How is Cushing's syndrome diagnosed?

Patients may be treated for several years for the symptoms of Cushing's syndrome before being correctly diagnosed. The clinical suspicion of Cushing's arises from clinical signs such as thin skin, bruising, hypertension, 'buffalo hump', plethora, moon face, purple striae, and proximal myopathy. The main steps in the process of diagnosis are:

  • confirmation of raised blood cortisol
  • the cause of this cortisol excess must be established
  • any tumours must be localised.

Confirmation of raised blood cortisol

A simple screening test is the midnight and 9 a.m cortisol level (see the diagram below). The Low-dose dexamethasone suppression test is the main test used. Such suppression is lost in Cushing's syndrome. Occasionally such suppression is also lost in elderly or depressed patients. Results from a 24 hour urinary collection of free cortisol can be used in addition to the suppression test in such situations.

Cortisol levels

Cortisol levels - click to enlarge

Establishing the cause of the raised cortisol

A variety of tests are used to determine whether the cortisol excess is caused by:

  1. Over-production by the adrenal gland (ACTH-independent Cushing's)
  2. Over-stimulation of the adrenal gland by pituitary ACTH (ACTH-dependent Cushing's)
  3. Over-stimulation of the adrenal gland by ectopic ACTH (ACTH-dependent Cushing's)

Plasma ACTH levels

These are used to distinguish between primary and secondary disease. ACTH is very low in primary Cushing's syndrome as the over-active adrenal, autonomously producing cortisol, inhibits ACTH production from the pituitary. In secondary disease it is the elevated production of ACTH from the pituitary that is stimulating the adrenal glands to produce excess cortisol. ACTH levels are therefore high in this situation.

High-dose dexamethasone test

This is used to demonstrate the presence of an ectopic source of ACTH or an adrenal tumour. The principle is that high doses of dexamethasone will suppress cortisol production in pituitary-dependent Cushing's disease but will not suppress either an autonomous adrenal tumour or an ectopic source of ACTH.

CRH Test

This test can be used to distinguish between pituitary-dependent Cushing's and an ectopic source of ACTH. CRH is administered intravenously and the cortisol response monitored. Normally there is a rise in both ACTH and cortisol. In pituitary-dependent Cushing's patients the response is exaggerated, and in ectopic ACTH syndrome there will be no response. This is illustrated here.

Diagram illustrating the CRH test

Diagram illustrating the CRH test - click to enlarge

Inferior petrosal sinus sampling

This test can be used to accurately distinguish pituitary and ectopic sources of ACTH causing Cushing's syndrome. The principle of the test is to sample the blood from the petrosal sinuses draining the pituitary gland, to compare the levels of ACTH with those found in the peripheral blood. A petrosal:peripheral ratio of > 2, indicating excess ACTH from the pituitary, is necessary to diagnose Cushing's disease with confidence. Accuracy can be improved using CRH stimulation to exaggerate the difference.

Localisation of the tumour

Abdominal CT & MRI scans

Adrenal adenomas and carcinomas tend to be large (>2cm and 6cm in diameter respectively). They therefore readily show up on CT or MRI, although there appears to be little difference on the image between benign and malignant lesions.

Pituitary MRI

MRI is the best modality for imaging the pituitary. It has a 77% sensitivity for the detection of pituitary microadenomas. Specificity is only 80%, therefore images must be viewed in the light of other test results.

Chest X-ray

This is useful in visualising lung tumours, such as bronchial carcinoid tumours, that may be ectopic sources of ACTH.


This is where octreotide (an analogue of somatostatin), labelled with a radioactive isotope is injected into the bloodstream. ACTH secreting tumours often have somatostatin receptors on their surface. The radiolabelled analogue therefore binds to the tumour cells. X-ray imaging then allows the tumour to be visualised before surgery