Cushing’s Syndrome

What is Cushing’s syndrome?

Cushing’s syndrome occurs as a result of prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids. The condition is associated with significant morbidity and mortality, therefore rapid diagnosis and management are essential.1



Glucocorticoid production is regulated by the hypothalamic-pituitary-adrenal-axis.

  1. Corticotropin-releasing hormone (CRH) is secreted from the hypothalamus. This release is influenced by stress levelstime of day and serum cortisol levels.
  2. CRH travels in the blood and binds to specific receptors in the pituitary gland. This binding causes increased production of adrenocorticotropic hormone (ACTH).
  3. ACTH is released into the bloodstream and travels to the adrenal glands, where it binds to specific receptors on the adrenal cortex.
  4. This binding of ACTH to the receptors stimulates the adrenal cortex to release cortisol into the bloodstream, where it has a wide range of effects (see below).
  5. Increased serum cortisol levels inhibit the production of CRH and ACTH via negative feedback, preventing the overproduction of cortisol.
Hypothalamic-Pituitary-Adrenal Axis Diagram
Hypothalamic-Pituitary-Adrenal axis diagram

Effects of Cortisol

  • Cortisol stimulates the synthesis of glucose from non-carbohydrate sources (known as gluconeogenesis), resulting in increased levels of glucose in the blood.
  • Cortisol promotes the breakdown of proteins, which can result in muscle wasting in chronic states of cortisol elevation.
  • An initial surge in cortisol levels triggers lipolysis, however, chronically elevated cortisol promotes lipogenesis.
  • Cortisol inhibits the production of several inflammatory cytokines causing downregulation of the immune response.
  • Cortisol reduces bone formation and therefore chronically elevated levels of cortisol can result in osteoporosis.
  • In high concentrations, cortisol exhibits mineralocorticoid effects, increasing sodium and water retention whilst increasing potassium excretion.

Causes of Cushing’s Syndrome


The most common cause of Cushing’s syndrome is the use of exogenous glucocorticoids (e.g. prednisolone, hydrocortisone).


Endogenous Cushing’s syndrome can be further sub-categorised as either corticotropin-dependent or corticotropin-independent.

Corticotropin-dependent Cushing’s syndrome

  • Corticotropin-dependent Cushing’s syndrome accounts for 80-85% of cases. 2
  • Pituitary adenomas account for 80% of corticotropin-dependent Cushing’s syndrome (known as “Cushing’s disease”).
  • Ectopic production of corticotropin (e.g. small cell lung cancer) accounts for around 20% of corticotropin-dependent Cushing’s syndrome. 2

Corticotropin-independent Cushing’s syndrome

  • The most common causes of corticotropin-independent Cushing’s syndrome are adrenal adenomas and adrenal carcinomas. 2

Symptoms and Signs


  • Weakness
  • Facial fullness
  • Weight gain
  • Low mood
  • Decreased libido
  • Polydipsia
  • Polyuria
  • Increased frequency of infections



  • Truncal obesity
  • Buffalo hump
  • Supraclavicular fat pads
  • Moon facies
  • Proximal muscle wasting
  • Hypertension
  • Oedema
  • Headaches, visual field defects and galactorrhoea (in Cushing’s disease)



Basic blood tests

  • Full blood count (white cell count may be raised due to glucocorticoid effects)
  • Urea and electrolytes (hyponatraemia, hyperkalemia)


Confirming the diagnosis of Cushing’s syndrome

Several investigations are typically required to accurately diagnose a patient with Cushing’s syndrome.

24-hour urinary free cortisol

  • Cortisol excretion of more than three times the upper limit of normal would be strongly suggestive of Cushing’s syndrome.


Low-dose dexamethasone suppression test

  • This test is particularly useful when screening patients for Cushing’s syndrome, as it is less cumbersome than a 24-hour urinary free cortisol collection.
  • 1mg of dexamethasone is administered at 11 pm and then serum cortisol is measured at 8 am the following morning.
  • If a patient has only mild Cushing’s syndrome, it may not be identified using this test alone.


Late-night salivary cortisol measurement

  • This test relies on the fact that in healthy individuals, the level of cortisol decreases in the evening compared to the morning.
  • In the case of Cushing’s syndrome, this normal diurnal variation is absent.
  • This test is simple and reliable. 4


Identifying the underlying cause of Cushing’s syndrome

Plasma ACTH

  • Levels of ACTH have a diurnal variation, with the plasma concentration being highest at 8 am and lowest at midnight.
  • An elevated ACTH level alongside a raised serum cortisol level suggests a diagnosis of ACTH-dependent Cushing’s syndrome (see causes above).4
  • An undetectable ACTH level alongside a raised serum cortisol level suggests a diagnosis of ACTH-independent Cushing’s syndrome (see causes above).5


High-dose dexamethasone suppression test

  • This test is indicated if ACTH levels are detectable.
  • The test is useful for differentiating between pituitary and ectopic ACTH production.
  • A reduction of basal urinary free cortisol of greater than 90% supports a diagnosis of a pituitary adenoma (ectopic ACTH causes a lesser degree of suppression).

Inferior petrosal sinus sampling

  • Inferior petrosal sinus sampling (IPSS) is an invasive procedure in which ACTH levels are sampled from veins that drain the pituitary gland.
  • These ACTH levels are compared with peripheral ACTH levels to determine whether a pituitary tumour is responsible for ACTH-dependent Cushing’s syndrome.
  • This method is used when neuroimaging along with the previous investigations has been insufficient to reach a diagnosis (e.g. no visible lesion on neuroimaging of the pituitary).


  • MRI of the pituitary (to confirm the presence of an adenoma)
  • CT chest and abdomen (to identify suspected adrenal tumours or other sources of ectopic ACTH production)


Exogenous Cushing’s Syndrome

Management of exogenous Cushing’s syndrome involves reviewing the patient’s current glucocorticoid treatments and reducing doses where possible (often through the use of steroid-sparing immunosuppressive agents).

Endogenous Cushing’s Syndrome

Definitive treatment of endogenous Cushing’s syndrome typically involves resection of the causative tumour, however medical therapies to reduce cortisol production are often used in the interim period to stabilise the patient prior to definitive therapy. 6


  • Ketoconazole, metyrapone and mitotane all directly inhibit glucocorticoid synthesis and secretion in the adrenal gland.
  • As a result, these medications can be used to temporarily reduce glucocorticoid levels to help prepare the patient for definitive therapy.
  • In some cases, these medications can be used long-term for patients who are too unfit to undergo definitive surgical management.

Surgical management

  • Adrenal tumours (e.g. adrenal adenoma) – laparoscopic excision
  • Pituitary tumours – trans-sphenoidal surgery (may also require adjunct radiotherapy)


  • Hypertension
  • Diabetes
  • Obesity
  • Metabolic syndrome
  • Osteoporosis


  1. Biller BM, Grossman AB, Stewart PM, et al; Treatment of ACTH-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2008 Apr 15. Available from: [LINK]
  2. Dr Roger Henderson. Cushing’s syndrome. Edited July 2015. Available from: [LINK]
  3. Boscaro M, Arnaldi G; Approach to the patient with possible Cushing’s syndrome. J Clin Endocrinol Metab. 2009 Sep94(9):3121-31. Available from: [LINK].
  4. Pecori Giraldi F, Invitti C, Cavagnini F; The corticotropin-releasing hormone test in the diagnosis of ACTH-dependent Cushing’s syndrome: a reappraisal. Clin Endocrinol (Oxf). 2001 May 54(5):601-7. Available from: [LINK]
  5. Stratakis CA; Cushing syndrome caused by adrenocortical tumours and hyperplasias (corticotropin- independent Cushing syndrome). Endocr Dev. 200813:117-32. doi: 10.1159/000134829. Available from: [LINK]
  6. Shalet S, Mukherjee A; Pharmacological treatment of hypercortisolism. Curr Opin Endocrinol Diabetes Obes. 2008 Jun15(3):234-8. Available from: [LINK]
  7. Newell-Price J, Bertagna X, Grossman AB, et al; Cushing’s syndrome. Lancet. 2006 May 13367(9522):1605-17. Available from: [LINK].


  1. Moon Facies. Ozlem Celik, Mutlu Niyazoglu, Hikmet Soylu and Pinar Kadioglu. CC BY. Available from: [LINK]
  2. Striae. Masry. CC BY-SA. Available from: [LINK]


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