Cushing syndrome is an endocrine disorder caused by hypercortisolism, most commonly due to exogenous glucocorticoid administration (iatrogenic Cushing syndrome). Cushing syndrome can also be caused by endogenous overproduction of cortisol. Primary hypercortisolism is caused by autonomous overproduction of cortisol by the adrenal gland (e.g., due to an adrenal adenoma or carcinoma). Secondary hypercortisolism is the result of elevated adrenocorticotropic hormone (ACTH) due to overproduction by either a pituitary adenoma (Cushing disease) or ectopic, paraneoplastic foci (e.g., in patients with small cell lung cancer). Typical clinical features include central obesity, thin and easily bruisable skin, abdominal striae, secondary hypertension, hyperglycemia, and proximal muscle weakness. Measurement of cortisol (urine free and/or late-night salivary cortisol) and/or the dexamethasone suppression test are used to diagnose hypercortisolism. Serum ACTH levels are used to differentiate between primary and secondary hypercortisolism. Depending on the suspected type of Cushing syndrome, additional studies may include imaging, further hormone testing, and bilateral sampling of the inferior petrosal sinus. The treatment of endogenous hypercortisolism primarily involves surgical removal of the source of excessive cortisol (e.g., adrenalectomy) or ACTH (e.g., transsphenoidal hypophysectomy) production. Pharmacological treatment aimed at normalizing cortisol levels (e.g., metyrapone) may be used in addition to surgical treatment or as second-line treatment if surgery is unsuccessful.
Exogenous (iatrogenic) Cushing syndrome
- Prolonged glucocorticoid therapy → hypercortisolism → decreased ACTH → bilateral adrenal atrophy
- Most common cause of hypercortisolism
|Overview of endogenous Cushing syndrome |
|Types||Primary hypercortisolism (ACTH-independent Cushing syndrome)||Secondary hypercortisolism|
|Pituitary ACTH production (Cushing disease)||Ectopic ACTH production|
|Relative frequency || || || |
While the term “Cushing syndrome” can be applied to any cause of hypercortisolism, “Cushing disease” refers specifically to secondary hypercortisolism that results from excessive production of ACTH by pituitary adenomas.
- Thin, easily bruisable skin with ecchymoses
- Stretch marks (classically purple abdominal striae)
- If secondary hypercortisolism: often hyperpigmentation (darkening of the skin due to an overproduction of melanin), especially in areas that are not normally exposed to the sun (e.g., palm creases, oral cavity)
- Delayed wound healing
- Flushing of the face
- Neuropsychological: : lethargy, , sleep disturbance, psychosis
- Musculoskeletal 
Endocrine and metabolic 
- Insulin resistance; → hyperglycemia (see “Diabetes mellitus”) → mild polyuria in the case of severe hyperglycemia
- Weight gain characterized by central obesity, moon facies, and a dorsocervical fat pad
- ♂: Decreased libido
- ♀: Decreased libido, virilization, and/or irregular menstrual cycles (e.g., amenorrhea)
- Growth delay (in children)
Other features 
- ∼ 90% of cases) (
- Increased susceptibility to infections (due to immunosuppression)
“CUSHINGOID” is the acronym for side effects of corticosteroids: Cataracts, Ulcers, Striae/Skin thinning, Hypertension/Hirsutism/Hyperglycemia, Infections, Necrosis (of the femoral head), Glucose elevation, Osteoporosis/Obesity, Immunosuppression, Depression/Diabetes.
Patients with secondary hypercortisolism due to ectopic ACTH production may present with rapid onset of hypertension and hypokalemia without other typical features of Cushing syndrome.Consider a diagnosis of hypercortisolism in patients who present with proximal muscle weakness, central obesity, thinning skin, weight gain, sleep disturbance, and/or depression.
- Evaluate for .
- Rule out exogenous Cushing syndrome caused by glucocorticoid administration.
- Obtain initial testing to confirm hypercortisolism; consult endocrinology if the diagnosis remains unclear.
- Refer to endocrinology for further diagnostics and treatment if hypercortisolism is confirmed.
- Identify the cause of hypercortisolism.
Routine laboratory studies 
Not required to establish the diagnosis, but if performed, may show the following typical findings:
- Hypernatremia, hypokalemia, metabolic alkalosis
- Hyperglycemia: due to stimulation of gluconeogenic enzymes (e.g., glucose-6-phosphatase) and inhibition of glucose uptake in peripheral tissue
- Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia)
- CBC: leukocytosis without left shift (predominantly neutrophilic), eosinopenia
Testing for hypercortisolism 
Any of the following tests can be used. The diagnosis is confirmed if at least two of the tests have abnormal results.
- Urine free cortisol 
- Low-dose dexamethasone suppression test
Late-night salivary cortisol
- A saliva sample is collected at the patient's usual bedtime.
- Supportive finding: ↑ salivary cortisol (> 4 nmol/L or > 145 ng/dL) 
Late-night serum cortisol: not routinely recommended as the initial test but can be used in patients with inconsistent results from previous tests
- A serum sample is taken from the patient (awake or asleep).
- Supportive finding: ↑ serum cortisol (> 7.5 mcg/dL) 
Consult an endocrinologist for further evaluation if any of the findings above are present or if the results are negative despite a high pretest probability.
Identifying the cause 
- Consider nonneoplastic and physiological causes of hypercortisolism based on clinical features and patient history (e.g., depression, heavy alcohol use, obesity) and in pregnant patients. 
- Measure serum ACTH levels.
Proceed based on the results.
- If ACTH-independent hypercortisolism is suspected: Obtain adrenal MRI and/or CT.
- If ACTH-dependent hypercortisolism is suspected: Obtain further testing.
Differentiating between Cushing syndrome and nonneoplastic-physiologic hypercortisolism can be very challenging. If there is any doubt, refer the patient to a specialized center.
Further testing in patients with 
- Obtain a pituitary MRI to evaluate for Cushing disease (see also “Diagnostics” in “ ”).
- Pituitary adenoma > 10 mm confirms Cushing disease.
- If there is no evidence of a pituitary adenoma or findings are unclear, obtain either: 
- Bilateral sampling of the inferior petrosal sinus
- Hormone testing in ACTH-dependent hypercortisolism
If ectopic ACTH production is suspected: imaging to locate the ACTH-producing primary malignancy (e.g., SCLC, RCC, carcinoid).
- Multiple studies are often necessary. 
- May include a thin-slice scan and functional imaging (e.g., )
|Hormone testing in ACTH-dependent hypercortisolism |
|CRH stimulation test |
|Desmopressin stimulation test|
|High-dose dexamethasone suppression test || |
The results of these tests must always be considered in the clinical context, and a combination of tests is usually necessary. Hormone-secreting pituitary microadenomas cannot always be detected on imaging and, conversely, small endocrine-inactive tumors may be detected in healthy individuals, potentially leading to overdiagnosis.
|Differential diagnosis of Cushing syndrome |
|Normal||Primary hypercortisolism||Ectopic ACTH secretion||Cushing disease|
|ACTH levels|| |
|Low-dose dexamethasone suppression test||↓ Cortisol||↔︎ Cortisol|
|High-dose dexamethasone suppression test||↓ Cortisol||↔︎ Cortisol||↓ Cortisol|
|CRH and desmopressin stimulation tests||↑ ACTH, ↑ cortisol||↔︎ ACTH, ↔︎ cortisol||↑ ACTH, ↑ cortisol|
General principles 
- All patients should be treated by a multidisciplinary team, including an endocrinologist.
- First-line treatment: surgical removal of the causative tumor
- Adjunctive or second-line therapy can include
Supportive management 
- Educate patients about the disease, including the risk of recurrence and the increased risk for venous thromboembolism.
- Ensure vaccinations are up-to-date in accordance with the American College of Physicians .
- Screen for and treat any common comorbidities (e.g., diabetes, hypertension, osteoporosis, psychiatric disorders).
First line: curative surgery 
- Primary hypercortisolism: : unilateral or bilateral laparoscopic or open adrenalectomy for adrenocortical tumors
- Cushing disease:
- Ectopic ACTH production: tumor resection with node dissection, as appropriate
- Patients should receive lifelong monitoring for recurrence by a specialist.
- Glucocorticoid replacement therapy is often necessary after surgery.
|Pharmacological treatment of Cushing syndrome |
|Enzyme inhibitors|| |
|Pituitary targeted drugs||Dopamine agonists|| |
|Somatostatin analogues|| |
Bilateral adrenalectomy 
Complication: Nelson syndrome (post adrenalectomy syndrome) 
- Etiology: bilateral adrenalectomy in patients with a previously undetected pituitary adenoma
- Pathophysiology: bilateral adrenalectomy → no endogenous cortisol production → no negative feedback from cortisol on the hypothalamus → ↑ CRH production → uncontrolled enlargement of preexisting but undetected → ↑ secretion of ACTH and MSH → manifestation of symptoms due to pituitary adenoma and ↑ MSH
- Clinical features: headache, bitemporal hemianopia (mass effect), cutaneous hyperpigmentation
- Treatment: surgery (e.g., transsphenoidal resection) and/or pituitary radiation therapy (e.g., if the tumor cannot be fully resected)