How should Cushing disease be diagnosed and managed?

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Last updated: February 27, 2026 • View editorial policy

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Diagnosis and Management of Cushing Disease

Diagnostic Approach

Begin by excluding exogenous glucocorticoid exposure through a thorough medication review—including oral, inhaled, topical, intra-articular, and over-the-counter preparations—before initiating any biochemical testing. 1, 2

Step 1: Confirm Hypercortisolism with First-Line Screening

Perform at least two to three of the following screening tests to confirm hypercortisolism: 1, 2

  • Late-night salivary cortisol (LNSC): Collect 2–3 samples on consecutive evenings at the patient's usual bedtime (approximately 11 PM–midnight), with sensitivity 95% and specificity 93–100%. 1, 2 This test is contraindicated in night-shift workers or anyone with disrupted sleep-wake cycles. 2

  • 24-hour urinary free cortisol (UFC): Obtain 2–3 separate collections on different days to account for day-to-day variability, with sensitivity 89% and specificity 100%. 1, 2

  • Overnight 1-mg dexamethasone suppression test (DST): Administer 1 mg dexamethasone at 11 PM–midnight and measure serum cortisol at 8 AM; normal suppression is <1.8 μg/dL (50 nmol/L). 1, 2 Simultaneously measure dexamethasone levels to confirm adequate absorption and exclude false-positives from rapid metabolism or CYP3A4-inducing drugs. 1, 2

Common pitfall: Pseudo-Cushing's states—including severe obesity, major depression, chronic alcoholism, uncontrolled diabetes, and pregnancy—can produce false-positive screening results. 1, 2 When mild hypercortisolism is detected in these contexts, treat the underlying condition and repeat testing after 3–6 months. 2

Step 2: Determine ACTH Dependency

Once hypercortisolism is confirmed, measure morning (8–9 AM) plasma ACTH to differentiate ACTH-dependent from ACTH-independent disease: 1

  • ACTH >5 ng/L (>1.1 pmol/L): Indicates ACTH-dependent Cushing's syndrome (pituitary or ectopic source). 1
  • ACTH >29 ng/L (>6.4 pmol/L): Provides 70% sensitivity and 100% specificity for Cushing disease specifically. 1
  • ACTH <5 ng/L or undetectable: Indicates ACTH-independent (adrenal) Cushing's syndrome; proceed directly to adrenal CT or MRI. 1, 2

Step 3: Localize the ACTH Source (for ACTH-Dependent Disease)

Pituitary MRI

Obtain a high-resolution 3-Tesla pituitary MRI with 1-mm thin slices and gadolinium contrast to detect corticotroph adenomas, which has 63% sensitivity and 92% specificity. 1 Microadenomas are frequently ≤2 mm in diameter, making detection challenging. 1

Interpretation based on lesion size: 3, 1

  • ≥10 mm adenoma: Proceed directly to transsphenoidal surgery without further testing (assuming dynamic tests are consistent with Cushing disease). 3, 1
  • 6–9 mm adenoma: Perform CRH or desmopressin stimulation testing; a cortisol rise >38 nmol/L at 15 minutes supports a pituitary source with >70% sensitivity. 1 Expert opinion differs on whether IPSS is needed in this range, but the majority recommend it. 3
  • <6 mm lesion or negative MRI: Bilateral inferior petrosal sinus sampling (IPSS) is mandatory to differentiate pituitary from ectopic ACTH secretion. 3, 1

Bilateral Inferior Petrosal Sinus Sampling (IPSS)

IPSS is the gold standard for distinguishing Cushing disease from ectopic ACTH syndrome when MRI is inconclusive, with 96–100% sensitivity and near-100% specificity. 1

Diagnostic criteria: 3, 1

  • Central-to-peripheral ACTH ratio ≥2:1 at baseline or ≥3:1 after CRH or desmopressin stimulation confirms a pituitary source.
  • An inter-petrosal ACTH gradient ≥1.4 after stimulation may suggest tumor lateralization, but concordance with surgical findings ranges only 58–87.5%. 1

Critical prerequisites: 3, 1

  • Confirm active hypercortisolism on the same morning before IPSS (essential for cyclic Cushing disease).
  • Discontinue all steroidogenesis inhibitors with appropriate washout periods.
  • Perform only in specialized centers with experienced interventional radiologists.
  • Measure prolactin simultaneously from petrosal sinuses to confirm adequate catheter placement. 3, 1

Evaluation for Ectopic ACTH Syndrome

When clinical features suggest ectopic ACTH (male sex, very high UFC, profound hypokalemia, rapid symptom onset), obtain a neck-to-pelvis thin-slice CT scan. 3, 1 If CT is negative, ⁶⁸Ga-DOTATATE PET imaging can identify approximately 65% of ectopic ACTH-secreting neuroendocrine tumors not visible on conventional imaging. 1 Pulmonary carcinoid tumors account for up to 40% of ectopic ACTH cases. 1

Important caveat: No single test achieves 100% specificity, and discordant results occur in up to one-third of patients; integrate clinical context with all test results. 3, 1

Management of Cushing Disease

First-Line Treatment: Transsphenoidal Surgery

Selective transsphenoidal removal of the corticotroph adenoma is the initial therapy of choice, inducing remission in approximately 80% of patients. 4, 5 However, long-term relapse occurs in up to 30% of cases. 4

Prognostic factors: Larger tumor size (macroadenomas ≥10 mm) is an unfavorable prognostic indicator for surgical cure. 1

Management of Perioperative Complications

Hypercoagulability and thromboprophylaxis: 3

  • The incidence of venous thromboembolic events (VTE) in Cushing disease is >10-fold higher than in patients with nonfunctioning adenomas undergoing surgery.
  • VTE risk persists in the first few months after surgery; at 30 days post-surgery, VTE risk is 3.4–4.75%.
  • Thromboprophylaxis is recommended perioperatively and for several months postoperatively, as biochemical remission does not immediately reverse hypercoagulability. 3

Second-Line Therapies

When surgery is unsuccessful, not feasible, or while awaiting definitive treatment: 4, 5

Medical therapy (steroidogenesis inhibitors): 4, 5

  • Ketoconazole is the medical treatment of choice for rapidly controlling hypercortisolism.
  • Alternatives include metyrapone, aminoglutethimide, and mitotane.
  • Pituitary-targeted drugs (pasireotide, cabergoline) and glucocorticoid receptor blockers (mifepristone) are additional options. 5

Repeat surgery: Can be successful when residual tumor is detectable on MRI, but carries high risk of hypopituitarism. 4

Bilateral adrenalectomy: May be a better choice in patients without visible residual tumors, particularly in women desiring fertility. 4 The odds ratio for thromboembolic events after bilateral adrenalectomy is 3.74 (95% CI: 1.69–8.27). 3

Radiation therapy: Radiotherapy combined with ketoconazole or radiosurgery has been found effective, but longer-term evaluation of hypopituitarism and brain function is required. 4 Current studies do not support systematic prophylactic radiotherapy after bilateral adrenalectomy to decrease Nelson's syndrome risk. 4

Management of Comorbidities

Address comorbidities concomitant with or even before Cushing disease-specific treatments: 3

  • Hypertension
  • Hyperglycemia and diabetes
  • Osteoporosis
  • Infections (due to immunosuppression)
  • Electrolyte abnormalities (particularly hypokalemia)

Long-term follow-up should include adequate glucocorticoid replacement, treatment of osteoporosis, and surveillance for relapse. 4

Special Considerations

Pediatric Patients

In children, screen for Cushing's syndrome only when weight gain is inexplicable and combined with either decreased height standard deviation score or height velocity—lack of height gain with weight gain is the most common pediatric presentation. 6 Cushing disease (pituitary adenoma) is the most common cause in children over age 6, while adrenal causes predominate in younger children. 6 The Dex-CRH test is not useful in children, and IPSS has a more limited role than in adults. 6

Cyclic Cushing Disease

For patients with cyclic disease, perform extended monitoring with multiple sequential LNSC measurements to capture active phases. 1, 2 Confirm active hypercortisolism immediately before performing IPSS or other dynamic localization studies. 1

References

1
Guideline

Cushing's Syndrome Classification and Diagnosis

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

2
Guideline

Diagnosing Cushing's Syndrome

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

3
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

6
Guideline

Diagnostic Approach for Cushing's Syndrome in Pediatric Patients

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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