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Cushing's syndrome

Medical Professionals

Professional Reference articles are designed for health professionals to use. They are written by UK doctors and based on research evidence, UK and European Guidelines. You may find the Cushing's syndrome article more useful, or one of our other health articles.

Synonym: hypercortisolism

Cushing's syndrome is caused by prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids. The degree of cortisol overproduction is very variable. When presentation is florid, diagnosis is usually straightforward. However, the presentation may be subtle and the combination of nonspecific clinical manifestations and variable cyclical biochemical parameters often makes the diagnosis difficult. Because of the significant morbidity and mortality of Cushing's syndrome, early diagnosis and prompt treatment are essential.

Causes of Cushing's syndrome can be divided into two groups:

  • Adrenocorticotropic hormone (ACTH)-dependent disease: excessive ACTH from the pituitary gland (Cushing's disease), ectopic ACTH-producing tumours or excess ACTH administration.

  • Non-ACTH-dependent: adrenal adenomas, adrenal carcinomas, excess glucocorticoid administration.

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  • The true incidence and prevalence of Cushing's syndrome are not known, but it is estimated to be nearly 40 per million1. The prevalence of the disease is highly variable across different ethnic and cultural groups and depends upon the frequency of medical conditions requiring steroid-based therapy2.

  • Of the known cases iatrogenic hypercortisolism outweighs the endogenous causes; of the endogenous causes pituitary-mediated ACTH production accounts for up to 80% of cases of hypercortisolism.

  • In obese patients with type 2 diabetes, especially those with poor blood glucose control and hypertension, the reported prevalence of Cushing's syndrome is between 2% and 5%.

Risk factors

  • Cushing's syndrome due to an adrenal or pituitary tumour is more common in females (ratio 5:1).

  • The peak incidence of Cushing's syndrome caused by an adrenal or pituitary adenoma is between the ages of 25 and 40 years.

  • Ectopic ACTH production due to lung cancer occurs later in life.

Common causes

The most common cause of Cushing's syndrome is the use of exogenous glucocorticoids. Endogenous Cushing's syndrome is divided into corticotropin-dependent and corticotropin-independent causes:

  • Corticotropin-dependent causes account for about 80-85% of cases:

    • 80% are due to pituitary adenomas (Cushing's disease).

    • The remaining 20% are due to ectopic corticotropin syndrome, which is usually due to small-cell carcinoma of the lung and bronchial carcinoid tumours but may occur with almost any endocrine tumour - eg, phaeochromocytoma, pancreatic neuroendocrine tumours, medullary thyroid cancer, gut carcinoids.

  • Corticotropin-independent Cushing's syndrome:

    • Is most often due to a unilateral tumour: adrenal adenoma in 60% and adrenal carcinoma in 40% of cases.

    • Very rare adrenal causes of Cushing's syndrome are corticotropin-dependent macronodular adrenal hyperplasia, primary pigmented nodular adrenal disease and McCune-Albright syndrome.

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  • Truncal obesity, supraclavicular fat pads, buffalo hump, weight gain.

  • Facial fullness, moon facies, facial plethora.

  • Proximal muscle wasting and weakness.

  • Diabetes or impaired glucose tolerance.

  • Gonadal dysfunction, reduced libido.

  • Hypertension.

  • Nephrolithiasis.

  • Skin: skin atrophy, purple striae, easy bruising, hirsutism, acne; pigmentation occurs with ACTH-dependent causes.

  • Psychological problems: depression, cognitive dysfunction and emotional lability4.

  • Osteopenia or osteoporosis.

  • Oedema.

  • Women may complain of irregular menses.

  • Thirst, polydipsia, polyuria.

  • Impaired immune function: increased infections, difficulty with wound healing.

  • Child: growth restriction.

  • Patients with an ACTH-producing pituitary tumour may develop headaches, visual problems and galactorrhoea.

  • Destruction of the anterior pituitary may cause hypothyroidism and amenorrhoea.

Differential diagnosis

Pseudo-Cushing's syndrome: all or some of the clinical features of Cushing's syndrome, combined with biochemical evidence of hypercortisolism (but not caused by pituitary-adrenal axis problems). Causes include:

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No single test is perfect and several different tests are usually needed.

  • Investigations are usually carried out following referral; it is often easier to co-ordinate the investigations in secondary care and ensure earlier diagnosis and effective management.

  • Investigations should be performed when there is no acute concurrent illness (eg, infection or heart failure), as these can cause false positive results.

Investigations to confirm the presence of Cushing's syndrome

The recommended diagnostic tests for the presence of Cushing's syndrome are 24-hour urinary free cortisol, 1 mg overnight dexamethasone suppression test and late-night salivary cortisol.

  • FBC: raised white cell count.

  • Electrolytes and acid-base balance: hypokalaemia (common with ectopic ACTH secretion as a result of mineralocorticoid activity), metabolic alkalosis.

  • 24-hour urinary free cortisol1:

    • Ideally three collections. Measure creatinine excretion at the same time.

    • Cushing's syndrome can be confidently diagnosed if two or more collections measure cortisol excretion as more than three times the laboratory upper limit of normal.

    • Need to repeat the test if creatinine excretion varies by more than 10% between collections.

    • False positives may occur with pregnancy, anorexia, exercise, psychoses, alcohol and alcohol withdrawal. Strenuous exercise and illness raise cortisol secretion.

  • Low-dose dexamethasone suppression test5:

    • A useful screening test in those who are unable to reliably collect a 24-hour urine sample.

    • 1 mg of dexamethasone is ingested at 11 pm and serum cortisol is measured at 8 am the next morning.

    • Mild Cushing's syndrome is often difficult to distinguish from normal cortisol secretion or pseudo-Cushing's syndrome and both false positive and false negative test results occur.

  • Midnight cortisol levels:

    • Taken between 11 pm and 1 am. Demonstrate loss of normal diurnal variation of reduced cortisol production in the evening compared to the morning.

    • Need to take blood from an indwelling cannula with the patient in a relaxed state.

    • Inconvenient but reliable test for Cushing's syndrome.

    • Late-night salivary cortisol measurement is a simple and reliable screening test for Cushing's syndrome.

  • Dexamethasone suppressed corticotropin-releasing hormone (CRH) test:

    • Modification of the low-dose dexamethasone suppression test.

    • IV CRH is given 2 hours after 48 hours (eight doses) of 0.5 mg dexamethasone. Serum cortisol is measured 15 minutes after ovine CRH administration.

    • Very reliable test for Cushing's syndrome.

Investigations to identify the cause of Cushing's syndrome

Plasma ACTH

  • Secretion is pulsatile and shows a diurnal variation, with the plasma concentrations highest at 8 am and lowest at midnight. The secretion of ACTH is increased by stress.

  • An undetectable plasma ACTH with an elevated serum cortisol level is diagnostic of ACTH-independent Cushing's syndrome, which is due to a primary cortisol-producing adrenal adenoma or carcinoma, or exogenous glucocorticoid use. This should then be followed by an abdominal CT or MRI scan if exogenous glucocorticoids are excluded as the cause.

  • An elevated ACTH level is consistent with ACTH-dependent Cushing's syndrome.

  • If the plasma ACTH level is detectable then the following tests are indicated:

    • High-dose dexamethasone suppression test:

      • The 8 mg overnight dexamethasone suppression test and the 48-hour high-dose dexamethasone test may be useful when baseline ACTH levels are equivocal. They also help in determining whether a patient has pituitary or ectopic ACTH production.

      • Greater than 90% reduction in basal urinary free cortisol levels supports the diagnosis of a pituitary adenoma; ectopic ACTH causes lesser degrees of suppression.

    • Inferior petrosal sinus sampling (IPS):

      • Performed with CRH stimulation to aid in determining the source of excess ACTH.

      • A baseline and stimulated ratio of IPS to peripheral ACTH of less than 1.8 is suggestive of ectopic ACTH, while a ratio of IPS to peripheral ACTH of greater than 2 is consistent with a pituitary adenoma.

    • MRI of the pituitary gland.

    • Chest and abdominal CT scans: for patients with suspected adrenal tumours or ectopic ACTH.

    • Plasma CRH: ectopic CRH production is a very rare cause of Cushing's syndrome.


Definitive therapy of endogenous Cushing's syndrome involves tumour resection. Indications for medical therapy include acutely ill patients in preparation for surgery, patients with unknown tumour location or unresectable lesions, patients unfit for surgery and patients with persistent raised glucocorticoid levels postoperatively.

  • The treatment of choice in most patients is surgical but the metabolic consequences, including increased tissue fragility, poor wound healing, hypertension and diabetes mellitus, increase the risks of surgery.

  • Drug therapy remains very important for normalising cortisol levels while awaiting the impact of more definitive treatment.

  • Cortisol hypersecretion must be controlled prior to surgery or radiotherapy if at all possible.


  • Metyrapone, ketoconazole, and mitotane can all be used to lower cortisol by directly inhibiting synthesis and secretion in the adrenal gland.

  • Metyrapone and ketoconazole are enzyme inhibitors and have rapid onset of action; however, control of hypercortisolism is often lost with corticotropin oversecretion in Cushing's disease. These drugs are not usually effective as long-term treatment and are used mainly for preparation for surgery or as adjunctive treatment after surgery or pituitary radiotherapy.

  • Mitotane acts as an adrenolytic drug with delayed onset but long-lasting action, but control of corticotropin oversecretion in Cushing's disease is maintained.

  • Medical treatment can also be used in patients who are unwilling or unfit for surgery. Treatment can be used long-term for patients with ectopic corticotropin secretion; however, adrenalectomy may be preferred. Multiple agents are more effective than monotherapy7.

  • Etomidate can be used for acute control of severe hypercortisolaemia.

Surgical treatment

Is the treatment of choice for the following conditions:

  • Pituitary tumours: trans-sphenoidal microsurgery. Radiation therapy may be used as an adjunct for patients who are not cured. Bilateral adrenalectomy may be necessary to control toxic cortisol levels.

  • Adrenocortical tumours: require surgical removal. Laparoscopic surgery is now the treatment of choice for unilateral adrenal adenomas.

  • Removal of neoplastic tissue is indicated for ectopic ACTH production. Metastatic spread makes a surgical cure unlikely or impossible. Bilateral adrenalectomy is indicated if necessary to control toxic cortisol levels.

Pituitary radiotherapy

  • Persisting hypercortisolaemia after trans-sphenoidal surgery can be treated with pituitary radiotherapy.

  • Conventional fractionated radiotherapy is very effective but is associated with long-term hypopituitarism and can be very delayed in effectiveness.


Patients with Cushing's syndrome often develop2:


  • Early studies reported a median survival of 4.6 years and five-year survival of only 50%; however with recent advances in treatment, the standard mortality ratio is similar to the age-matched population2.

  • The causes of premature death in untreated Cushing's syndrome are vascular disease (myocardial infarction/stroke), uncontrolled diabetes mellitus and complications of diabetes, and infections1.

  • The usual course is chronic, with cyclic exacerbations and rare remissions.

  • The prognosis is guardedly favourable with surgery.

  • The rare adrenocortical carcinomas have a five-year survival rate of 30% or less.

Further reading and references

  1. Nishioka H, Yamada S; Cushing's Disease. J Clin Med. 2019 Nov 12;8(11). pii: jcm8111951. doi: 10.3390/jcm8111951.
  2. Chaudhry HS, Singh G; Cushing Syndrome
  3. Nieman LK; Cushing's syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol. 2015 Oct;173(4):M33-8. doi: 10.1530/EJE-15-0464. Epub 2015 Jul 8.
  4. Fujii Y, Mizoguchi Y, Masuoka J, et al; Cushing's Syndrome and Psychosis: A Case Report and Literature Review. Prim Care Companion CNS Disord. 2018 Sep 13;20(5). doi: 10.4088/PCC.18br02279.
  5. Vassiliadi DA, Tsagarakis S; Diagnosis of Endocrine Disease: The role of the desmopressin test in the diagnosis and follow-up of Cushing's syndrome. Eur J Endocrinol. 2018 May;178(5):R201-R214. doi: 10.1530/EJE-18-0007. Epub 2018 Feb 22.
  6. Nieman LK; Recent Updates on the Diagnosis and Management of Cushing's Syndrome. Endocrinol Metab (Seoul). 2018 Jun;33(2):139-146. doi: 10.3803/EnM.2018.33.2.139.
  7. Broersen LHA, Jha M, Biermasz NR, et al; Effectiveness of medical treatment for Cushing's syndrome: a systematic review and meta-analysis. Pituitary. 2018 Dec;21(6):631-641. doi: 10.1007/s11102-018-0897-z.

Article history

The information on this page is written and peer reviewed by qualified clinicians.

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