Cushing's syndrome


Definition & classification

Cushing’s syndrome is caused by prolonged exposure to an excess of glucocorticoids.

Exogenous administration of steroids is the most common cause of Cushing's syndrome. Endogenous causes are rare (estimated at 5 in 1,000,000).

Cushing’s disease refers to cases caused by a pituitary adenoma. These are responsible for the majority of endogenous cases.


Cortisol secretion is controlled by the hypothalamus-pituitary-adrenal axis.

HPA axis

1. Corticotropin-releasing hormone 

Corticotropin-releasing hormone (CRH) is released by the paraventricular nucleus of the hypothalamus. It is transported via the hypophyseal portal system to the anterior pituitary where it stimulates the release of adrenocorticotropic hormone (ACTH).

2. Adrenocorticotropic hormone

ACTH, released from the corticotrophs of the anterior pituitary, stimulates the release of cortisol.

The precursor of ACTH is POMC, this is also the precursor of beta-melanocyte-stimulating hormone. In addition, to this ACTH may be cleaved to form alpha-melanocyte-stimulating hormone. As a result ACTH excess results in hyperpigmentation (resulting from melanocyte stimulation), particularly affecting the oral mucosa and palmar creases.

ACTH excess is a feature of both Addison's disease (primary adrenocortical insufficiency) and ACTH dependent Cushing's syndrome.

3. Cortisol

Cortisol is released from the adrenal cortex in response to ACTH. It exerts negative feedback on the release of both ACTH and CRH.

Cortisol exhibits diurnal variation, that is to say, the plasma concentration of cortisol levels vary during a 24 hour period.

It reaches a zenith (highest point) at around 8 am and a nadir (lowest point) at around midnight to 1 am.

Cortisol diurnal variation


The causes of Cushing’s may be divided into those that are ACTH dependent and those that are ACTH independent.

ACTH dependent

Cushing’s disease refers to Cushing's syndrome caused by a pituitary adenoma. It results in corticotrophs releasing excess ACTH.

ACTH dependent disease may also result from ectopic ACTH producing tissues. It manifests as a paraneoplastic syndrome in a number of malignancies including small-cell lung cancer and a number of neuroendocrine tumours.

ACTH independent

Prolonged exposure to exogenous glucocorticoids is the most common cause of Cushing's syndrome.

Primary cortisol secreting adrenal tumours (adenomas and carcinomas) and hyperplasia are rare causes of ACTH independent Cushing's syndrome.

Clinical features

The clinical features asssociated with Cushing's syndrome are related to the effects of excess cortisol.


  • Tiredness
  • Depression
  • Weight gain
  • Easy bruising
  • Amenorrhoea
  • Reduced libido
  • Striae


  • Acne
  • Moon facies
  • Plethora
  • Buffalo hump
  • Hypertension
  • Proximal muscle weakness
  • Hyperpigmentation (in ACTH dependent causes)



It is vital to take a detailed drug history to exclude an exogenous cause of Cushing's syndrome


24-hour urinary cortisol

A 24-hour urinary cortisol is often the initial test in a patient with suspected Cushing's syndrome. Three or more collections are usually needed. Levels 3-4x normal are highly suggestive of Cushing's syndrome.

Importantly, creatinine levels also need to be measured as the variation in levels between samples (>10 %) indicates that the test needs to be repeated. 

Midnight cortisol

Taking midnight cortisol levels helps to demonstrate a loss of the normal circadian pattern.

Cortisol levels can be salivary or blood based. If blood, samples should ideally be taken from an indwelling cannula, which helps minimise stress.

Low-dose dexamethasone suppression

The low-dose dexamethasone suppression test is aimed at demonstrating the loss of normal negative feedback on the pituitary gland and hypothalamus.

1 mg of dexamethasone is given at 11pm and serum cortisol is then measured at 8am. In a normal individual, the administration of dexamethasone should suppress the morning rise in serum cortisol. However, in patients' with Cushing's syndrome, there is a lack of suppression, which warrants further investigation. 

Dexamethasone-CRH test

In the dexamethasone-CRH test, 8 doses of 0.5 mg dexamethasone are given over a 48 hour period. This is followed by the administration of CRH. Serum cortisol (and ACTH) levels can then be measured. This test is reliable in borderline cases and can also be useful in the assessment of pituitary function.

Identifying a cause

After diagnosing cortisol excess we must identify the underlying aetiology.


Plasma ACTH

Undetectable levels of plasma ACTH are indicative of an ACTH independent cause of Cushing's syndrome. Once exogenous causes are excluded, abdominal imaging for an adrenal adenoma/carcinoma may be indicated. 

On the other hand, normal or high levels of plasma ACTH are suggestive of an ACTH dependent cause. 

High-dose dexamethasone suppression test

The high-dose dexamethasone suppression test helps to determine, in ACTH dependent causes, if ACTH production is from the pituitary or an ectopic source.

With pituitary adenomas, ACTH production is suppressed by the high dose dexamethasone, while ectopic tissues are not suppressed.


MRI/CT imaging may be useful in the detection of both pituitary and adrenal pathology (e.g. adenomas/carcinomas).

Petrosal sinus sampling

This is an invasive test that may be used to help identify a microscopic pituitary adenoma. A catheter is passed into the petrosal sinuses that surrounds the pituitary gland and the level of ACTH (+/- CRH stimulation) can be assessed.

This can be compared to levels from a peripheral vein. Petrosal sinus sampling may be used to identify the side of the tumour.


Untreated Cushing’s syndrome can be lethal with death from cardiac, thromboembolic or infective complications.


Medical therapy is most commonly used as a bridge to more definitive treatment.

Metyrapone can be used, an inhibitor of 11β-hydroxylase, that leads to a reduction in cortisol synthesis.


Surgical treatment is indicated in cases where the development of Cushing's syndrome is related to a tumour. 

Management of Cushings syndrome

Cushing’s disease is typically treated with transsphenoidal surgery, adrenal tumours require an adrenalectomy, and ectopic ACTH producing tumours should be resected where possible. 

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