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Cushing's Syndrome

Introduction and background

Cushing's syndrome is caused by a chronic inappropriate elevation of free circulating cortisol.

It is more common in women and can present at any age.  There are many different causes of Cushing's syndrome. Cases of pituitary adenoma peak between 25-40 years of age, whereas ectopic ACTH production, which can be associated with lung cancer, occurs later on in life.

Normal secretion and function of cortisol

Cortisol is a glucocorticoid secreted by the zona fasciculata of the adrenal gland.  The release of cortisol is stimulated by ACTH. Release of cortisol is circadian (ie. Levels are highest around 8am and lowest around midnight)

The secretion of cortisol is part of a negative feedback loop (illustrated in the diagram below). It begins with the secretion of CRH from the hypothalamus, this positively stimulates the anterior pituitary gland to release ACTH, this then positively stimulates the adrenal glands to release cortisol. Cortisol will then negatively feedback to the hypothalamus and anterior pituitary to prevent the secretion of CRH and ACTH.  This helps to regulate the amount of cortisol released.

Cortisol is a lipid soluble hormone that crosses the cellular membrane and binds to its intracellular receptors to exert its actions, which are:

  • An increase in hepatic gluconeogenesis
  • Inhibition of T and B cell immune responses
  • Increased transciption of genes coding for anti-inflammatory products
  • Inhibition of the synthesis and secretion of cytokines
  • Redistribution of body fat
  • Inhibition of keratinocyte division and collagen synthesis in the skin
  • Decrease in protein synthesis in muscle
  • Increased osteoclast activity in bone
  • Increase in blood pressure via increased vascular sensitivity to catecholamines



Disease Aetiology

Cushing's syndrome can be caused by high exogenous or endogenous cortisol levels


Exogenous cause: Iatrogenic from excess exogenous glucocorticoids (most common cause)

Endogenous causes

  • ACTH dependent (80%):  This can be caused by a pituitary adenoma which secretes ACTH (Cushing's disease) or ACTH secreted from an ectopic source (eg. from a small cell carcinoma).
  • ACTH independent:  Excess cortisol secreted from an adrenal carcinoma, a benign adenoma or adrenal nodular hyperplasia
  • Rarer causes: CRH secreting tumour


Pseudo-Cushing's syndrome: there are other conditions that can push the cortisol level up including obesity, alcoholism and depression.  Pseudo-Cushing's has several features that help to distinguish it from Cushing's syndrome these include; cortisol levels falling when alcohol abuse stops and normal diurnal variation of cortisol secretion being maintained.



If you suspect Cushing's syndrome then the first line tests are a 24 hour urinary free cortisol and a dexamethasone suppression test.

If the patient has Cushing's syndrome then a 24 hour urinary free cortisol test result will show abnormally high cortisol levels in the urine (i.e. >280nmol/24hours).

In the dexamethasone suppression test: a serum cortisol is measured before midnight, 1mg of dexamethasone is then given at midnight and then the serum cortisol is rechecked at 8am.  In a patient without Cushing's syndrome, the high dose of steroid given in this test will cause negative feedback to the hypothalamus and pituitary to reduce production of CRH and ACTH and therefore cortisol secretion. In Cushing's syndrome, cortisol secretion is autonomous and therefore does not respond to feedback loops.  This means that the cortisol level will remain high.


Now that the patient has confirmed Cushing's syndrome we need to work out where the problem lies: in the hypothalamus, the pituitary, the adrenals or an ectopic site.  Therefore the ACTH level needs to be measured. 

If ACTH is undetectable then it is most likely to be a problem with the adrenals as cortisol is feeding back to inhibit ACTH secretion.  If the level of ACTH is normal or high it could either be due to a pituitary tumour or an ectopic source. 

An MRI of the pituitary is the next choice of investigation.  If this detects a tumour in the pituitary then it is Cushing's disease.  If there is no tumour then inferior petrosal sinus sampling (IPSS) should be considered.  This is where a blood sample is taken from the inferior petrosal sinuses (the veins draining blood from the pituitary) to measure the level of ACTH . If the cause is due to pituitary pathology then the levels of ACTH will be higher here than in a peripheral venous sample.

If this does not expose the cause of Cushing's syndrome then an ectopic source is most likely so a CT or MRI of the neck, thorax and abdomen should then be carried out, in attempt to locate the source. 


Cushing's syndrome has many causes therefore management involves treating the principle underlying cause.

  1. Iatrogenic Cause: If the patient is receiving exogenous steroids, stop medications if possible or reduce the dosage
  2. Cushing's disease- a pituitary tumour.  This can be managed surgically by trans-sphenoidal removal. Radiotherapy is often used in children.  If the source cannot be localised then a bilateral adrenalectomy can be performed to prevent high cortisol secretion and then the patient will need exogenous cortisol replacement
  3. Adrenal Tumor- adrenalectomy is usually successful for an adenoma, this is followed by radiotherapy for carcinoma
  4. Ectopic ACTH- surgery if the tumour has not spread



If Cushing's is left untreated then it it has an increased mortality rate due to cardiovascular complications.

With treatment it has a good prognosis and many of the symptoms and signs will resolve.  Some that may not resolve are hypertension, glucose intolerance or diabetes mellitus and osteoporosis. These conditions require treatment separately.

References and further reading

Holt R I G, Hanley N A.  Essential Endocrinology and Diabetes 5th ed.  Oxford: Blackwell's publishing; 2007

Longmore M, Wilkinson I, Turmezei T, Cheung C K.  Oxford handbook of clinical medicine 7th ed.  United States: Oxford University Press; 2007

Newell-Price J, Bertagna X, Grossman A B, Nieman L K.  Cushing's syndrome. The Lancet 2006: 367; 1605-17

Boscaro M, Arnaldi G.  Approach to the patient with possible Cushing's syndrome.  The Journal of Clinical Endocrinology and Metabolism 2009: 94; 9; 3121-3131



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