What is the treatment for hypercortisolism?

Treatment of High Cortisol Levels (Hypercortisolism)

For patients with hypercortisolism, adrenal steroidogenesis inhibitors (ketoconazole, osilodrostat, or metyrapone) are the first-line medical therapy due to their reliable effectiveness in rapidly normalizing cortisol levels. 1

Diagnostic Confirmation

Before initiating treatment, confirm hypercortisolism with:

• 24-hour urinary free cortisol measurements (multiple collections)
• Late-night salivary cortisol tests
• 1mg overnight dexamethasone suppression test 2

Treatment Algorithm

First-Line Treatment Options

1. Surgical Approach (when appropriate):

   • Transsphenoidal surgery for Cushing's disease (pituitary origin) - first-line with remission rates of 65-90% for microadenomas 2
   • Laparoscopic adrenalectomy for adrenal adenomas 2
   • Surgical resection for ectopic ACTH-secreting tumors 2

2. Medical Therapy (when surgery is contraindicated, unsuccessful, or delayed):

   • Adrenal Steroidogenesis Inhibitors:

     • Ketoconazole: 400-1200mg/day (divided doses)

       • Rapid effect (within days)
       • Monitor liver function tests due to hepatotoxicity risk 1, 3
       • May cause hypogonadism in men 1

     • Metyrapone: 1-4.5g/day (divided doses)

       • Rapid effect (within hours)
       • Monitor for hypokalemia and hypertension 1, 4
       • May increase adrenal androgens 1

     • Osilodrostat:

       • Rapid effect (within hours)
       • Newer FDA-approved option 1
       • Potent 11β-hydroxylase inhibitor 1

   • Glucocorticoid Receptor Antagonist:

     • Mifepristone:
       • Effective for controlling glucose abnormalities and hypertension 1
       • Cannot monitor with cortisol levels
       • Risk of adrenal insufficiency and hypokalemia 1

   • Pituitary-Directed Therapies (for Cushing's disease):

     • Pasireotide: Somatostatin analog (risk of hyperglycemia)
     • Cabergoline: Dopamine agonist (less effective but fewer side effects) 1, 2

Treatment Selection Based on Disease Severity

Mild Disease

• For patients with mild disease and no visible tumor on MRI: ketoconazole, osilodrostat, or metyrapone 1
• Cabergoline may be used for mild Cushing's disease (slower onset but less frequent dosing) 1

Moderate Disease

• For patients with mild-to-moderate disease and visible tumor: consider cabergoline or pasireotide for potential tumor shrinkage 1

Severe Disease

• For severe hypercortisolism requiring rapid control:
  • Osilodrostat or metyrapone (effect within hours)
  • Ketoconazole (effect within days)
  • Etomidate (IV) for hospitalized patients unable to take oral medications 1, 5
  • Consider combination therapy with multiple steroidogenesis inhibitors 1
  • Bilateral adrenalectomy if medical therapy fails 1, 5

Monitoring and Complications

• Monitor cortisol levels with 24-hour urinary free cortisol and late-night salivary cortisol 2
• Watch for adrenal insufficiency with steroidogenesis inhibitors 2
• With mifepristone, monitor for clinical signs of adrenal insufficiency (cannot use cortisol levels) 1
• Monitor for drug-specific side effects:
  • Ketoconazole: liver function tests, QT prolongation 3
  • Metyrapone: hypokalemia, hypertension 4
  • Mifepristone: hypokalemia, endometrial thickening in women 1

Important Considerations

• Combination therapy may be needed for severe or resistant cases 1
• Common combinations include ketoconazole with metyrapone, or a steroidogenesis inhibitor plus cabergoline 1
• Treatment should be aggressive in severe hypercortisolism to prevent complications and mortality 6, 5
• Long-term monitoring is essential as recurrence can occur years after initial remission 2

Special Populations

• Pregnancy: None of these medications are approved for use in pregnancy, though metyrapone may be considered in selected cases with precautions 1
• Children: Surgical resection is first-line; medical therapy follows similar principles as in adults 2