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For further information, see CMDT Part 26-23: Cushing Syndrome (Hypercortisolism)

Key Features

Essentials of Diagnosis

  • Central obesity, muscle wasting, thin skin, psychological changes, hirsutism, purple striae

  • Osteoporosis, hypertension, poor wound healing

  • Hyperglycemia, leukocytosis, lymphocytopenia, hypokalemia, glycosuria

  • Elevated serum cortisol and urinary free cortisol. Lack of normal suppression by dexamethasone

General Considerations

  • Cushing "syndrome" refers to manifestations of excessive corticosteroids

    • Commonly due to supraphysiologic doses of corticosteroid drugs

    • Rarely due to excessive spontaneous corticosteroid production

    • ~68% of such cases are due to ACTH hypersecretion by a pituitary adenoma (so-called Cushing "disease"), which is usually small and benign

    • ~25% are due to excessive autonomous secretion of cortisol

    • Cortisol secretion is independent of ACTH, and plasma ACTH levels are usually low or low-normal

    • ~7% are due to nonpituitary ACTH-secreting neuroendocrine neoplasms that produce ectopic ACTH

    • ~15% are due to ACTH from a source that cannot be initially located

    • May result from excessive ingestion of gamma-hydroxybutyric acid; resolves when drug is stopped

  • Impaired glucose tolerance from insulin resistance


  • Spontaneous Cushing syndrome is rare: 2.6 new cases yearly per million population in the United States

  • ACTH-secreting pituitary adenoma (Cushing "disease") > 3 times more common in women than men

Clinical Findings

Symptoms and Signs

  • Fatigue and reduced endurance

  • Central obesity with plethoric "moon face," "buffalo hump," supraclavicular fat pads, protuberant abdomen, and thin extremities

  • Muscle atrophy causes weakness, with difficulty standing up from a seated position or climbing stairs

  • Oligomenorrhea or amenorrhea in women (or erectile dysfunction in men)

  • Backache, headache

  • Hypertension

  • Osteoporosis or avascular bone necrosis

  • Skin

    • Acne

    • Superficial skin infections

    • Purple striae (especially around the thighs, breasts, and abdomen)

    • Easy bruising, impaired wound healing

  • Thirst and polyuria (with or without glycosuria); renal calculi

  • Glaucoma

  • Unusual bacterial or fungal infections occur more commonly

  • Mental symptoms range from diminished concentration to increased mood lability to psychosis

  • Increased susceptibility to opportunistic infections

Differential Diagnosis

  • Chronic alcoholism (alcoholic pseudo-Cushing syndrome)

  • Diabetes mellitus

  • Depression (may have hypercortisolism)

  • Osteoporosis due to other cause

  • Obesity due to other cause

  • Primary hyperaldosteronism

  • Anorexia nervosa (high urine free cortisol)

  • Striae distensae ("stress marks") seen in adolescence and in pregnancy

  • Lipodystrophy from antiretroviral agents


Laboratory Tests

  • Hyperglycemia

  • Leukocytosis; relative granulocytosis and lymphopenia

  • Hypokalemia (not hypernatremia), particularly with ectopic ACTH secretion

  • Easiest screening test involves dexamethasone suppression test

    • 1 mg is given orally at 11 PM and serum is collected for cortisol determination at 8 AM the next morning

    • Cortisol level < 1.8 mcg/dL (50 nmol/L, high-performance liquid chromatography [HPLC] assay) excludes Cushing syndrome with some certainty

  • If hypercortisolism is not excluded, measure 24-hour urine for free cortisol and creatinine

    • High 24-hour urine free cortisol (or free ...

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