Cushing syndrome is defined as a prolonged increase in plasma cortisol levels that is not due to a physiological etiology. Although the most frequent cause of Cushing syndrome is exogenous steroid use, the estimated incidence of Cushing syndrome due to endogenous overproduction of cortisol ranges from 2 to 8 per million people annually. Cushing syndrome is associated with hyperglycemia, protein catabolism, immunosuppression, hypertension, weight gain, neurocognitive changes, and mood disorders.
Cushing syndrome characteristically presents with skin changes such as facial plethora, easy bruising, and purple striae and with metabolic manifestations such as hyperglycemia, hypertension, and excess fat deposition in the face, back of the neck, and visceral organs. Cushing disease, in which corticotropin excess is produced by a benign pituitary tumor, occurs in approximately 60% to 70% of patients with Cushing syndrome due to endogenous cortisol production. Evaluation of patients with possible Cushing syndrome begins with ruling out exogenous steroid use. Screening for elevated cortisol is performed with a 24-hour urinary free cortisol test or late-night salivary cortisol test or by evaluating whether cortisol is suppressed the morning after an evening dexamethasone dose. Plasma corticotropin levels can help distinguish between adrenal causes of hypercortisolism (suppressed corticotropin) and corticotropin-dependent forms of hypercortisolism (midnormal to elevated corticotropin levels). Pituitary magnetic resonance imaging, bilateral inferior petrosal sinus sampling, and adrenal or whole-body imaging can help identify tumor sources of hypercortisolism. Management of Cushing syndrome begins with surgery to remove the source of excess endogenous cortisol production followed by medication that includes adrenal steroidogenesis inhibitors, pituitary-targeted drugs, or glucocorticoid receptor blockers. For patients not responsive to surgery and medication, radiation therapy and bilateral adrenalectomy may be appropriate.
Conclusions and Relevance
The incidence of Cushing syndrome due to endogenous overproduction of cortisol is 2 to 8 people per million annually. First-line therapy for Cushing syndrome due to endogenous overproduction of cortisol is surgery to remove the causative tumor. Many patients will require additional treatment with medications, radiation, or bilateral adrenalectomy.
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Accepted for Publication: June 6, 2023.
Corresponding Author: Martin Reincke, MD, Department of Medicine, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München (LMU), Ziemssenstrasse 1, 80336 München, Germany (email@example.com).
Author Contributions: Drs Reincke and Fleseriu contributed equally to this review article.
Conflict of Interest Disclosures: Dr Reincke reported receiving personal fees from Novartis, Recordati, HRA Pharma, Crinetics, Lundbeck, and support from Crinetics for participation in phase 3 studies outside the submitted work; and serving as the president of European Society of Endocrinology. Dr Fleseriu reported receiving grants from Crinetics, Novartis, Xeris (acquired Strongbridge), Recordati, and Sparrow, all to the university; serving as a consultant to Crinetics, Novartis, Xeris, HRA Pharma, Recordati, and Sparrow; being a deputy editor of the European Journal of Endocrinology; and serving on the Pituitary Society’s board of directors.
Funding/Support: Dr Reincke is supported by grants 2012_A103 and 2015_A228 from Else Kröner-Fresenius Stiftung, and CRC/TRR 205/1 from Deutsche Forschungsgemeinschaft (the German Research Foundation).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank Dunja Reiß, PhD, at Ludwig-Maximilians-Universität and Shirley McCartney, PhD, at Oregon Health & Science University for assistance with references.
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