27th May 2025

Cushing’s syndrome

Background

Cushing’s syndrome arises from long-term exposure to excessive glucocorticoids of either endogenous or exogenous source. Exogenous steroids are the most common cause, and this should be excluded first. The presentation can be subtle, but presents with central obesity, proximal muscle weakness, dorsal and supraclavicular fat pads, abdominal violaceous striae, bruising and moon facies. Metabolic syndrome can arise from Cushing’s disease, as well as metabolic bone disease and hypertension.

Image Source: Wikimedia Commons (2015). Cuching’s Syndrome (Vector image), Licensed under a creative commons licence. Available for free at: https//commons.wikimedia.org/wiki/File:Cushing%27s_syndrome_(vector_image).svg (Accessed 13 May 2025).

Image Source: Wikimedia Commons (2012). Cushing’s Body, Licensed under a creative commons licence. Available for free at: https://en.wikipedia.org/wiki/Cushing%27s_syndrome#/media/File:CushingsBody.jpg  (Accessed 13 May 2025).

Epidemiology

Cushing’s syndrome is uncommon with an incidence of 40 per million. It more commonly affects females than males (3:1). Cushing’s disease (from pituitary secretion of ACTH) affects females to a greater degree (3:1 to 5:1), with a peak age of onset between 25 to 40 years of age. A greater prevalence of 2% to 5% is found in obese patients with type 2 diabetes mellitus.

Aetiology

There are two groups of causes:

• ACTH-dependent disease: excessive ACTH secretion by the pituitary (known as Cushing’s disease) is the most common endogenous cause responsible for 70 – 80% of cases. Other causes include ectopic ACTH-secreting tumours (e.g. in small cell lung cancer) or excess ACTH administration.
• ACTH-independent disease: the most common cause overall is excess exogenous glucocorticoids. Other causes include adrenal adenomas, adrenal carcinomas and macronodular adrenal hyperplasia.

Diagnosis

The signs and symptoms of Cushing’s syndrome are summarised in Figure 4. 

The first-line investigations are:

• FBC, U&Es and glucose: may show raised WCC, hypokalaemia, and hyperglycaemia respectively.
• 24-hour urinary cortisol: levels will be elevated to >50 mcg/24 hours. This test should not be used in those with renal failure.
• Low-dose dexamethasone suppression test: 1mg dexamethasone is given at 11pm, and plasma cortisol is measured at 8am the following morning, where levels elevated to >50 nmol/L indicate Cushing’s syndrome.
• Midnight cortisol levels: collected between 11pm and 1am, and will be elevated due to loss of normal diurnal variation in cortisol levels.
• Plasma ACTH: suppressed ACTH and high cortisol indicates an ACTH-independent cause such as adrenal adenoma. Elevated ACTH can suggest ACTH-dependent Cushing’s disease.

If plasma ACTH is detectable, there is benefit in the following tests:

• High-dose dexamethasone suppression test: 8mg dexamethasone is given at 11pm. Initial plasma cortisol is measured, and again at 8am the following morning. Suppression of cortisol <50% of baseline, indicates ACTH-dependent Cushing’s disease. High or normal cortisol, with a low ACTH suggests ACTH-independent causes such as adrenal adenoma. Whereas high-normal cortisol with a high ACTH suggests ectopic ACTH secretion.
• Inferior petrosal sinus sampling: blood is sampled peripherally and from the inferior petrosal sinus. If there is an elevated central : peripheral ACTH ratio, this indicates a pituitary cause.
• MRI pituitary gland: should be requested for suspected ACTH-dependent disease to investigate for pituitary adenoma.
• CT chest, abdomen and pelvis: to assess adrenals to identify adrenal adenoma, carcinoma or hyperplasia. It is also warranted to look for tumours that may be a source of ectopic ACTH secretion e.g. small cell lung cancer.

Management

The management of Cushing’s syndrome depends on the aetiology. Management in each case is summarised below:

Table 2: Management of Cushing’s syndrome dependent on aetiology.

Complications

Complications of Cushing’s syndrome include adrenal insufficiency following surgery, due to adrenal suppression as described in the Secondary Adrenal Insufficiency chapter. This can necessitate replacement glucocorticoid therapy. 

Hypercortisolism also carries an increased risk of metabolic syndrome (diabetes mellitus, hypertension and obesity), cardiovascular disease, thrombophilia, osteoporosis and impaired immunity. 

Treatment-related complications include Nelson’s syndrome following bilateral adrenalectomy, where loss of adrenal feedback causes growth of pre-existing ACTH-secreting pituitary adenomas. Transsphenoidal pituitary resection can also cause deficiency of other pituitary hormones e.g. thyrotropin, somatotropin, desmopressin and androgens.