What is the treatment for hypercortisolism (high cortisol levels)?

Treatment of Hypercortisolism (High Cortisol Levels)

The treatment of hypercortisolism should be individualized based on the underlying cause, with adrenal steroidogenesis inhibitors such as ketoconazole, osilodrostat, or metyrapone typically used as first-line medical therapy due to their reliable effectiveness. 1

Diagnostic Approach

Before initiating treatment, confirm hypercortisolism through:

• 24-hour urinary free cortisol measurements
• Late-night salivary cortisol
• Dexamethasone suppression test (1 mg overnight or 2 mg/day for 2 days) 1, 2

Then determine ACTH dependence by measuring plasma ACTH levels to identify the source:

• ACTH-dependent (pituitary or ectopic source)
• ACTH-independent (adrenal source) 3

Treatment Algorithm Based on Cause

1. Cushing's Disease (Pituitary Source)

• First-line: Transsphenoidal surgery 1
• Medical therapy (if surgery fails or is contraindicated):
  • Mild disease: Ketoconazole, osilodrostat, metyrapone, or cabergoline 1
  • Moderate disease with visible tumor: Consider cabergoline or pasireotide (note: pasireotide has high risk of hyperglycemia) 1, 4

2. Ectopic ACTH Syndrome

• First-line: Surgical resection of the primary tumor 3
• Medical therapy (to control hypercortisolism before surgery):
  • Steroidogenesis inhibitors: ketoconazole, metyrapone, osilodrostat 1
  • For severe cases requiring rapid control: etomidate (IV) 1, 5

3. Adrenal Causes (adenoma, carcinoma, bilateral hyperplasia)

• First-line: Surgical resection (unilateral or bilateral adrenalectomy) 1
• Medical therapy (if surgery is contraindicated):
  • Steroidogenesis inhibitors: ketoconazole, metyrapone, osilodrostat 1

Medical Therapy Selection Based on Disease Severity

Mild Disease

• Ketoconazole, osilodrostat, or metyrapone are preferred 1
• Cabergoline can be used but has slower onset and lower efficacy 1

Severe Disease

• Rapid normalization of cortisol is critical 1
• Osilodrostat and metyrapone work within hours 1
• Ketoconazole works within days 1
• Etomidate (IV) for hospitalized patients unable to take oral medications 1, 5
• For very severe hypercortisolism unresponsive to optimized medical therapy, bilateral adrenalectomy should be considered 1

Specific Medications and Monitoring

Steroidogenesis Inhibitors

• Ketoconazole:

  • Starting dose: 200-400 mg/day, can be increased to 1200 mg/day
  • Monitor liver function tests regularly 1

• Metyrapone:

  • Works rapidly by inhibiting 11-β-hydroxylase
  • May be considered in pregnant women with precautions 1, 6

• Osilodrostat:

  • FDA-approved for Cushing's disease
  • Rapid onset of action 1

• Fluconazole:

  • Alternative when ketoconazole is unavailable or poorly tolerated
  • Typically used at 400 mg daily 7, 8

Pituitary-Directed Agents

• Pasireotide:

  • FDA-approved for Cushing's disease
  • Initial dose: 10 mg IM every 4 weeks
  • Monitor for hyperglycemia 1, 4

• Cabergoline:

  • Less effective but requires less frequent dosing
  • Avoid in patients with history of bipolar or impulse control disorders 1

Glucocorticoid Receptor Antagonists

• Mifepristone:
  • Improves hyperglycemia and weight gain
  • No reliable biochemical markers for monitoring
  • Risk of adrenal insufficiency and hypokalemia
  • Should be used only by clinicians with extensive experience 1

Combination Therapy

For patients not responding to monotherapy, consider combinations:

• Ketoconazole + metyrapone (maximizes adrenal blockade)
• Steroidogenesis inhibitor + tumor-targeting agent (e.g., ketoconazole + cabergoline)
• Monitor for potential additive adverse effects 1

Monitoring Treatment Response

• Clinical improvement (weight, blood pressure, glucose control)
• Normalization of free cortisol levels
• Regular monitoring every 3-6 months 1, 3

Cautions and Pitfalls

• Risk of adrenal insufficiency with overtreatment
• Provide stress-dose glucocorticoid coverage for patients undergoing surgery
• Monitor for hypokalemia, especially with mifepristone
• Liver function monitoring with ketoconazole
• Hyperglycemia monitoring with pasireotide 1, 3