4: Molecular mechanisms of adrenal causes of Cushing syndrome.
Fig. 5: Strategy for the differential diagnosis of CS.
Fig. 6: Management of ACTH-dependent CS.

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Authors and Affiliations

  1. Section on Translational Endocrinology, Diabetes, Endocrine and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA

    Lynnette K. Nieman

  2. Aix Marseille Univ, INSERM, UMR1251, Marseille Medical Genetics, Institut MarMaRa, Marseille, France

    Frederic Castinetti

  3. APHM, Department of Endocrinology, French Reference Center on Rare Pituitary Diseases HYPO, Hôpital La Conception, Marseille, France

    Frederic Castinetti

  4. School of Medicine & Population Health, University of Sheffield, Sheffield, UK

    John Newell-Price

  5. Endocrinology Department, Germans Trias i Pujol Hospital and Research Institute, CIBERER Unit 747, Badalona, Spain

    Elena Valassi

  6. Universitat Internacional de Catalunya (UIC), Barcelona, Spain

    Elena Valassi

  7. Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada

    Jacques Drouin

  8. Département de Biochimie, Université de Montréal, Montréal, Québec, Canada

    Jacques Drouin

  9. Department of Biochemistry, McGill University, Montreal, Québec, Canada

    Jacques Drouin

  10. Department of Diabetes and Endocrinology, Nara Medical University, Kashihara, Nara, Japan

    Yutaka Takahashi

  11. Endocrine Division, Department of Medicine, Centre hospitalier de l’Université de Montréal (CHUM), Montreal, Québec, Canada

    André Lacroix

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  1. Lynnette K. Nieman
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  2. Frederic Castinetti
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  3. John Newell-Price
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  4. Elena Valassi
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  6. Yutaka Takahashi
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  7. André Lacroix
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Contributions

Introduction (L.K.N., F.C., J.N.-P. and A.L.); Epidemiology (L.K.N., F.C., J.N.-P. and E.V.); Mechanisms/pathophysiology (L.K.N., J.D., Y.T. and A.L.); Diagnosis, screening and prevention (L.K.N., J.N.-P., E.V. and A.L.); Management (L.K.N., F.C., J.N.-P., E.V., Y.T. and A.L.); Quality of life (L.K.N. and E.V.); Outlook (L.K.N., F.C., J.N.-P. and A.L.); overview of Primer (L.K.N., A.L., F.C. and J.N.-P.).

Corresponding author

Correspondence to Lynnette K. Nieman.

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Competing interests

J.N.-P. has received research support and consultancy paid to his institution from Recordati Rare Diseases, Crinetics Pharmaceuticals and Sparrow Pharmaceuticals, and is President of the Endocrine Society. F.C. received research grants and honoraria for expert advice from Recordati Rare Diseases, HRA Pharma Rare Diseases and Lundbeck. Y.T. has received honoraria from Novo Nordisk, Recordati Rare Diseases, Otsuka Pharma and Ascendis. A.L. has received research grants from Pfizer Canada and Recordati Canada Rare Diseases, serves on an advisory board for Recordati Canada Rare Diseases, is on a speakers bureau for Medunik Canada, and has spoken on behalf of Recordati Canada Rare Diseases; he receives royalties for work as an editor of the adrenal section of UpToDate and Encyclopedia of Endocrine Diseases, and is an inventor on a patent for endocrine diseases related to KDM1A for work performed at the Universite Paris–Saclay. L.K.N. receives royalties as an author and editor for UpToDate and has received research support paid to her institution from Crinetics Pharmaceuticals. E.V. received honoraria for consulting, lectures and advisory boards from HRA Pharma and Recordati Rare Diseases. J.D. declares no competing interests.

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Nature Reviews Disease Primers thanks I. Bancos, who co-reviewed this manuscript with S. R. Chacko; M. Fragoso; C. Scaroni, who co-reviewed this manuscript with A. Mondin; and K. C. J. Yuen, who co-reviewed this manuscript with A. Vincent.

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Nieman, L.K., Castinetti, F., Newell-Price, J. et al. Cushing syndrome. Nat Rev Dis Primers 11, 4 (2025). https://doi.org/10.1038/s41572-024-00588-w

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