Cushing syndrome

Last updated: July 12, 2022

Summarytoggle arrow icon

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

Endogenous Cushing syndrome

Overview of endogenous Cushing syndrome [1][2]
Types Primary hypercortisolism (ACTH-independent Cushing syndrome) Secondary hypercortisolism
Pituitary ACTH production (Cushing disease) Ectopic ACTH production
Relative frequency [3]
  • 5–10%
  • ∼ 75%
  • ∼ 15%
Sex
Causes

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.

Secondary hypercortisolism is also called ACTH-dependent Cushing syndrome because hypercortisolism is the result of increased ACTH levels.

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.

Approach [1][4][5]

Prolonged glucocorticoid therapy is the most common cause of hypercortisolism (exogenous Cushing syndrome); further testing is not required in these patients.

Routine laboratory studies [6]

Not required to establish the diagnosis, but if performed, may show the following typical findings:

Testing for hypercortisolism [2][3][4][5][7]

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 [2]
    • Free cortisol is measured in a complete 24-hour urine collection.
    • Supportive finding: ↑ urine free cortisol [2][3]
  • Low-dose dexamethasone suppression test
    • 1 mg of dexamethasone is administered between 11 pm and midnight and serum cortisol is measured the following morning between 8 and 9 am.
    • Supportive finding: ↑ early morning serum cortisol level (> 50 nmol/L or > 1.8 mcg/dL) [5]
  • 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) [5][8]
  • 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) [4]

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 [5]

Initial evaluation

  1. 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. [9]
  2. Measure serum ACTH levels.
  3. Proceed based on the results.

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 ACTH-dependent hypercortisolism [2][5]

The goal is to differentiate between Cushing disease and ectopic ACTH production. A combination of tests is often necessary.

Abdominal CT or MRI in a patient with Cushing disease will show bilateral hyperplasia of both the zona fasciculata and zona reticularis.

Hormone testing in ACTH-dependent hypercortisolism [2][5]
Important considerations Findings
CRH stimulation test [10]
Desmopressin stimulation test
High-dose dexamethasone suppression test [2]
  • Not routinely recommended due to low accuracy

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 [2][5]
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

In Cushing syndrome, only patients with Cushing disease remain (partially) susceptible to cortisol suppression (high-dose dexamethasone suppression test) and stimulation (CRH stimulation test).

The following section applies to endogenous Cushing syndrome. For patients with exogenous Cushing syndrome, consider lowering the dose of glucocorticoids or replacing them.

Approach [2][3][5][11]

  • Manage with a multidisciplinary team including an endocrinologist.
  • First-line treatment: tumor resection
  • Second-line or adjunctive therapy: pharmacological treatment

Patients who develop adrenal insufficiency after surgery require lifelong glucocorticoid replacement therapy.

Enzyme inhibitors (e.g., metyrapone, ketoconazole) suppress cortisol synthesis, while glucocorticoid antagonists block the action of cortisol in peripheral tissues.

Supportive management [11]

First line: curative surgery [12]

Radiotherapy and/or chemotherapy may be indicated as part of the management of the causative tumor.

Surgical procedures

Follow-up

Pharmacological treatment

Pharmacological treatment of Cushing syndrome [5][11]
Examples Indications
Enzyme inhibitors
  • Adjunctive treatment for patients with overt Cushing syndrome
  • Second-line treatment for Cushing syndrome of any cause
Glucocorticoid antagonists
Pituitary targeted drugs Dopamine agonists
Somatostatin analogues
  • Pasireotide

Bilateral adrenalectomy [11]

  1. Castinetti F, Morange I, Conte-Devolx B, Brue T. Cushing’s disease. Orphanet J Rare Dis. 2012; 7 (1): p.41. doi: 10.1186/1750-1172-7-41 . | Open in Read by QxMD
  2. Feelders R, Sharma S, Nieman L. Cushing's syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015 : p.281. doi: 10.2147/clep.s44336 . | Open in Read by QxMD
  3. Nieman LK, Ilias I. Evaluation and treatment of Cushing’s syndrome. Am J Med. 2005; 118 (12): p.1340-1346. doi: 10.1016/j.amjmed.2005.01.059 . | Open in Read by QxMD
  4. Lynnette K. Nieman, Beverly M. K. Biller, James W. Findling, John Newell-Price, Martin O. Savage, Paul M. Stewart, Victor M. Montori. The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 2008; 93 (5): p.1526-1540. doi: 10.1210/jc.2008-0125 . | Open in Read by QxMD
  5. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing's disease: a guideline update. The Lancet Diabetes & Endocrinology. 2021; 9 (12): p.847-875. doi: 10.1016/s2213-8587(21)00235-7 . | Open in Read by QxMD
  6. Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2). McGraw-Hill Education / Medical ; 2018
  7. Carroll TB, Findling JW. The diagnosis of Cushing's syndrome.. Rev Endocr Metab Disord. 2010; 11 (2): p.147-53. doi: 10.1007/s11154-010-9143-3 . | Open in Read by QxMD
  8. Papanicolaou DA, Yanovski JA, Cutler GB, Chrousos GP, Nieman LK. A Single Midnight Serum Cortisol Measurement Distinguishes Cushing’s Syndrome from Pseudo-Cushing States1. The Journal of Clinical Endocrinology & Metabolism. 1998; 83 (4): p.1163-1167. doi: 10.1210/jcem.83.4.4733 . | Open in Read by QxMD
  9. Findling JW, Raff H. DIAGNOSIS OF ENDOCRINE DISEASE: Differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome). European Journal of Endocrinology. 2017; 176 (5): p.R205-R216. doi: 10.1530/eje-16-0946 . | Open in Read by QxMD
  10. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and Complications of Cushing’s Syndrome: A Consensus Statement. J Clin Endocrinol Metab. 2003; 88 (12): p.5593-5602. doi: 10.1210/jc.2003-030871 . | Open in Read by QxMD
  11. Lynnette K. Nieman, Beverly M. K. Biller, James W. Findling, M. Hassan Murad, John Newell-Price, Martin O. Savage, Antoine Tabarin. Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 2015; 100 (8): p.2807-2831. doi: 10.1210/jc.2015-1818 . | Open in Read by QxMD
  12. R. van der Pas, F.W.G. Leebeek, L.J. Hofland, W.W. de Herder, R.A. Feelders. Hypercoagulability in Cushing's syndrome: prevalence, pathogenesis and treatment. Clin Endocrinol (Oxf). 2013; 78 (4): p.481-488. doi: 10.1111/cen.12094 . | Open in Read by QxMD
  13. Banasiak MJ, Malek AR. Nelson syndrome: comprehensive review of pathophysiology, diagnosis, and management. Neurosurg Focus. 2007; 23 (3): p.1-10. doi: 10.3171/foc.2007.23.3.15 . | Open in Read by QxMD

3 free articles remaining

You have 3 free member-only articles left this month. Sign up and get unlimited access.
 Evidence-based content, created and peer-reviewed by physicians. Read the disclaimer