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Establishing the diagnosis of Cushing's syndrome

Lynnette K Nieman, MD
Section Editor
André Lacroix, MD
Deputy Editor
Kathryn A Martin, MD


The possible presence of Cushing's syndrome (CS) is suggested by certain symptoms and signs. Unfortunately, none of these are pathognomonic, and many are nonspecific (eg, obesity, hypertension, menstrual irregularity, and glucose intolerance). As a result, the diagnosis must be confirmed by biochemical tests.

The laboratory diagnostic evaluation to determine if the patient has hypercortisolism (CS) will be reviewed here. The approach to the differential diagnosis of established hypercortisolism is discussed separately. (See "Establishing the cause of Cushing's syndrome".)


Who should be tested? — We suggest testing for hypercortisolism in patients in whom a diagnosis is most likely, including the following (table 1) [1,2]:

Unusual findings for their age (osteoporosis or hypertension in young adults)

Multiple progressive features of Cushing’s syndrome (CS), particularly those that are predictive of CS such as facial plethora, proximal myopathy, striae (>1 cm wide and red/purple), and easy bruising


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Literature review current through: Sep 2016. | This topic last updated: Jun 19, 2015.
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  1. 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; 93:1526.
  2. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing's syndrome. Lancet 2015; 386:913.
  3. Weber SL. Cushing'S syndrome attributable to topical use of lotrisone. Endocr Pract 1997; 3:140.
  4. Nutting CM, Page SR. Iatrogenic Cushing's syndrome due to nasal betamethasone: a problem not to be sniffed at! Postgrad Med J 1995; 71:231.
  5. Hughes JM, Hichens M, Booze GW, Thorner MO. Cushing's syndrome from the therapeutic use of intramuscular dexamethasone acetate. Arch Intern Med 1986; 146:1848.
  6. Mann M, Koller E, Murgo A, et al. Glucocorticoidlike activity of megestrol. A summary of Food and Drug Administration experience and a review of the literature. Arch Intern Med 1997; 157:1651.
  7. Samaras K, Pett S, Gowers A, et al. Iatrogenic Cushing's syndrome with osteoporosis and secondary adrenal failure in human immunodeficiency virus-infected patients receiving inhaled corticosteroids and ritonavir-boosted protease inhibitors: six cases. J Clin Endocrinol Metab 2005; 90:4394.
  8. Schwarze-Zander C, Klingmüller D, Klümper J, et al. Triamcinolone and ritonavir leading to drug-induced Cushing syndrome and adrenal suppression: description of a new case and review of the literature. Infection 2013; 41:1183.
  9. Olumide YM, Akinkugbe AO, Altraide D, et al. Complications of chronic use of skin lightening cosmetics. Int J Dermatol 2008; 47:344.
  10. Oldenburg-Ligtenberg PC, van der Westerlaken MM. A woman with Cushing's syndrome after use of an Indonesian herb: a case report. Neth J Med 2007; 65:150.
  11. Quddusi S, Browne P, Toivola B, Hirsch IB. Cushing syndrome due to surreptitious glucocorticoid administration. Arch Intern Med 1998; 158:294.
  12. Kelly CJ, Ogilvie A, Evans JR, et al. Raised cortisol excretion rate in urine and contamination by topical steroids. BMJ 2001; 322:594.
  13. Cizza G, Nieman LK, Doppman JL, et al. Factitious Cushing syndrome. J Clin Endocrinol Metab 1996; 81:3573.
  14. Lin CL, Wu TJ, Machacek DA, et al. Urinary free cortisol and cortisone determined by high performance liquid chromatography in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 1997; 82:151.
  15. Workman RJ, Nicholson WE, McCammon DK. Factitious hypercortisoluria. J Clin Endocrinol Metab 1995; 80:3050.
  16. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab 2003; 88:5593.
  17. Newell-Price J, Trainer P, Besser M, Grossman A. The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's states. Endocr Rev 1998; 19:647.
  18. LIDDLE GW. Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 1960; 20:1539.
  19. Loosen PT, Chambliss B, DeBold CR, et al. Psychiatric phenomenology in Cushing's disease. Pharmacopsychiatry 1992; 25:192.
  20. Pfohl B, Sherman B, Schlechte J, Winokur G. Differences in plasma ACTH and cortisol between depressed patients and normal controls. Biol Psychiatry 1985; 20:1055.
  21. Pfohl B, Sherman B, Schlechte J, Stone R. Pituitary-adrenal axis rhythm disturbances in psychiatric depression. Arch Gen Psychiatry 1985; 42:897.
  22. Gold PW, Loriaux DL, Roy A, et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease. Pathophysiologic and diagnostic implications. N Engl J Med 1986; 314:1329.
  23. Amsterdam JD, Maislin G, Winokur A, et al. The oCRH stimulation test before and after clinical recovery from depression. J Affect Disord 1988; 14:213.
  24. Kirkman S, Nelson DH. Alcohol-induced pseudo-Cushing's disease: a study of prevalence with review of the literature. Metabolism 1988; 37:390.
  25. Groote Veldman R, Meinders AE. On the mechanism of alcohol-induced pseudo-Cushing's syndrome. Endocr Rev 1996; 17:262.
  26. Yanovski JA, Nieman LK, Doppman JL, et al. Plasma levels of corticotropin-releasing hormone in the inferior petrosal sinuses of healthy volunteers, patients with Cushing's syndrome, and patients with pseudo-Cushing states. J Clin Endocrinol Metab 1998; 83:1485.
  27. Biller BM, Federoff HJ, Koenig JI, Klibanski A. Abnormal cortisol secretion and responses to corticotropin-releasing hormone in women with hypothalamic amenorrhea. J Clin Endocrinol Metab 1990; 70:311.
  28. Luger A, Deuster PA, Kyle SB, et al. Acute hypothalamic-pituitary-adrenal responses to the stress of treadmill exercise. Physiologic adaptations to physical training. N Engl J Med 1987; 316:1309.
  29. Gold PW, Gwirtsman H, Avgerinos PC, et al. Abnormal hypothalamic-pituitary-adrenal function in anorexia nervosa. Pathophysiologic mechanisms in underweight and weight-corrected patients. N Engl J Med 1986; 314:1335.
  30. O'Brien, JT, Ames, D, Schweitzer, I. HPA axis function in depression and dementia: a review. Int J Geriatr Psychiatry 1993; 8:887.
  31. Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudo-Cushing's states. JAMA 1993; 269:2232.
  32. Martin NM, Dhillo WS, Banerjee A, et al. Comparison of the dexamethasone-suppressed corticotropin-releasing hormone test and low-dose dexamethasone suppression test in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 2006; 91:2582.
  33. Gatta B, Chabre O, Cortet C, et al. Reevaluation of the combined dexamethasone suppression-corticotropin-releasing hormone test for differentiation of mild cushing's disease from pseudo-Cushing's syndrome. J Clin Endocrinol Metab 2007; 92:4290.
  34. Erickson D, Natt N, Nippoldt T, et al. Dexamethasone-suppressed corticotropin-releasing hormone stimulation test for diagnosis of mild hypercortisolism. J Clin Endocrinol Metab 2007; 92:2972.
  35. Pecori Giraldi F, Pivonello R, Ambrogio AG, et al. The dexamethasone-suppressed corticotropin-releasing hormone stimulation test and the desmopressin test to distinguish Cushing's syndrome from pseudo-Cushing's states. Clin Endocrinol (Oxf) 2007; 66:251.
  36. Valassi E, Swearingen B, Lee H, et al. Concomitant medication use can confound interpretation of the combined dexamethasone-corticotropin releasing hormone test in Cushing's syndrome. J Clin Endocrinol Metab 2009; 94:4851.
  37. Reimondo G, Bovio S, Allasino B, et al. The combined low-dose dexamethasone suppression corticotropin-releasing hormone test as a tool to rule out Cushing's syndrome. Eur J Endocrinol 2008; 159:569.
  38. Baid SK, Rubino D, Sinaii N, et al. Specificity of screening tests for Cushing's syndrome in an overweight and obese population. J Clin Endocrinol Metab 2009; 94:3857.
  39. Crapo L. Cushing's syndrome: a review of diagnostic tests. Metabolism 1979; 28:955.
  40. Mengden T, Hubmann P, Müller J, et al. Urinary free cortisol versus 17-hydroxycorticosteroids: a comparative study of their diagnostic value in Cushing's syndrome. Clin Investig 1992; 70:545.
  41. Hellman L, Weitzman ED, Roffwarg H, et al. Cortisol is secreted episodically in Cushing's syndrome. J Clin Endocrinol Metab 1970; 30:686.
  42. Sederberg-Olsen P, Binder C, Kehlet H, et al. Episodic variation in plasma corticosteroids in subjects with Cushing's syndrome of differing etiology. J Clin Endocrinol Metab 1973; 36:906.
  43. Van Cauter E, Refetoff S. Evidence for two subtypes of Cushing's disease based on the analysis of episodic cortisol secretion. N Engl J Med 1985; 312:1343.
  44. Elamin MB, Murad MH, Mullan R, et al. Accuracy of diagnostic tests for Cushing's syndrome: a systematic review and metaanalyses. J Clin Endocrinol Metab 2008; 93:1553.
  45. Kidambi S, Raff H, Findling JW. Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing's syndrome. Eur J Endocrinol 2007; 157:725.
  46. Elias PC, Martinez EZ, Barone BF, et al. Late-night salivary cortisol has a better performance than urinary free cortisol in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 2014; 99:2045.
  47. Raff H, Auchus RJ, Findling JW, Nieman LK. Urine free cortisol in the diagnosis of Cushing's syndrome: is it worth doing and, if so, how? J Clin Endocrinol Metab 2015; 100:395.
  48. Carroll BJ, Curtis GC, Davies BM, et al. Urinary free cortisol excretion in depression. Psychol Med 1976; 6:43.
  49. Mericq MV, Cutler GB Jr. High fluid intake increases urine free cortisol excretion in normal subjects. J Clin Endocrinol Metab 1998; 83:682.
  50. Meinardi JR, Wolffenbuttel BH, Dullaart RP. Cyclic Cushing's syndrome: a clinical challenge. Eur J Endocrinol 2007; 157:245.
  51. Alwani RA, Schmit Jongbloed LW, de Jong FH, et al. Differentiating between Cushing's disease and pseudo-Cushing's syndrome: comparison of four tests. Eur J Endocrinol 2014; 170:477.
  52. Invitti C, Pecori Giraldi F, de Martin M, Cavagnini F. Diagnosis and management of Cushing's syndrome: results of an Italian multicentre study. Study Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis. J Clin Endocrinol Metab 1999; 84:440.
  53. Castro M, Elias PC, Quidute AR, et al. Out-patient screening for Cushing's syndrome: the sensitivity of the combination of circadian rhythm and overnight dexamethasone suppression salivary cortisol tests. J Clin Endocrinol Metab 1999; 84:878.
  54. Laudat MH, Cerdas S, Fournier C, et al. Salivary cortisol measurement: a practical approach to assess pituitary-adrenal function. J Clin Endocrinol Metab 1988; 66:343.
  55. Bonnin R, Villabona C, Rivera A, et al. Is salivary cortisol a better index than free cortisol in serum or urine for diagnosis of Cushing syndrome? Clin Chem 1993; 39:1353.
  56. Raff H, Raff JL, Findling JW. Late-night salivary cortisol as a screening test for Cushing's syndrome. J Clin Endocrinol Metab 1998; 83:2681.
  57. Putignano P, Toja P, Dubini A, et al. Midnight salivary cortisol versus urinary free and midnight serum cortisol as screening tests for Cushing's syndrome. J Clin Endocrinol Metab 2003; 88:4153.
  58. Papanicolaou DA, Mullen N, Kyrou I, Nieman LK. Nighttime salivary cortisol: a useful test for the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 2002; 87:4515.
  59. Yaneva M, Mosnier-Pudar H, Dugué MA, et al. Midnight salivary cortisol for the initial diagnosis of Cushing's syndrome of various causes. J Clin Endocrinol Metab 2004; 89:3345.
  60. Viardot A, Huber P, Puder JJ, et al. Reproducibility of nighttime salivary cortisol and its use in the diagnosis of hypercortisolism compared with urinary free cortisol and overnight dexamethasone suppression test. J Clin Endocrinol Metab 2005; 90:5730.
  61. Raff H, Homar PJ, Burns EA. Comparison of two methods for measuring salivary cortisol. Clin Chem 2002; 48:207.
  62. Liu H, Bravata DM, Cabaccan J, et al. Elevated late-night salivary cortisol levels in elderly male type 2 diabetic veterans. Clin Endocrinol (Oxf) 2005; 63:642.
  63. Papanicolaou DA, Yanovski JA, Cutler GB Jr, et al. A single midnight serum cortisol measurement distinguishes Cushing's syndrome from pseudo-Cushing states. J Clin Endocrinol Metab 1998; 83:1163.
  64. Newell-Price J, Trainer P, Perry L, et al. A single sleeping midnight cortisol has 100% sensitivity for the diagnosis of Cushing's syndrome. Clin Endocrinol (Oxf) 1995; 43:545.
  65. Blethen SL, Chasalow FI. Overnight dexamethasone suppression test: normal responses and the diagnosis of Cushing's syndrome. Steroids 1989; 54:185.
  66. Findling JW, Raff H, Aron DC. The low-dose dexamethasone suppression test: a reevaluation in patients with Cushing's syndrome. J Clin Endocrinol Metab 2004; 89:1222.
  67. Meikle AW. Dexamethasone suppression tests: usefulness of simultaneous measurement of plasma cortisol and dexamethasone. Clin Endocrinol (Oxf) 1982; 16:401.
  68. Borcherding SM, Baciewicz AM, Self TH. Update on rifampin drug interactions. II. Arch Intern Med 1992; 152:711.
  69. Manetti L, Rossi G, Grasso L, et al. Usefulness of salivary cortisol in the diagnosis of hypercortisolism: comparison with serum and urinary cortisol. Eur J Endocrinol 2013; 168:315.
  70. Tsagarakis S, Vassiliadi D, Thalassinos N. Endogenous subclinical hypercortisolism: Diagnostic uncertainties and clinical implications. J Endocrinol Invest 2006; 29:471.
  71. Alexandraki KI, Kaltsas GA, Isidori AM, et al. The prevalence and characteristic features of cyclicity and variability in Cushing's disease. Eur J Endocrinol 2009; 160:1011.
  72. Petersenn S, Newell-Price J, Findling JW, et al. High variability in baseline urinary free cortisol values in patients with Cushing's disease. Clin Endocrinol (Oxf) 2014; 80:261.