What are the medical management options for Cushing syndrome?

Medical Management Options for Cushing's Syndrome

First-line treatment for Cushing's disease is transsphenoidal surgery, but when surgery fails or is contraindicated, medical therapy is essential for controlling hypercortisolism and reducing associated morbidity and mortality. 1, 2

Treatment Algorithm

First-Line Approach

1. Surgical Management

   • Selective transsphenoidal adenomectomy for pituitary microadenomas
   • Adrenal surgery for adrenal causes
   • Tumor resection for ectopic ACTH sources

2. When Surgery Fails or Is Contraindicated

   • Medical therapy becomes necessary

Medical Management Options

Adrenal Steroidogenesis Inhibitors

1. Ketoconazole

   • Dosing: Initially 400-600 mg/day in 2-3 divided doses, increased to 800-1,200 mg/day until cortisol normalization, then maintenance at 400-800 mg/day 2
   • Efficacy: Normalizes UFC in approximately 64% of patients 1, 2
   • Monitoring: Weekly liver function tests during first 6 months 2
   • Side effects:
     • Hepatotoxicity (10-20% of patients) 1, 2
     • Gastrointestinal disturbances (5-20%) 2
     • Hypogonadism and gynecomastia in men 1

2. Metyrapone

   • Dosing: 250-750 mg every 4 hours 2
   • Efficacy: Rapid cortisol reduction within hours 2
   • Best for: Severe hypercortisolism requiring rapid control 2
   • Side effects:
     • Hirsutism, dizziness, arthralgia, fatigue 1, 2
     • Hypokalaemia and nausea 1, 2
     • Hyperandrogenism (can lead to advanced bone age in children) 1

3. Osilodrostat (FDA approved)

   • Indication: Treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative 3
   • Efficacy: 86% UFC normalization with rapid cortisol reduction 2
   • Advantage: Higher efficacy compared to other medical options 2

Pituitary-Directed Therapies

1. Pasireotide

   • Mechanism: Targets somatostatin receptors in the pituitary 2
   • Efficacy: 15-26% UFC normalization 2
   • Best for: Mild-to-moderate disease with visible tumor 2
   • Major side effect: Hyperglycemia requiring close monitoring 2, 4

2. Cabergoline

   • Mechanism: Dopamine agonist targeting pituitary tumor 2
   • Efficacy: ~40% of patients 2
   • Best for: Mild disease, particularly in young women desiring pregnancy 2

3. Mifepristone (Glucocorticoid Receptor Antagonist)

   • Efficacy: Improves hyperglycemia and weight gain 2
   • Challenges:
     • No reliable biochemical markers for monitoring 2
     • Risk of adrenal insufficiency 2

Special Considerations

Severity-Based Approach

• Mild hypercortisolism: Start with ketoconazole, osilodrostat, or metyrapone 2
• Moderate hypercortisolism with visible tumor: Consider cabergoline or pasireotide 2
• Severe hypercortisolism: Use osilodrostat or metyrapone for rapid cortisol normalization 2

Pediatric Considerations

• In children and adolescents, medical therapies should primarily be used to reduce cortisol burden while awaiting definitive surgery or radiotherapy effects 1, 2
• Prolonged use of metyrapone can lead to hyperandrogenism and advanced bone age in children 1
• Growth hormone deficiency should be evaluated and treated promptly after successful treatment of Cushing's disease in children 1

Monitoring and Follow-up

• Efficacy monitoring: 24-hour UFC, morning cortisol, and late-night salivary cortisol 2
• Treatment adjustment: Consider if cortisol levels remain elevated after 2-3 months on maximum tolerated doses 2
• Lifelong follow-up: Essential due to potential recurrence up to 15 years after apparent surgical cure 2

Common Pitfalls to Avoid

1. Undertreatment: Persistent hypercortisolism leads to continued morbidity 2
2. Overtreatment: Can cause adrenal insufficiency 2
3. Misinterpreting insufficient disease control: Due to under-dosing as treatment resistance 2
4. Failing to monitor for drug-specific side effects:
   • Hepatotoxicity with ketoconazole
   • Hyperandrogenism with metyrapone 2
5. Not recognizing drug-drug interactions: Particularly with mifepristone 2
6. Failing to recognize cyclical Cushing's syndrome: Can lead to inappropriate treatment adjustments 2

Medical management of Cushing's syndrome requires careful selection of agents based on disease severity, patient characteristics, and treatment goals, with close monitoring for efficacy and adverse effects.