Cushing Syndrome

General Principles

  • Cushing syndrome is most often iatrogenic because of glucocorticoid therapy.
  • ACTH-secreting pituitary microadenomas (Cushing disease) account for 80% of cases of endogenous Cushing syndrome.
  • Adrenal tumors and ectopic ACTH secretion account for the remainder.


Clinical Presentation

  • Findings include truncal obesity, rounded face, fat deposits in the supraclavicular fossae and over the posterior neck, hypertension, hirsutism, amenorrhea, and depression. More specific findings include thin skin, easy bruising, reddish striae, proximal muscle weakness, and osteoporosis.
  • Hyperpigmentation or hypokalemic alkalosis suggests Cushing syndrome due to ectopic ACTH secretion.
  • Diabetes mellitus develops in some patients.

Diagnostic Testing

  • Diagnosis requires the establishment of hypercortisolism due to increased cortisol excretion, lack of normal feedback inhibition of ACTH and cortisol secretion, or loss of the normal diurnal rhythm of cortisol secretion. Three initial tests are available:
    • The best initial test is the 24-hour urine cortisol measurement;
    • Alternatively, an overnight dexamethasone suppression test may be performed (1 mg dexamethasone given PO at 11:00 PM; plasma cortisol measured at 8:00 AM. the next day; normal range: plasma cortisol <1.8 μg/dL); reflex dexamethasone levels can be obtained to ensure the test was performed appropriately; or
    • Salivary cortisol may be measured at home during the nadir of normal plasma cortisol at 11:00 PM.
  • All these tests are very sensitive, and a normal value virtually excludes the diagnosis. If the overnight dexamethasone suppression test or 11:00 PM. salivary cortisol is abnormal, 24-hour urine cortisol should be measured.
    • If the 24-hour urine cortisol excretion is more than 3–4 times the upper limit of the reference range in a patient with compatible clinical findings, the diagnosis of Cushing syndrome is established.
    • Testing should not be done during severe illness or depression, which may cause false-positive results. Phenytoin therapy also causes a false-positive test by accelerating metabolism of dexamethasone.
  • After the diagnosis of Cushing syndrome is made, tests to determine the cause and appropriate treatment are best done in consultation with an endocrinologist.


  1. Nieman LK, Biller BMK, Findling JW, et al. The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008;93:1526-1540.  [PMID:18334580]


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