How should an elevated cortisol level be evaluated and managed?

Evaluation and Management of Elevated Cortisol

When you encounter an elevated cortisol level, immediately proceed with formal Cushing's syndrome screening using at least two of the following tests: 24-hour urinary free cortisol, late-night salivary cortisol (2-3 occasions), overnight 1-mg dexamethasone suppression test, or midnight serum cortisol. 1

Initial Diagnostic Workup

The critical first step is confirming pathologic hypercortisolism versus physiologic elevation:

• Obtain at least two screening tests to confirm autonomous cortisol production, as no single test is preferred by the Endocrine Society 1
• Measure 09:00h plasma ACTH once hypercortisolism is confirmed to differentiate ACTH-dependent (pituitary or ectopic) from ACTH-independent (adrenal) causes 1
• If ACTH is normal or low (e.g., ~15 pg/mL) with elevated cortisol, this indicates ACTH-independent Cushing's syndrome from an adrenal source 2
• If ACTH is elevated, this suggests ACTH-dependent disease requiring pituitary MRI and potentially inferior petrosal sinus sampling 1

Key Diagnostic Thresholds

• Post-dexamethasone suppression cortisol >50 nmol/L (>1.8 μg/dL) is diagnostic of Cushing's syndrome 1
• Midnight serum cortisol ≥50 nmol/L (≥1.8 μg/dL) has 100% sensitivity for Cushing's syndrome and indicates loss of normal circadian rhythm 1
• 24-hour urinary free cortisol above the upper limit of normal on 2-3 collections suggests Cushing's syndrome, though this has the lowest sensitivity among screening tests 1

Critical Pitfalls to Avoid

Before interpreting results, rule out confounding factors:

• Ensure 2-week washout from exogenous steroids including inhaled fluticasone, which can suppress the HPA axis 1
• Stop oral contraceptives as increased cortisol-binding globulin from oral estrogens falsely elevates total serum cortisol 1
• Consider CYP3A4 inducers (anticonvulsants, rifampin) that accelerate dexamethasone metabolism causing false-positive suppression tests 1
• Recognize pseudo-Cushing's states from depression, alcoholism, or severe obesity that cause physiologic hypercortisolism; manage the underlying condition and retest after 3-6 months 1
• Do not use late-night cortisol testing in night-shift workers due to disrupted circadian rhythm 1

Imaging and Localization

Once biochemical hypercortisolism is confirmed:

• For ACTH-independent disease, obtain adrenal CT or MRI with adrenal protocol to assess for adenoma, carcinoma, or bilateral hyperplasia and evaluate size, laterality, and malignant features 2
• For ACTH-dependent disease, obtain pituitary MRI to localize adenoma, though 40% of microadenomas may not be visible 3

Treatment Algorithm Based on Etiology

For Adrenal Adenoma (ACTH-independent)

• Laparoscopic adrenalectomy is the treatment of choice for benign adrenal tumors 2
• Postoperative corticosteroid supplementation is mandatory until HPA axis recovery, which may take 6-18 months 2

For Adrenal Carcinoma

• Open adrenalectomy with lymph node removal and possible resection of adjacent structures for complete tumor clearance 2
• Mitotane or ketoconazole (400-1200 mg/day) for medical management 2
• Follow-up imaging and biomarkers every 3-6 months to monitor for recurrence 2

For Pituitary Cushing's Disease (ACTH-dependent)

• Transsphenoidal surgery is first-line treatment when adenoma is localized 3
• If surgery fails or is contraindicated, medical therapy is indicated 3

Medical Management for Persistent Hypercortisolism

For severe hypercortisolism requiring rapid cortisol normalization, osilodrostat or metyrapone are first-line medical therapies. 1

Efficacy Hierarchy Based on UFC Normalization

• Osilodrostat has the highest efficacy based on prospective clinical trials 3
• Metyrapone is second-line with retrospective and prospective data 3
• Ketoconazole for mild-to-moderate disease with retrospective data 3, 1
• Pasireotide has potential for tumor shrinkage but carries high hyperglycemia risk 3, 1
• Cabergoline may be considered for potential tumor shrinkage 3, 1

Treatment Monitoring and Adjustment

• Reassess treatment if cortisol remains elevated after 2-3 months on maximum tolerated doses 3
• Consider combination therapy if cortisol is reduced with some clinical improvement but not normalized 3
• Switch to different therapy if there is clear treatment resistance, but ensure under-dosing is not misinterpreted as resistance 3
• Monitor ACTH levels with adrenal-targeting agents as significant elevations may indicate tumor growth from interrupted ACTH-cortisol feedback 3
• Perform MRI 6-12 months after initiating treatment and repeat every few years depending on clinical scenario 3
• Monitor for overlapping toxicities with combination therapy, particularly QTc prolongation and drug-drug interactions 3

Post-Treatment Monitoring

• Use multiple serial urinary free cortisol and late-night salivary cortisol tests to assess treatment response 1
• Assess for adrenal insufficiency symptoms including hypotension, fatigue, nausea, and hyponatremia 1
• Monitor for improvement in Cushing's manifestations including hypertension, hyperglycemia, hypokalemia, muscle atrophy, and osteoporosis 2

Special Consideration: Cyclic Cushing's Syndrome

• Multiple sequential late-night measurements over weeks to months may be required to capture episodic cortisol excess in cyclic disease 1