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Cushing's Disease


Cushing syndrome is caused by prolonged exposure to elevated levels of either endogenous glucocorticoids or exogenous glucocorticoids.

Symptoms of Cushing syndrome include: proximal muscle weakness, easy bruising, weight gain, hirsutism, and, in children, growth retardation. Hypertension, osteopenia, diabetes mellitus, and impaired immune function may occur.

Signs of Cushing syndrome include: moon facies, facial plethora, supraclavicular fat pads, buffalo hump, truncal obesity, and purple striae.


The most common cause of Cushing syndrome is the use of exogenous glucocorticoids, which can cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis that can last for as long as a year after exogenous steroid administration has ended.

Endogenous glucocorticoid overproduction or hypercortisolism that is independent of adrenocorticotropic hormone (ACTH) usually is due to a primary adrenocortical neoplasm (usually an adenoma but rarely a carcinoma). Bilateral micronodular hyperplasia and macronodular hyperplasia are rare causes of Cushing syndrome.

ACTH-secreting neoplasms cause ACTH-dependent Cushing syndrome. They usually are due to an anterior pituitary tumor, ie, classic Cushing disease (80%). Nonpituitary ectopic sources of ACTH, such as an oat cell, small-cell lung carcinoma, or carcinoid tumor, cause the balance of ACTH-dependent disease. Some rare newly described cases of ectopic corticotropin-releasing hormone (CRH) secretion comprise a very rare group of patients with Cushing syndrome.

Acute illness activates the HPA axis, resulting in increases in ACTH and cortisol, the laboratory workup for Cushing syndrome should not be performed when subjects are acutely ill.

Conventional Labs

Urinary free cortisol (UFC) determination has been widely used as an initial screening tool for Cushing syndrome because it provides measurement of cortisol over a 24-hour period.

Dexamethasone suppression tests involve administration of 1 mg of dexamethasone at 11 pm with subsequent measurement of cortisol level at 8 am. Steroids decrease the release of ACTH causing a fall in plasma and urine cortisol level. In healthy individuals, the serum cortisol level should be less than 2-3 mcg/dL.

AM-PM cortisol levels via serum are seldom ordered because they must be taken within 5-10 minutes of waking and late at night. Salivary testing is more convenient and can be done at home. Four samples through the day show the circadian rhythm of cortisol secretion, which should be high in the morning and low at night.

The dexamethasone-CRH test is intended to distinguish patients with Cushing syndrome from those with pseudo-Cushing states. It combines a 48-hour low-dose dexamethasone suppression test with CRH stimulation. Dexamethasone (0.5 mg every 6 hours) is given 8 times, CRH is then administered intravenously and plasma cortisol and ACTH levels are obtained at 15-minute intervals for 1 hour. A cortisol value greater than 50 nmol/L (1.4 mcg/dL) identifies Cushing syndrome. This test is reserved for patients with high clinical suspicion for Cushing syndrome but equivocal results on other diagnostic tests.




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