Adrenal Hyperfunction - Cushing Syndrome


Indications for Testing

  • High clinical suspicion based on discriminatory physical features and refractory hypertension
  • Clinical evaluation has ruled out metabolic syndrome or polycystic ovarian syndrome in females
  • Do not test patients who have hypercortisolism secondary to administration of glucocorticoids

Laboratory Testing (recommendations from Endocrine Society, 2008; National Comprehensive Cancer Network [NCCN], 2014)

  • Initial testing – salivary cortisol (collected between 2300 and 0100) or 24-hour urine free cortisol (UFC)
    • Repeat either test at least once to confirm elevated values
    • If positive – follow up with low-dose (1 mg) dexamethasone suppression testing (DST) with plasma cortisol level and adrenocorticotropic hormone (ACTH) test (see the Adrenal Hyperfunction [Cushing Syndrome] Testing algorithm)
      • Likelihood ratios with positive test result (recommendations from Elanin, 2008)
        • UFC – 10.6
        • Salivary cortisol – 8.8
        • Overnight DST – 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 equivocal – 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, free urine 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 most common

Imaging Studies

  • CT/MRI to visualize adenomas/hyperplasia after hypercortisolemia is identified
    • MRI of pituitary
      • 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

Clinical Background

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


  • 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

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Cortisol, Saliva 0081117
Method: Quantitative Enzyme Immunoassay
Initial screen for Cushing syndrome

Do not use for patients taking glucocorticoids

Cortisol Urine Free by LC-MS/MS 0097222
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry
Initial screen for Cushing syndrome

Do not use for patients taking glucocorticoids

Cortisol, Serum or Plasma 0070030
Method: Quantitative Chemiluminescent Immunoassay

Most useful to measure cortisol level after dexamethasone suppression test

Adrenocorticotropic Hormone 0070010
Method: Quantitative Chemiluminescent Immunoassay
Differentiate source of cortisol hypersecretion

Use for pre- and post-petrosal sampling testing
ACTH by Immunohistochemistry 2003427
Method: Immunohistochemistry

Aid in histologic diagnosis of adrenal hyperfunction

Stained and returned to client pathologist for interpretation; consultation available if needed

Additional Tests Available
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Adrenocorticotropic Hormone Stimulation, 0 Minutes 0070031
Method: Quantitative Chemiluminescent Immunoassay
Adrenocorticotropic Hormone Stimulation, 30 Minutes 0070032
Method: Quantitative Chemiluminescent Immunoassay
Adrenocorticotropic Hormone Stimulation, 60 Minutes 0070033
Method: Quantitative Chemiluminescent Immunoassay
Dexamethasone, Serum or Plasma by LC-MS/MS 2003248
Method: Liquid Chromatography-Tandem Mass Spectrometry

Compliance assessment of dexamethasone suppression testing

Do not use for patients taking glucocorticoids

Cortisol, Free 0098391
Method: Equilibrium Dialysis/Quantitative Electrochemiluminescent Immunoassay

Screen for Cushing syndrome

Do not use for patients taking glucocorticoids