What is the management of Cushing's disease?

Management of Cushing's Disease

The first-line treatment for Cushing's disease is selective transsphenoidal adenomectomy, which offers the best chance for cure with remission rates of 70-80% when performed by experienced surgeons. 1

Diagnostic Approach

• Confirm hypercortisolism through:
  • 24-hour urinary free cortisol (UFC)
  • Late-night salivary cortisol
  • Morning serum cortisol after low-dose dexamethasone suppression test
• Determine ACTH-dependency (elevated or normal ACTH levels)
• Localize source with pituitary MRI
• Consider bilateral inferior petrosal sinus sampling (BIPSS) if MRI is negative (75-80% predictive value for lateralization) 1

Treatment Algorithm

1. Surgical Management

• Selective transsphenoidal adenomectomy:
  • First-line treatment for pituitary microadenomas
  • Maximizes preservation of normal pituitary tissue
  • Post-operative morning serum cortisol <1 μg/dl predicts success
  • Surgeon experience is critical for outcomes 1
• Repeat transsphenoidal surgery:
  • Consider for persistent or recurrent disease
  • Early biochemical remission rates up to 93% 1

2. Medical Therapy (for persistent/recurrent disease or when surgery contraindicated)

Steroidogenesis Inhibitors:

• Ketoconazole:

  • Initial dose: 400-600 mg/day in 2-3 divided doses
  • Increase to 800-1,200 mg/day until cortisol normalization
  • Maintenance: 400-800 mg/day
  • Efficacy: 64% UFC normalization
  • Monitor liver function tests weekly for first 6 months (hepatotoxicity in 10-20%) 1

• Metyrapone:

  • Dose: 250-750 mg every 4 hours
  • Rapid cortisol reduction within hours
  • Best for severe hypercortisolism requiring rapid control
  • Side effects: hirsutism, dizziness, hypokalaemia 1

• Osilodrostat:

  • Achieves 86% UFC normalization
  • Rapid cortisol reduction within hours 1

Pituitary-directed Therapies:

• Pasireotide:

  • FDA-approved for adult patients with Cushing's disease when surgery not an option or not curative 2
  • Efficacy: 15-26% UFC normalization
  • Best for mild-to-moderate disease with visible tumor
  • Monitor for hyperglycemia 1

• Cabergoline:

  • Efficacy: ~40% of patients
  • Best for mild disease, particularly in young women desiring pregnancy 1

• Mifepristone:

  • Improves hyperglycemia and weight gain
  • No reliable biochemical markers for monitoring
  • Risk of adrenal insufficiency 1

3. Radiation Therapy

• Offered for recurrent disease not amenable to curative surgery
• Options:
  • Stereotactic radiosurgery (SRS)
  • Conventional external-beam radiotherapy
  • Fractionated proton beam radiotherapy
  • Gamma knife radiosurgery
• Typically initiated 2-4 weeks after unsuccessful surgery
• Fractionated treatment: 45 Gy in 25 fractions over 35 days
• Achieves biochemical remission in approximately 80% of patients during years after treatment 3
• Hypopituitarism occurs in 25-50% of patients and increases over time 3

4. Bilateral Adrenalectomy

• Last resort for persistent disease not responsive to other therapies
• Immediate control of cortisol excess
• Requires lifelong glucocorticoid and mineralocorticoid replacement
• Complication rate: 10-18%, mortality <1%
• Risk of corticotroph tumor progression (25-40% after 5-10 years) 3

Monitoring and Follow-up

• Lifelong monitoring is essential due to recurrence risk up to 15 years after apparent cure
• For patients in remission:
  • 6-monthly clinical examination, 24h UFC, electrolytes, morning serum cortisol for at least 2 years
  • Annual clinical assessment thereafter 3
• Monitor for pituitary hormone deficiencies (GH deficiency most common) 3
• Consider monitoring for psychiatric and neurocognitive co-morbidities 3

Special Considerations

• In children and adolescents:

  • Medical therapy primarily to reduce cortisol burden while awaiting definitive treatment
  • Evaluate for GH deficiency after normalization of cortisol
  • Early GH replacement therapy to promote catch-up growth 3

• Severity-based approach:

  • Mild hypercortisolism: ketoconazole, osilodrostat, or metyrapone
  • Moderate with visible tumor: cabergoline or pasireotide
  • Severe hypercortisolism: osilodrostat or metyrapone for rapid control 1

Common Pitfalls

• Undertreatment leading to persistent hypercortisolism
• Overtreatment causing adrenal insufficiency
• Misinterpreting insufficient dosing as treatment resistance
• Failing to monitor for drug-specific side effects
• Not recognizing drug-drug interactions, particularly with mifepristone 1
• Distance of at least 3-5 mm between tumor and optic chiasm and chiasm dose <8 Gy recommended for SRS to limit damage 3