What is the recommended medication for treating Cushing syndrome?

Medical Treatment of Cushing Syndrome

For Cushing syndrome, ketoconazole (400-1200 mg/day) is the recommended first-line medical therapy due to its established efficacy in normalizing cortisol levels in approximately 64% of patients and its relatively tolerable toxicity profile. 1

Treatment Algorithm Based on Etiology

1. First Determine the Cause of Cushing Syndrome

• ACTH-dependent (elevated ACTH levels)
  • Pituitary adenoma (Cushing's disease) - most common
  • Ectopic ACTH-producing tumors (lung, thyroid, pancreas, bowel)
• ACTH-independent (normal/low ACTH levels)
  • Adrenal adenoma
  • Adrenal carcinoma
  • Bilateral adrenal hyperplasia

2. Primary Treatment Approach

• Surgical approach is first-line when possible:
  • Transsphenoidal surgery for pituitary adenomas
  • Laparoscopic adrenalectomy for adrenal adenomas
  • Removal of ectopic ACTH-producing tumors when feasible

3. Medical Therapy (When Surgery Is Not Possible/Successful)

First-Line Medical Options:

• Ketoconazole: 400-600 mg/day initially in 2-3 divided doses, increased to 800-1200 mg/day until cortisol normalization, then maintenance at 400-800 mg/day 1

  • Efficacy: Normalizes UFC in ~64% of patients
  • Monitoring: Weekly liver function tests during first 6 months
  • Side effects: Hepatotoxicity (10-20%), gastrointestinal disturbances (5-20%)

• Metyrapone: 250-750 mg every 4 hours

  • Best for severe hypercortisolism requiring rapid control
  • Side effects: Hirsutism, dizziness, arthralgia, fatigue, hypokalemia, nausea

Second-Line Medical Options:

• Osilodrostat: Achieves 86% UFC normalization with rapid cortisol reduction 1

• Pasireotide: For pituitary-dependent Cushing's disease

  • Initial dose: 10 mg IM every 28 days 2
  • Efficacy: 15-26% UFC normalization
  • Best for mild-to-moderate disease with visible tumor
  • Major side effect: Hyperglycemia requiring monitoring

• Cabergoline: ~40% efficacy, best for mild disease, particularly in young women 1

• Mifepristone: Improves hyperglycemia and weight gain but has monitoring challenges 1

Treatment Selection Based on Disease Severity

Mild Hypercortisolism

• Start with ketoconazole, osilodrostat, or metyrapone 1

Moderate Hypercortisolism with Visible Pituitary Tumor

• Consider cabergoline or pasireotide 1

Severe Hypercortisolism

• Use osilodrostat or metyrapone for rapid cortisol normalization
• Ketoconazole is an alternative 1

Monitoring and Follow-up

• Monitor efficacy using:
  • 24-hour urinary free cortisol
  • Morning serum cortisol
  • Late-night salivary cortisol
• Consider treatment adjustment if cortisol levels remain elevated after 2-3 months on maximum tolerated doses 1
• Lifelong follow-up is essential due to potential recurrence up to 15 years after apparent surgical cure 1

Common Pitfalls to Avoid

1. Undertreatment: Leading to persistent hypercortisolism and associated comorbidities
2. Overtreatment: Causing adrenal insufficiency
3. Misinterpreting insufficient disease control due to under-dosing as treatment resistance
4. Failing to monitor for drug-specific side effects:
   • Hepatotoxicity with ketoconazole (occurs in 11-13.5% of patients) 3
   • Hyperandrogenism with metyrapone
5. Not recognizing drug-drug interactions, particularly with mifepristone 1

Long-term ketoconazole therapy has been shown to be effective and generally well-tolerated for periods ranging from several months to up to 13 years in patients with persistent hypercortisolism 4, making it a viable option for chronic management when definitive treatment is not possible.