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Cushing Syndrome

The hypothalamus secretes corticotrophin releasing hormone (CRF), which stimulates the pituitary to secrete ACTH.ACTH then stimulates the adrenal gland to produce cortisol and contributes to skin pigmentation. Cortisol exerts a negative feedback effect on both the pituitary and the hypothalamus.

Cushing syndrome is relatively rare; the prevalence is only 10 cases per 1 million people. It occurs most commonly in women between 30 and 50 years of age. Early stages of the syndrome include hypertension and weight gain. Later, The more common manifestations become apparent including truncal obesity, moon face, buffalo hump, hirsutism, facial plethora, menstrual disorders, hyperglycemia, proximal muscular weakness, wide purple striae, acne, easy bruising and unexplained osteoporosis.

Cushing syndrome is caused by any condition that produces an elevation in glucocorticoid levels. There are 4 basic causes.

  • Administration of exogenous glucocorticoids
  • Primary hypothalamic-pituitary diseases associated with hypersecretion of ACTH
  • Adrenal hypersecretion of cortisol
  • Ectopic secretion of ACTH by a nonendocrine neoplasm.

Administration of exogenous glucocorticoids is the most common cause of Cushing syndrome seen in clinical practice. Topical preparations, such as hemorrhoid medications need to be considered. Most cortisol immunoassays cross react with synthetic steroids.

Primary hypersecretion of ACTH accounts for more than half of the cases of endogenous Cushing syndrome. Most of these cases are caused by a small ACTH producing adenoma in the pituitary gland. This pituitary form of Cushing syndrome is called Cushing disease.

Classification & Etiology of Cushing Syndrome

Classification & Etiology

Frequency (%)

ACTH Dependent

Cushing Disease


Ectopic ACTH syndrome


ACTH Independent

Adrenal adenoma


Adrenal carcinoma


Approximately 15 to 30% of the cases of endogenous Cushing syndrome are caused by adrenal adenoma, carcinoma or cortical hyperplasia. This form of Cushing syndrome is also designated ACTH independent because the adrenals produce cortisol autonomously. Adrenal Cushing syndrome is characterized by high serum levels of cortisol but levels of ACTH.

Secretion of ectopic ACTH by nonpituitary tumors accounts for most of the remaining cases of Cushing syndrome. Small cell carcinoma of the lung , carcinoid tumors, medullary carcinomas of the thyroid and islet cell tumors of the pancreas have been associated with this syndrome. Occasionally ectopic tumors may secrete corticotropin releasing factor, which causes ACTH hypersecretion and hypercortisolism.

Cushing syndrome is characterized by an increased 24-hour urinary free cortisol level and loss of the normal diurnal pattern of cortisol secretion. The best screening test is a 24-hour urine free cortisol. More than 90% of patients with Cushing syndrome have urinary cortisol values greater than 100 ug/24 hours (reference range is less than 55 ug/24 hours). Urine free cortisol is not increased in simple obesity, high estrogen states or by drugs such as phenytoin. Alcoholic patients should refrain from drinking at least one month before testing because chronic alcohol abuse causes hypercortisolism, which can mimic Cushing syndrome.

Some medical centers recommend the 1-mg overnight dexamethasone suppression test followed by morning plasma cortisol measurement as the preferred screening test for Cushing syndrome. However, this test generally does not perform as well as urinary free cortisol. Obesity, depression, alcoholism, high estrogen states, and uremia can cause false positive results. Chronic renal failure and liver failure can cause false negative results. The 1-mg overnight dexamethasone suppression test is most useful in patients with ambiguous urinary free cortisol values.

The single-dose overnight dexamethasone suppression test is performed by administering 1 mg of dexamethasone p.o. at 23:00 and collecting a specimen for plasma cortisol measurement at 08:00 the next morning.Normally, plasma cortisol should be suppressed below 5 ug/dL. Cortisol levels <5 ug/dL virtually exclude the diagnosis of Cushing syndrome, while levels >10 ug/dL support the diagnosis.

Once a diagnosis of endogenous hypercortisolism has been made, the next step is to localize the site of the lesion. Paired measurement of ACTH and cortisol determines whether the disease is ACTH independent or ACTH dependent. Plasma ACTH levels <5 ng/L are consistent with ACTH independent Cushing syndrome. ACTH independent disease generally implies an adrenal tumor, which typically can be documented by MRI. ACTH levels >10 ng/L support ACTH dependent Cushing syndrome due to a pituitary tumor. ACTH dependent and borderline cases require further testing, usually involving ACTH releasing hormone stimulation and/or dexamethasone suppression with either low or high dose protocols.

In the low dose dexamethasone suppression test, 0.5 mg of dexamethasone is given every 6 hours for 2 days. Twenty four-hour urine specimens are obtained before the first dose and during the last 24 hours for measurement of urine free cortisol. A plasma cortisol level is drawn six hours after the last dose. Failure of cortisol suppression indicates Cushing syndrome. A urine free cortisol level below 25 ug/24 hours and a plasma cortisol <5ug/dL exclude the diagnosis. False-positive results can occur with illness, depression, alcoholism, and rarely with obesity and high estrogen states.

The high dose dexamethasone test consists of 9 doses of 2 mg or 4 mg of dexamethasone every 6 hours with follow-up cortisol measurements. Most patients with pituitary dependent Cushing syndrome will have suppressed cortisol measurements, whereas patients with adrenal neoplasms or ectopic ACTH syndrome usually have minimal suppression.

If the sources of ACTH cannot be localized conclusively, it may be necessary to sample blood from the left and right inferior petrosal sinuses, which drain blood from the pituitary gland. Comparison of ACTH concentrations in these specimens with the ACTH concentration in a concurrently collected peripheral blood sample allows calculation of flow gradients. Measurements of ACTH before and after stimulation with ACTH releasing hormone enhance diagnostic accuracy. A ratio >2.0 for the baseline inferior petrosal sinus to peripheral blood ACTH concentration or a ratio >3.0 after stimulation is consistent with pituitary dependent Cushing syndrome.

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