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Cushing's syndrome describes the signs and symptoms associated with prolonged exposure to elevated levels of endogenous or exogenous glucocorticoids. This can be caused by taking glucocorticoid drugs, or by diseases that result in excess cortisol, adrenocorticotropic hormone (ACTH), or corticotropin-releasing hormone (CRH) levels.1,2

Cushing's syndrome most commonly arises from iatrogenic causes when glucocorticoids have been used as anti-inflammatory and/or immunosuppressive treatment. The pathogenetic mechanisms of endogenous Cushing's syndrome can be divided into ACTH dependent (80%) and ACTH independent (20%).

The most common (80%) ACTH-dependent type, known as Cushing's disease, is caused by ACTH-secreting pituitary adenomas.1-3 In 1932, Harvey Cushing first described the presence of basophilic pituitary adenomas as a cause of Cushing's disease.4 The remaining 20% of ACTH-dependent forms are due to nonpituitary ectopic sources of ACTH, such as the paraneoplastic manifestations of oat cell carcinoma, small-cell lung carcinoma, or a carcinoid tumor. When ACTH is ectopically secreted by small cell carcinoma of the lung or widely metastatic cancer, patients can have a rapid and sever onset of Cushing's syndrome.1,2,5

Approximately 20% of Cushing's syndrome is ACTH independent, resulting in excess of cortisol secretion by adrenocortical tumors. In the majority of cases, these tumors are unilateral and 60% are benign adenomas and 40% are adrenal carcinomas. Rarely, ACTH-independent Cushing's syndrome is caused by bilateral macronodular hyperplasia, primary pigmented nodular adrenocortical disease (which may be a part of Carney complex), or McCune–Albright syndrome.1-3,5


Exogenous corticosteroid exposure is the most common cause of Cushing's syndrome. More than 10 million Americans receive pharmacologic doses of glucocorticoids each year; however, there is no data as to the exact number of patients with exogenous Cushing's syndrome.6

Previously, endogenous Cushing's syndrome was thought to be a rare disorder with an incidence of approximately two to three cases per million per year. However, recent data have demonstrated an incidence of Cushing's syndrome between 2% and 5% in obese patients with type 2 diabetes with poor blood glucose control and hypertension.7-9 Cushing's syndrome caused by disease of the adrenal glands occurs four times more commonly in women than in men. Cushing's disease (pituitary tumor secreting ACTH) has a 3.5 to 1 female-to-male predominance. No ethnic disparities are identified. Most cases are diagnosed in adults between the ages of 20 and 50, although it can occur at any age. Pediatric cases are unusual but well documented.1


Patients with uncontrolled Cushing's syndrome have a fivefold increased risk in mortality.10,11 Risk factors for developing endogenous Cushing's syndrome are being delineated as more is learned about the disease. There is a genetic predisposition in patients with Carney complex, McCune–Albright syndrome and multiple endocrine neoplasia type 1 (MEN1) ...

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