About This Page
This is a clinician-written, evidence-based summary aligned to the 2026 MLA Content Map. It is intended for medical students and junior doctors preparing for the UKMLA. Always cross-reference with NICE guidance, local protocols, and clinical judgement.
The Bottom Line
- Most common cause = iatrogenic (exogenous glucocorticoid therapy). Always exclude this first
- Endogenous Cushing's: ACTH-dependent (pituitary adenoma 70% = "Cushing's disease"; ectopic ACTH 10%) or ACTH-independent (adrenal tumour 20%)
- Clinical features: central obesity, moon face, buffalo hump, striae (purple/wide), proximal myopathy, thin skin, easy bruising, hypertension, hyperglycaemia
- Screening: overnight 1 mg dexamethasone suppression test (cortisol >50 nmol/L at 9 AM = positive), 24 h urinary free cortisol, or late-night salivary cortisol
- Localisation: measure ACTH → if high: MRI pituitary → if normal pituitary: consider IPSS or CT chest/abdomen for ectopic source
- Treatment: remove cause — transsphenoidal surgery (pituitary), adrenalectomy (adrenal), or resect ectopic source. Medical therapy if surgery not possible
Overview
Cushing's syndrome refers to the clinical manifestations of chronic glucocorticoid excess from any cause. The most common cause is exogenous (iatrogenic) glucocorticoid use. Endogenous Cushing's syndrome is subdivided into ACTH-dependent (80%) and ACTH-independent (20%). ACTH-dependent causes include pituitary corticotroph adenoma (Cushing's disease, ~70% of endogenous cases) and ectopic ACTH production (small cell lung cancer, carcinoid tumours, ~10%). ACTH-independent causes include adrenal adenoma, adrenal carcinoma, and bilateral adrenal hyperplasia. Chronic cortisol excess causes widespread metabolic, cardiovascular, musculoskeletal, and psychiatric morbidity, with significantly increased mortality if untreated.
Epidemiology
Endogenous Cushing's syndrome is rare, with an incidence of approximately 2–3 per million per year. Cushing's disease (pituitary adenoma) has a female:male ratio of approximately 4:1, with peak incidence at 25–40 years. Ectopic ACTH syndrome is more common in men (due to association with lung cancer). Adrenal tumours causing Cushing's can occur at any age. Iatrogenic Cushing's is extremely common given widespread glucocorticoid prescribing — always consider this in any patient on steroids presenting with cushingoid features.
Clinical Features
Symptoms
Weight gain — central/truncal obesity
Proximal muscle weakness (difficulty standing from chair, climbing stairs)
Easy bruising and thin fragile skin
Mood disturbance: depression, anxiety, psychosis, insomnia
Menstrual irregularity or amenorrhoea in women
Reduced libido, erectile dysfunction in men
Increased susceptibility to infections
Back pain (vertebral compression fractures)
Signs
Moon face (facial plethora and rounding)
Buffalo hump (interscapular fat pad)
Purple/violaceous striae (>1 cm wide, on abdomen, flanks, thighs — distinguishes from normal striae)
Proximal myopathy (inability to rise from squat)
Thin skin, easy bruising, poor wound healing
Hypertension
Hirsutism and acne (androgen excess — especially adrenal carcinoma or ectopic ACTH)
Hyperpigmentation (ACTH-dependent only — particularly ectopic ACTH)
Investigations
First-line
Overnight 1 mg dexamethasone suppression testGive dexamethasone 1 mg at midnight, measure cortisol at 9 AM. Cortisol >50 nmol/L = failure to suppress = positive screen
24 h urinary free cortisolTwo separate collections. Elevated >3× upper limit of normal strongly suggests Cushing's
Late-night salivary cortisolTwo samples. Loss of normal diurnal rhythm (cortisol should be at nadir at midnight). Elevated = positive screen
Second-line
Plasma ACTHKEY test for localisation. Suppressed (<10 pg/mL) = ACTH-independent (adrenal). Elevated/normal = ACTH-dependent (pituitary or ectopic)
48 h low-dose dexamethasone suppression test0.5 mg 6-hourly for 48 h — confirmatory test if screening equivocal
High-dose dexamethasone suppression test2 mg 6-hourly for 48 h. Cortisol suppresses >50% = pituitary (Cushing's disease). Does NOT suppress = ectopic or adrenal
Specialist
MRI pituitaryDetects pituitary adenoma in ~60–70% of Cushing's disease. Microadenomas may be small and difficult to see
CT chest/abdomen/pelvisIf ectopic ACTH suspected — search for bronchial carcinoid, SCLC, pancreatic NET. CT adrenals if ACTH-independent
Inferior petrosal sinus sampling (IPSS)Gold standard to distinguish pituitary from ectopic ACTH. ACTH gradient >2:1 (or >3:1 post-CRH) = pituitary source
1
First-line: surgical removal of source
- Cushing's disease: transsphenoidal surgery (TSS) to remove pituitary adenoma — cure rate ~65–90% with experienced surgeon
- Adrenal adenoma: laparoscopic adrenalectomy — curative
- Ectopic ACTH: resect source tumour if localised (e.g. bronchial carcinoid)
- Post-operative hydrocortisone replacement until HPA axis recovers (may take 6–18 months)
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Second-line: medical therapy (if surgery not possible or fails)
- Metyrapone: inhibits 11β-hydroxylase → reduces cortisol synthesis. First-line medical therapy in UK
- Ketoconazole: inhibits multiple steroidogenic enzymes. Monitor LFTs closely (hepatotoxicity)
- Pasireotide: somatostatin analogue — licensed for Cushing's disease if surgery unsuccessful
- Block-and-replace: metyrapone/ketoconazole + hydrocortisone (avoids adrenal insufficiency)
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Other options
- Bilateral adrenalectomy: definitive cure of hypercortisolaemia but causes lifelong adrenal insufficiency. Risk of Nelson syndrome (expanding pituitary tumour post-adrenalectomy)
- Pituitary radiotherapy: second-line for Cushing's disease. Slow onset (months–years). Risk of hypopituitarism
- Manage comorbidities: hypertension, diabetes, osteoporosis, depression, VTE prophylaxis
Complications
- Cardiovascular: Hypertension, accelerated atherosclerosis, increased VTE risk — major cause of mortality
- Metabolic: Diabetes (steroid-induced), dyslipidaemia, central obesity
- Musculoskeletal: Osteoporosis, vertebral fractures, proximal myopathy, avascular necrosis
- Psychiatric: Depression (~60%), psychosis, cognitive impairment — may persist after treatment
- Infections: Immunosuppression → opportunistic infections (PJP, fungal). May mask signs of sepsis
- Nelson syndrome: Aggressive pituitary tumour growth after bilateral adrenalectomy — causes hyperpigmentation and mass effect
- Adrenal crisis: After successful surgery — HPA axis suppressed, requires glucocorticoid replacement during recovery
UKMLA Exam Tips
- 1Most common cause of Cushing's syndrome = IATROGENIC. Always ask about steroid use (inhaled, topical, oral, injections)
- 2Cushing's SYNDROME = cortisol excess from any cause. Cushing's DISEASE = specifically pituitary ACTH-secreting adenoma
- 3Purple striae (>1 cm, violaceous) are much more specific than simple stretch marks. Combined with proximal myopathy = high suspicion
- 4Screening: overnight DST is easiest. Confirmatory: 24 h UFC or late-night salivary cortisol
- 5ACTH level is the KEY localisation step: suppressed = adrenal source, elevated = pituitary or ectopic
- 6High-dose DST: suppresses in pituitary Cushing's, does NOT suppress in ectopic ACTH or adrenal tumours
- 7Ectopic ACTH: think lung cancer (SCLC, bronchial carcinoid). Often severe + hypokalaemia + hyperpigmentation
practicetest your knowledge on cushing's syndromeApply what you've learnt with UKMLA-style questions from the iatroX Q-Bank — endocrine and beyond.
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