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  3. Cushing's Syndrome

Cushing's Syndrome

NICE CKS Cushing's syndrome. Last revised: Dec 2024. NICE BNF Treatment summaries Cushing's syndrome.

Background Information

Cushing's syndrome is the clinical state of chronic glucocorticoid excess

Causes can be largely categorised into exogenous vs endogenous causes
  • Exogenous (most common overall): secondary to glucocorticoid therapy (mainly from systemic steroids)
  • Endogenous: can be sub-categorised further

Endogenous causes of Cushing's syndrome:
  • ACTH-dependent causes
    • Cushing's disease (ACTH-secreting pituitary adenoma) - most common endogenous cause
    • Ectopic ACTH-secreting tumours - mostly lung cancer (small cell), or other neuroendocrine tumours
 
  • ACTH-independent causes
    • Adrenal adenoma - most common ACTH-independent cause
    • Adrenal carcinoma
    • Rare causes
      • Primary bilateral macronodular adrenal hyperplasia (usually in adults).
      • Primary pigmented nodular adrenal disease (isolated or as part of Carney complex, often in young adults).
      • McCune-Albright syndrome

 

 The 3 bolded causes above (Cushing's disease, ectopic tumour, and adrenal adenoma) are the most frequently examined causes. Students are often expected to interpret test results to reach the most likely diagnosis. It is important to appreciate which is ACTH-dependent and ACTH-independent in order to answer these questions correctly.

Note that Cushing's syndrome is NOT the same as Cushing's disease:

  • Cushing’s syndrome: the clinical state caused by chronic exposure to excess glucocorticoids, from any cause
  • Cushing’s disease: a specific cause of Cushing’s syndrome — due to an ACTH-secreting pituitary adenoma

Diagnosis Guidelines

Key biochemical changes:
  • Hypernatraemia
  • Hypokalaemia
  • Metabolic alkalosis
 
  • Metabolic panel
    • Hyperglycaemia
    • Hyperlipidaemia

 

Endocrinology is one of the few topics where physiology is truly useful... Instead of memorising the above-mentioned biochemical changes, one can reason them out.

  • Cortisol usually raises blood glucose and lipid levels → cortisol excess would result in hyperglycaemia and hyperlipidaemia
  • In Cushing's disease, the excess cortisol is able to bind and activate mineralocorticoid receptors (this is normally regulated by 11β-HSD, which converts cortisol into cortisone to prevent cortisol from activating mineralocorticoid receptors) (however, in Cushing's disease, 11β-HSD becomes saturated)
    • This results in excess mineralocorticoid receptor activity (aldosterone usually retains sodium, excretes potassium, and excretes hydrogen) → hypernatraemia + hypokalaemia + metabolic alkalosis

As mentioned above, the 3 main causes of Cushing's syndrome that students are expected to be able to diagnose based on endocrine studies are:
  • Cushing's disease (ACTH-secreting pituitary adenoma)
  • Ectopic ACTH cause (most common small cell lung cancer)
  • Adrenal cause (adenoma / carcinoma)
 

NICE CKS states that if exogenous Cushing's syndrome is suspected, investigations are not routinely required.

NICE CKS recommends any of the following as 1st line tests to confirm hypercortisolism:
 
Test Interpreation
Overnight (low-dose) dexamethasone suppression test Cortisol NOT suppressed (higher than reference range)

*In those without Cushing's syndrome, the dexamethasone would suppress cortisol secretion, and its level would be undetectable
24-hour urinary free cortisol ↑
Late-night salivary cortisol ↑
 
 

For exam purposes, overnight dexamethasone suppression test is often considered the 'gold standard' screening test for diagnosing Cushing's syndrome. However, it is more important to know how to interpret its results.

To localise the cause of Cushing's syndrome, measure morning ACTH level
  • ↑ ACTH → ACTH-dependent (i.e. pituitary or ectopic cause likely)
  • ↓ ACTH → ACTH-independent (i.e. adrenal cause likely)

Depending on the ACTH levels, there are 2 work-up pathways.
 

Dynamic endocrine tests to differentiate pituitary cause (i.e. Cushing's disease) from other causes:

Test Method Key Interpretation
High-dose dexamethasone suppression test Give 8mg dexamethasone overnight or 2mg 6-hourly for 48 hr, then measure cortisol level
  • Cortisol level suppressed → suggests Cushing's disease
  •  No suppression → non-Cushing's disease (i.e. ectopic or adrenal cause)
CRHCorticotropin-releasing hormone stimulation test Give IV CRHCorticotropin-releasing hormone, then measure ACTH & cortisol levels
  • ↑ Cortisol and/or ACTH → suggests Cushing's disease
  • No / minimal rise → ectopic ACTH cause

Imaging studies (depending on what is suspected based on dynamic endocrine tests):
  • Likely Cushing's disease → pituitary MRI
 
  • Likely ectopic cause →
    • 1st line: neck to pelvis CT or CT TAPThorax Abdomen Pelvis
    • 2nd line: PET scan

Gold standard test: bilateral inferior petrosal sinus sampling
  • Confirm pituitary vs ectopic ACTH source when imaging is equivocal
  • ↑ ACTH suggests Cushing's disease
  • Normal / ↓ ACTH suggests other causes (ectopic or adrenal cause)

Perform CT / MRI adrenal glands 

Management Guidelines

If it's due to corticosteroid use:
  • Gradual reduction and withdrawal of corticosteroid treatment
  • Consider non-steroidal treatment for the reason of corticosteroid treatment

Management depends on the underlying cause:
 
Cause Treatment
Cushing's disease (ACTH-secreting pituitary tumour)
  • 1st line: trans-sphenoidal resection + life-long monitoring (recurrence is common)
  • 2nd line: medical therapy
    • Dopamien agonist (e.g. carbergoline)
    • Somatostatin analogue (e.g. pasireotide)
  • Last resort: bilateral adrenalectomy with life-long glucocorticoid and mineralocorticoid replacement
Adrenal adenoma carcinoma
  • 1st line: surgical resection
  • 2nd line: adjunctive medical therapy (see below)
  • Last resort: bilateral adrenalectomy with life-long glucocorticoid and mineralocorticoid replacement
Ectopic ACTH-secreting tumours
  • 1st line: surgical resection
  • 2nd line: adjunctive medical therapy (see below) while awaiting oncology treatment

Licensed medical therapy for Cushing's syndrome (not for Cushing's disease):
  • Metyrapone (inhibits 11β-hydroxylase → reduce cortisol synthesis)
  • Ketoconazole (inhibits multiple enzymes involved in steroid synthesis at high doses)

Summary Table

This table provides an overview of how frequently examined tests and various differential diagnoses of Cushing's syndrome correlate. Please use this table in conjunction with the information above.
 
Parameter / Test No Cushing's syndrome Cushing's disease (ACTH-secreting pituitary adenoma) Ectopic ACTH source (e.g. small cell lung cancer) Adrenal adenoma / carcinoma
Cortisol level - ↑ ↑ ↑
ACTH level - ↑ ↑ ↓
Low-dose dexamethasone suppression test ↓ Cortisol No cortisol suppression No cortisol suppression No cortisol suppression
High-dose dexamethasone suppression test ↓ Cortisol ↓ Cortisol No cortisol suppression No cortisol suppression
CRH stimulation test ↑ ACTH
↑ Cortisol		 ↑ ACTH
↑ Cortisol		 No changes to ACTH and cortisol No changes to ACTH and cortisol
 

References

Author: Adams Lau
Reviewer:
Last edited: 14/08/25