Cushing syndrome

Cushing syndrome refers to the signs and symptoms that result from excess cortisol. These include central obesity, facial puffiness or roundness, peripheral oedema, thinning of the skin, and weakness, as well as complications such as diabetes, elevated blood pressure, dyslipidaemia and osteoporosis. In children, cortisol excess can also cause growth failure and delay of maturation (except in children with coincident androgen excess).

Cushing syndrome can be caused by:

  • exogenous administration of glucocorticoids (most common cause in children)
  • endogenous production of cortisol by an adrenal adenoma or carcinoma
  • bilateral nodular adrenal hyperplasia (rare)
  • overstimulation of both adrenal glands by excess adrenocorticotrophic hormone (ACTH) production from:

Initial screening tests for Cushing syndrome include the 1 mg overnight dexamethasone suppression test, and measurements of free cortisol (24-hour urinary cortisol and late-night salivary cortisol). Some drugs can cause a false-positive result for Cushing syndrome on the 1 mg overnight dexamethasone suppression test; see Drugs that can cause a false-positive result for Cushing syndrome on the 1 mg overnight dexamethasone suppression test.

Table 1. Drugs that can cause a false-positive result for Cushing syndrome on the 1 mg overnight dexamethasone suppression test

Drug

Mechanism of effect

estrogen-containing preparations (eg oral contraceptive pill, menopausal hormone therapy) [NB1]

estrogen stimulates cortisol binding globulin, causing increased total cortisol concentration

cytochrome P450 3A4 (CYP3A4) inducers (eg rifampicin, carbamazepine, phenytoin, phenobarbital [phenobarbitone], bosentan, modafinil, St. John’s wort, efavirenz, enzalutamide, mitotane)

increased hepatic clearance of dexamethasone

Note:

NB1: Estrogen-containing preparations do not interfere with measurements of free cortisol (24-hour urinary cortisol or late-night salivary cortisol).

Adrenal and pituitary tumours are treated by surgical removal. Pituitary tumours can usually be removed transsphenoidally. A unilateral adrenal adenoma can cause suppression of the adjacent adrenal gland, so following successful surgery to remove an adrenal tumour, or an ACTH-producing pituitary adenoma, the patient will be transiently glucocorticoid deficient. Use glucocorticoid replacement until the pituitary–adrenal axis recovers (typically several months, and up to 1 year), then gradually withdraw the glucocorticoid. Mineralocorticoid replacement is not required.

Pharmacological blockade of adrenal corticosteroid production is used if:

  • the source of ACTH excess is unclear
  • preoperative control of cortisol excess is required
  • surgical resection has been unsuccessful.

Pharmacological blockade should be managed in a specialist centre with experience in managing Cushing syndrome.