Adrenal Hyperfunction - Cushing Syndrome

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • High clinical suspicion based on discriminatory physical features and refractory hypertension
  • Do not test patients who have hypercortisolism secondary to administration of glucocorticoids

Laboratory Testing (recommendations from Endocrine Society, 2008; National Comprehensive Cancer Network [NCCN], 2015)

  • Initial testing – salivary cortisol (collected between 2300 and midnight) or 24-hour urine free cortisol (UFC)
    • Repeat either test at least once to confirm elevated values
    • If cortisol elevated – follow up with low-dose (1 mg) dexamethasone suppression testing (DST) with serum cortisol level and adrenocorticotropic hormone (ACTH) test (see the Adrenal Hyperfunction [Cushing Syndrome] Testing algorithm)
      • Likelihood ratios for positive test result (Elamin, 2008)
        • UFC – 10.6
        • Salivary cortisol – 8.8
        • Overnight DST (serum cortisol) – 11.6
        • Combination UFC and DST (1 night) – 15.4
        • Negative testing has likelihood ratio <0.5 for all tests
        • False-positive results may be seen in up to 50% of women taking oral contraceptives (Endocrine Society, 2008)
      • If low dose test, follow up with overnight high-dose DST (4-8 mg/day) and serum ACTH, cortisol at 0800; or longer low-dose DST (2 mg/day for 48 hours)
        • Likelihood ratio with positive test – 7.3
      • Negative suppression testing – suggests against Cushing disease
    • Once hypercortisolism is confirmed, further evaluations should include an endocrinologist
    • If results after DST are consistent with hypercortisolism
      • Serum ACTH – determine whether disease is adrenal, pituitary, or ectopic ACTH-based


  • Pathology review of specimen (biopsy tumor) to classify type of tumor
    • Immunohistochemistry stain – ACTH stain most common

Imaging Studies

  • CT/MRI to visualize adenomas/hyperplasia after hypercortisolism is identified
    • MRI of pituitary demonstrates abnormality – perform inferior bilateral petrosal sampling of ACTH to differentiate between Cushing disease and ectopic source
      • If ACTH is low – MRI of adrenal glands
      • If ACTH >200 pg/mL – search for ectopic ACTH-secreting tumor


  • Untreated Cushing syndrome – associated with excess morbidity/mortality secondary to cardiovascular disease
  • If tumor is benign and removed – mortality associated with comorbid diseases developed in association with tumor may normalize
  • Malignant tumors – poor prognosis

Differential Diagnosis

Adrenal hyperfunction (Cushing syndrome) causes excess cortisol secretion by the adrenal gland and is manifested by a constellation of symptoms, including weight gain, easy bruisability, and myopathy.


  • Incidence – 2-3/100,000 (Endocrine Society, 2008)
  • Age – uncommon in children; peaks in 20s-50s
  • Sex – M<F, 1:4-6


  • Endogenous
    • Pituitary (Cushing syndrome)
      • Hyperplasia
      • Adenoma
    • Adrenal
      • Adenoma
      • Carcinoma – most are sporadic tumors
        • Hereditary syndromes (eg, Li-Fraumeni) may present as carcinoma
    • Ectopic production of adrenocorticotropic hormone (ACTH)
  • Exogenous
    • Glucocorticoid administration
  • Genetics (Lacroix, 2015)
    • Bilateral macronodular adrenal hyperplasia
      • ARMC5, MEN1, FH, GNAS1, PDE11A, PDE88, MC2R, PRKACA
    • Adrenal adenoma
    • Primary pigmented nodular adrenocortical disease
      • PRKAR1A, PDE11A, PDE88, PRKACA


  • Corticotropin-releasing hormone (CRH) in the hypothalamus stimulates release of ACTH from the pituitary gland
  • ACTH acts on the adrenal glands to produce cortisol
  • Most endogenous cases are caused by hypersecretion of pituitary ACTH or ectopic production of ACTH from non-pituitary source

Clinical Presentation

  • Centripetal obesity, moon facies, buffalo hump, hirsutism, reddish-purple striae
  • Hypertension
  • Menstrual abnormalities (eg, amenorrhea)
  • Irritability, impaired memory
  • Osteoporosis
  • Fatigue, weakness
  • Proximal myopathy
  • Impaired glucose tolerance
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Cortisol, Saliva 0081117
Method: Quantitative Enzyme Immunoassay


Do not use for patients taking glucocorticoids

Cortisol Urine Free by LC-MS/MS 0097222
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry


Do not use for patients taking glucocorticoids

Cortisol, Serum 0070030
Method: Quantitative Chemiluminescent Immunoassay

Adrenocorticotropic Hormone 0070010
Method: Quantitative Chemiluminescent Immunoassay

ACTH by Immunohistochemistry 2003427
Method: Immunohistochemistry


NCCN Clinical Practice Guidelines in Oncology, Neuroendocrine Tumors. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Mar 2016]

Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008; 93(5): 1526-40. PubMed

General References

Alexandraki KI, Grossman AB. Novel insights in the diagnosis of Cushing's syndrome. Neuroendocrinology. 2010; 92 Suppl 1: 35-43. PubMed

Batista DL, Riar J, Keil M, Stratakis CA. Diagnostic tests for children who are referred for the investigation of Cushing syndrome. Pediatrics. 2007; 120(3): e575-86. PubMed

Bertagna X, Guignat L, Groussin L, Bertherat J. Cushing's disease. Best Pract Res Clin Endocrinol Metab. 2009; 23(5): 607-23. PubMed

Elamin MB, Murad H, Mullan R, Erickson D, Harris K, Nadeem S, Ennis R, Erwin PJ, Montori VM. Accuracy of diagnostic tests for Cushing's syndrome: a systematic review and metaanalyses. J Clin Endocrinol Metab. 2008; 93(5): 1553-62. PubMed

Findling JW, Raff H. Cushing's Syndrome: important issues in diagnosis and management. J Clin Endocrinol Metab. 2006; 91(10): 3746-53. PubMed

Guaraldi F, Salvatori R. Cushing syndrome: maybe not so uncommon of an endocrine disease. J Am Board Fam Med. 2012; 25(2): 199-208. PubMed

Jehle S, Walsh JE, Freda PU, Post KD. Selective use of bilateral inferior petrosal sinus sampling in patients with adrenocorticotropin-dependent Cushing's syndrome prior to transsphenoidal surgery. J Clin Endocrinol Metab. 2008; 93(12): 4624-32. PubMed

Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing's syndrome Lancet. 2015; 386(9996): 913-27. PubMed

Newell-Price J. Diagnosis/differential diagnosis of Cushing's syndrome: a review of best practice. Best Pract Res Clin Endocrinol Metab. 2009; 23 Suppl 1: S5-14. PubMed

Pivonello R, De Martino MC, De Leo M, Lombardi G, Colao A. Cushing's Syndrome. Endocrinol Metab Clin North Am. 2008; 37(1): 135-49, ix. PubMed

Raff H. Cushing's syndrome: diagnosis and surveillance using salivary cortisol. Pituitary. 2012; 15(1): 64-70. PubMed

Turpeinen U, Hämäläinen E. Determination of cortisol in serum, saliva and urine. Best Pract Res Clin Endocrinol Metab. 2013; 27(6): 795-801. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Kushnir MM, Rockwood AL, Nelson GJ, Terry AH, Meikle W. Liquid chromatography-tandem mass spectrometry analysis of urinary free cortisol. Clin Chem. 2003; 49(6 Pt 1): 965-7. PubMed

La'ulu SL, Roberts WL. Performance characteristics of the Architect cortisol immunoassay. Clin Chim Acta. 2008; 388(1-2): 219-21. PubMed

Medical Reviewers

Last Update: August 2016