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This is a clinician-written, evidence-based summary aligned to the USMLE Step 2 CK Content Outline. It is intended for medical students preparing for USMLE Step 2 CK. Management reflects current ACC/AHA, USPSTF, and APA guidelines. Always cross-reference with UpToDate, institutional protocols, and clinical judgment.
The Bottom Line
- Most common cause of Cushing syndrome overall: exogenous glucocorticoids
- High-yield clinical clues: proximal muscle weakness, easy bruising, wide purple striae, facial plethora, early osteoporosis
- Screen with one of: 1-mg overnight dexamethasone suppression, late-night salivary cortisol, or 24-hour urinary free cortisol
- After confirming hypercortisolism, measure ACTH to classify ACTH-dependent vs ACTH-independent disease
- Cushing disease = ACTH-secreting pituitary adenoma; ectopic ACTH often causes severe hypokalemic metabolic alkalosis
Overview
Cushing syndrome is the clinical state of chronic glucocorticoid excess. It may be exogenous from prescribed steroids or endogenous from ACTH-dependent or ACTH-independent causes. ACTH-dependent disease includes pituitary corticotroph adenoma (Cushing disease) and ectopic ACTH production, commonly small cell lung cancer or bronchial carcinoid. ACTH-independent disease includes adrenal adenoma, carcinoma, or hyperplasia. Because common conditions such as obesity, diabetes, depression, and alcohol use can mimic some features, testing is targeted to patients with multiple progressive or discriminatory features.
Epidemiology
Endogenous Cushing syndrome is rare, while exogenous glucocorticoid exposure is common. Cushing disease is more common in women and accounts for most endogenous ACTH-dependent cases. Ectopic ACTH should be suspected in rapid onset, severe weakness, hyperpigmentation, hypokalemia, metabolic alkalosis, and very high cortisol. Adrenal carcinoma may present with very high cortisol, androgen excess, and a large adrenal mass.
Clinical Features
Symptoms
Central weight gain, facial rounding, dorsocervical fat pad
Proximal muscle weakness: difficulty rising from chair or climbing stairs
Mood changes, depression, insomnia, cognitive difficulty
Menstrual irregularity, decreased libido, hirsutism or acne
Recurrent infections, poor wound healing, easy bruising
Fragility fracture or early osteoporosis
Signs
Wide purple striae >1 cm, thin skin, ecchymoses
Facial plethora and supraclavicular fat pads
Hypertension, glucose intolerance or diabetes
Proximal myopathy with preserved distal strength
Hyperpigmentation in ACTH-dependent disease, especially ectopic ACTH
Hypokalemic metabolic alkalosis in severe ectopic ACTH
Investigations
First-line
Medication reviewIdentify exogenous glucocorticoids including oral, inhaled, injected, topical, and steroid-containing supplements
1-mg overnight dexamethasone suppression testFailure to suppress morning cortisol suggests Cushing syndrome
Late-night salivary cortisolLoss of normal circadian nadir; useful screening test
24-hour urinary free cortisolElevated in endogenous hypercortisolism; repeat testing often needed
Second-line
Plasma ACTHLow ACTH = adrenal source; normal/high ACTH = pituitary or ectopic ACTH
High-dose dexamethasone suppression or CRH stimulationMay help distinguish pituitary from ectopic ACTH in selected cases
BMP, glucose/A1c, lipids, DXAAssess metabolic and bone complications
Specialist
Pituitary MRIFor ACTH-dependent disease suspicious for Cushing disease
Inferior petrosal sinus samplingGold standard to distinguish pituitary from ectopic ACTH when imaging is equivocal
Adrenal CT/MRIIf ACTH-independent Cushing or adrenal malignancy suspected
1
Confirm true hypercortisolism
- Use recommended first-line screening tests; repeat abnormal testing because false positives occur
- Avoid testing during acute severe illness when physiologic hypercortisolism may confound results
- Address pseudo-Cushing states such as severe depression, alcohol use disorder, and uncontrolled diabetes when relevant
2
Classify by ACTH
- Suppressed ACTH: adrenal adenoma/carcinoma/hyperplasia — image adrenals
- Normal/high ACTH: pituitary Cushing disease vs ectopic ACTH — pituitary MRI and endocrine referral
3
Definitive treatment
- Exogenous steroid: gradual taper when safe; never stop abruptly if chronic exposure
- Cushing disease: transsphenoidal pituitary surgery first-line
- Adrenal adenoma/carcinoma: adrenalectomy; carcinoma may need adjuvant therapy
- Ectopic ACTH: resect or treat source tumor when possible
4
Medical control
- Steroidogenesis inhibitors such as ketoconazole, metyrapone, osilodrostat, or mitotane may be used while awaiting definitive treatment or if unresectable
- Treat complications: hypertension, diabetes, infection risk, osteoporosis, VTE risk
Complications
- Cardiovascular disease: Hypertension, diabetes, dyslipidemia, and thrombosis increase mortality
- Osteoporosis and fracture: Glucocorticoids rapidly reduce bone formation
- Infection: Immune suppression can mask fever and inflammatory signs
- Psychiatric disease: Depression, mania, psychosis, cognitive impairment
- Adrenal insufficiency after cure: HPA axis suppression may require temporary replacement
USMLE Step 2 CK Exam Tips
- 1Exogenous steroids are the most common cause — always review medications first
- 2Wide purple striae, proximal muscle weakness, and easy bruising are more specific than simple obesity
- 3Do not diagnose Cushing with a random cortisol level
- 4After abnormal screening, ACTH tells you adrenal vs pituitary/ectopic source
- 5Low ACTH = adrenal tumor; high ACTH + pituitary adenoma = Cushing disease
- 6Ectopic ACTH: severe hypokalemic metabolic alkalosis and hyperpigmentation, often rapid onset
- 7Inferior petrosal sinus sampling is the best test when ACTH-dependent source is unclear
practicetest your knowledge on cushing syndromeApply what you've learnt with USMLE Step 2 CK-style questions from the iatroX Q-Bank — endocrine and beyond.
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