Cushing's Disease
With symptoms similar to other conditions, the path to diagnosis can be challenging.
A rare, but serious condition
Although rare, Cushing’s disease (CD) is the most prevalent of all Cushing’s syndrome (CS) cases.1 And while it’s uncommon, it’s a serious condition:
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Prevalence of nearly 22 cases per million2,*
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2.4 new cases/million/year2,*
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3x more likely to develop in women, most commonly between ages 30 and 603
*True incidence and prevalence rates for CD in the United States are unknown. Estimated data are pooled rates based on a meta-analysis of global CD epidemiology.2
In fact, about 70% of all patients with endogenous Cushing’s syndrome have Cushing’s disease:4
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40% to 60% of patients with Cushing’s disease have a tumor that is visible on conventional MRI4,5
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Average time to diagnosis is 7 years due to the rare nature of the disease, similarity of symptoms to other conditions, and diversity of symptoms6
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50% estimated 5-year survival rate in patients with untreated Cushing’s disease7
Is it Cushing’s disease?
Knowing what to look for is important when evaluating the clinical presentation of hypercortisolism, which can present with varying phenotypes.8 Clinical suspicion of CD may arise without a complete picture of classic discriminatory symptoms, especially if other comorbidities are present.9,10
Symptoms vary greatly from patient to patient
Often a common symptom — or combination of symptoms — could signal the disease.11 Knowing the symptoms is critical when attempting to diagnose CD. If it is suspected, initiating an early screening is an important step towards confirming a diagnosis.
Cushing’s disease can go undiagnosed for years
Undiagnosed Cushing’s disease puts patients at risk for potentially life-threatening comorbidities.7 Because CD patients experience comorbidities at a higher rate than the general population,12 early diagnosis is key. Although biochemical remission or a cure is usually associated with significant clinical improvement, some comorbidities may not completely normalize.13 Hypertension and diabetes are the main long-term controllable risk factors for cardiovascular events and mortality, and repeated follow-up is mandatory.13
Hypercortisolism exposure poses risks
In fact, the longer the length of hypercortisolism exposure, the greater the mortality risk.14,15 Even transient exposure to excess cortisol is associated with increased mortality.15 So evaluating and treating the long-term negative effects of chronic hypercortisolism may be important to reduce morbidity, improve quality of life, and reduce the long-term mortality associated with Cushing’s disease.13
Uncontrolled chronic hypercortisolism also leads to elevated risks of multi-system morbidity and mortality.16 Patients with chronic, uncontrolled hypercortisolism have a ~3.5-5x higher mortality risk than in the general population.17 While the risk of all-cause morbidity and mortality decreases with remission, it’s not entirely eliminated.18
Untangling the Effects of High Cortisol

Risk of VTE, AMI, Stroke, and Heart Failure in Patients With CS
Chronic exposure to excess cortisol increases risk for all-cause morbidity and mortality 21
VTE
~8.4X Higher Risk
Heart
Failure
~6.8X Higher Risk
Stroke
~5.0X Higher Risk
AMI
~2.2X Higher Risk
The predicted mortality rate is nearly 2x higher for patients with persistent CD vs that for patients in remission.22
Model adjusted for age, sex, calendar time, cancer, diabetes, hypertension, chronic obstructive pulmonary disease, liver disease, and alcoholism-related diseases.
AMI, acute myocardial infarction; VTE, venous thromboembolism.
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REFERENCES: 1. Bertagna X, Guignat L, Groussin L, Bertherat J. Cushing’s disease. Best Pract Res Clin Endocrinol Metab. 2009 Oct;23(5):607-23. 2. Giuffrida G, Crisafulli S, Ferraù F, et al. Global Cushing’s disease epidemiology: a systematic review and meta-analysis of observational studies. J Endocrinol Invest. 2022 Jun;45(6):1235-1246. doi: 10.1007/s40618-022-01754-1. 3. Nishioka H, Yamada S. Cushing’s Disease. J Clin Med. 2019 Nov 12;8(11):1951. doi: 10.3390/jcm8111951. 4. Lonser RR, Nieman L, Oldfield EH. Cushing’s disease: pathobiology, diagnosis, and management. J Neurosurg. 2017 Feb;126(2):404-417. doi: 10.3171/2016.1.JNS152119. 5. Patronas N, Bulakbasi N, Stratakis CA, et al. Spoiled gradient recalled acquisition in the steady state technique is superior to conventional postcontrast spin echo technique for magnetic resonance imaging detection of adrenocorticotropin-secreting pituitary tumors. J Clin Endocrinol Metab. 2003 Apr;88(4):1565-9. doi: 10.1210/jc.2002-021438. 6. Papoian V, Biller BMK, Webb SM, et al. Patients’ perception on clinical outcome and quality of life after a diagnosis of Cushing syndrome. Endocr Pract. 2016;22(1):51-67. doi:10.4158/EP15855.OR. 7. Clayton RN. Mortality in Cushing’s disease. Neuroendocrinology. 2010;92(suppl 1):71-76. doi:10.1159/000315813. 8. Nieman LK. Cushing’s syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol. 2015 Oct;173(4):M33-8. doi: 10.1530/EJE-15-0464. 9. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008 May;93(5):1526-40. doi: 10.1210/jc.2008-0125. 10. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2003 Dec;88(12):5593-602. doi: 10.1210/jc.2003-030871. 11. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;17(7):281-293. doi:10.2147/CLEP.S44336. 12. Nieman LK. Recent Updates on the Diagnosis and Management of Cushing’s Syndrome. Endocrinol Metab (Seoul). 2018 Jun;33(2):139-146. doi: 10.3803/EnM.2018.33.2.139. 13. Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831. doi: 10.1210/jc.2015-1818. 14. Feelders RA, Pulgar SJ, Kempel A, Pereira AM. The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol. 2012;167(3):311-326. doi:10.1530/EJE-11-1095. 15. Dekkers OM, Biermasz NR, Pereira AM, et al. Mortality in patients treated for Cushing’s disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab. 2007 Mar;92(3):976-81. doi: 10.1210/jc.2006-2112. 16. Lacroix A, Feelders RA, Stratakis CA, et al. Cushing’s syndrome. Lancet. 2015;386(9996):913-927. doi: 10.1016/S0140-6736(14)61375-1. 17. Fleseriu M, Castinetti F. Updates on the role of adrenal steroidogenesis inhibitors in Cushing’s syndrome: a focus on novel therapies. Pituitary. 2016;19(6):643-653. doi: 10.1007/s11102-016-0742-1. 18. Pivonello R, De Leo M, Cozzolino A, Colao A. The Treatment of Cushing’s Disease. Endocr Rev. 2015 Aug;36(4):385-486. doi: 10.1210/er.2013-1048. 19. Newell-Price J. Cushing’s syndrome. Clin Med (Lond). 2008;8(2):204-208. doi:10.7861/clinmedicine.8-2-204. 20. Boscaro M, Barzon L, Sonino N. The diagnosis of Cushing’s syndrome: atypical presentations and laboratory shortcomings. Arch Intern Med. 2000;160(20):3045-3053. doi:10.1001/archinte.160.20.3045. 21. Dekkers OM, Horváth-Puhó E, Jørgensen JOL, et al. Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab. 2013;98(6):2277-2284. doi: 10.1210/jc.2012-3582. 22. van Haalen FM, Broersen LHA, Jorgensen JO, Pereira AM, Dekkers OM. Management of endocrine disease: Mortality remains increased in Cushing’s disease despite biochemical remission: a systematic review and meta-analysis. Eur J Endocrinol. 2015;172(4):R143-R149. doi: 10.1530/EJE-14-0556.