What is the initial evaluation and treatment approach for a patient presenting with hypercortisolism?

Initial Evaluation and Treatment of Hypercortisolism

Begin by ruling out exogenous glucocorticoid use, then confirm hypercortisolism with at least one screening test (24-hour urinary free cortisol, late-night salivary cortisol, or 1 mg overnight dexamethasone suppression test), followed by plasma ACTH measurement to determine ACTH-dependent versus ACTH-independent disease, which dictates the treatment pathway. 1, 2

Diagnostic Confirmation

Initial Screening Tests

• Perform at least one of the following screening tests, preferably two if clinical suspicion is intermediate or high: 1, 2

  • 24-hour urinary free cortisol (UFC): Elevated proportionally more than plasma cortisol because transcortin binding capacity is exceeded above 500 nmol/L 3
  • Late-night salivary cortisol (LNSC): Particularly useful for patients with disrupted circadian rhythm or shift workers 2
  • 1 mg overnight dexamethasone suppression test (DST): Administer dexamethasone at midnight, measure plasma cortisol at 8 AM; normal suppression is <80 nmol/L, while incomplete suppression suggests hypercortisolism 3

• Avoid DST in patients on estrogen-containing medications due to false positives, and note that LNSC has lower specificity for suspected adrenal tumors 2

Excluding Non-Neoplastic Causes

• Rule out conditions causing false-positive results before proceeding: severe obesity, uncontrolled diabetes, pregnancy, alcohol use disorder, major depression/psychiatric disorders, and chronic kidney disease 2, 4
• Sustained activation of the hypothalamic-pituitary-adrenal axis from alcohol, inflammation, psychological stress, or chronic intense exercise can mimic neoplastic hypercortisolism 4

Determining Etiology

ACTH Measurement

• Measure plasma ACTH to classify hypercortisolism: 1, 2
  • Low or undetectable ACTH (<5 ng/L or <1.1 pmol/L): ACTH-independent Cushing syndrome (adrenal source) 5, 6
  • Normal or elevated ACTH (>29 ng/L or >6.4 pmol/L has 70% sensitivity and 100% specificity for Cushing disease): ACTH-dependent Cushing syndrome (pituitary or ectopic source) 5

ACTH-Dependent Hypercortisolism

• Obtain pituitary MRI with contrast to identify adenoma 5, 2
• Perform CRH stimulation test: Administer CRH 1.0 μg/kg IV, measure ACTH and cortisol at baseline and post-stimulation; ≥20% increase in cortisol from baseline suggests pituitary origin (Cushing disease) 5, 7
• If no adenoma visible on MRI and ACTH-dependent disease confirmed, offer bilateral inferior petrosal sinus sampling (BSIPSS) with CRH or desmopressin stimulation: 5
  • Central-to-peripheral ACTH ratio ≥2:1 before stimulation or ≥3:1 after stimulation confirms pituitary source 5
  • Inter-petrosal sinus ACTH gradient ≥1.4 after stimulation may indicate tumor lateralization 5
  • Confirm active hypercortisolemia immediately before BSIPSS to ensure patient is not in remission phase of cyclical disease 5

ACTH-Independent Hypercortisolism

• Perform adrenal CT or MRI to identify adenoma, carcinoma, or bilateral disease 2, 6
• All patients with primary adrenal disease should have undetectable ACTH and no suppression with high-dose dexamethasone 6

Treatment Approach Based on Disease Severity

Mild Disease (No Visible Tumor on MRI)

• First-line medical therapy: Ketoconazole, osilodrostat, or metyrapone 1
• Alternative for mild Cushing disease: Cabergoline, but avoid in patients with bipolar disorder or impulse control disorders 1
• Women desiring pregnancy may prefer cabergoline, though metyrapone can be considered with precautions in selected pregnant women 1

Moderate Disease (Visible Tumor Present)

• Consider medications with tumor-shrinking potential: Cabergoline or pasireotide 1, 2
• Monitor both biochemical control and tumor response 1
• Combination therapy is rational: steroidogenesis inhibitor plus tumor-targeting agent 1

Severe Disease (Life-Threatening)

• Primary goal: Rapid normalization of cortisol to prevent mortality from complications 8
• First-line options: Osilodrostat, metyrapone, ketoconazole, or etomidate (for critical cases) 1, 8
• Consider combination therapy with multiple steroidogenesis inhibitors if monotherapy fails 1, 8
• Ketoconazole with metyrapone can maximize adrenal blockade 1
• When medical therapy fails or is contraindicated: Bilateral adrenalectomy as life-saving measure 8
• Postpone etiological investigation until patient is stabilized 8

Definitive Treatment for Cushing Disease

• First-line: Transsphenoidal surgery (TSS) 2
• For persistent/recurrent disease after TSS: Second TSS, radiation therapy, medical therapy, or bilateral adrenalectomy 2

Monitoring Treatment Response

• Use multiple serial tests of both UFC and LNSC to monitor treatment outcomes 1, 2
• Monitor for resolution of clinical features and specific adverse effects of medical therapy 2
• Critical caveat with mifepristone: Cortisol measurements are not reliable for dosing or safety monitoring 1

Common Pitfalls to Avoid

• Failing to rule out exogenous glucocorticoid use before initiating diagnostic workup 1, 7
• Not considering cyclical variations in cortisol secretion, which can cause false-negative results 7
• Ignoring disease severity when selecting initial therapy—severe disease requires rapid cortisol normalization, not slow-acting agents 1
• Missing drug-drug interactions, particularly with ketoconazole and mifepristone 1
• Attempting laboratory confirmation of adrenal insufficiency in patients on high-dose corticosteroids for other conditions until treatment discontinuation 5
• Not stopping medications affecting pituitary or adrenocortical function before metyrapone testing (consider at least 5 half-lives) 9