What are the treatment options for Cushing's syndrome?

Treatment Options for Cushing's Syndrome

The first-line treatment for Cushing's syndrome depends on the underlying cause, with selective adenomectomy being the treatment of choice for Cushing's disease (pituitary-dependent), surgical resection for adrenal causes, and tumor removal for ectopic ACTH syndrome. 1, 2

Treatment Algorithm Based on Etiology

1. Cushing's Disease (Pituitary-Dependent)

First-Line Treatment:

• Transsphenoidal selective adenomectomy performed by an experienced neurosurgeon 1, 2
  • Success rates: 75-80% in adults 2
  • Early post-operative remission in children associated with adenoma identification during surgery 1
  • Morning serum cortisol <1 μg/dl (<28 nmol/l) after surgery correlates with long-term remission 1

For Persistent or Recurrent Disease:

1. Repeat transsphenoidal surgery 1

   • Resulted in early biochemical remission in 93% of pediatric patients 1

2. Radiotherapy 1, 2

   • Initiated 2-4 weeks after unsuccessful surgery 1
   • Options include:
     • Focal external beam radiotherapy
     • Stereotactic radiotherapy
     • Fractionated proton beam therapy
     • Gamma knife radiosurgery
   • Cure rates: 70-80% within 9-18 months in children 2
   • Fractionated treatment: total dose of 45 Gy in 25 fractions over 35 days 1
   • Caution: Risk of hypopituitarism 1

3. Medical Therapy 2, 3

   • Adrenal steroidogenesis inhibitors:

     • Metyrapone: 15 mg/kg every 4h or 300 mg/m² every 4h 2
     • Ketoconazole: 400-600 mg/day in 2-3 divided doses 2
     • Osilodrostat: Achieves 86% UFC normalization 2

   • Pituitary-directed medications:

     • Pasireotide LAR: Starting dose 10 mg every 4 weeks, can be increased to maximum 40 mg 3
       • FDA-approved for Cushing's disease when surgery is not an option or has not been curative 3
       • Achieves 15-26% UFC normalization 2
     • Cabergoline: Achieves ~40% UFC normalization 2

   • Glucocorticoid receptor antagonist:

     • Mifepristone: Improves hyperglycemia and weight gain 2

4. Bilateral adrenalectomy (last resort) 1

   • Induces adrenal insufficiency requiring lifelong replacement 4

2. Adrenal Causes of Cushing's Syndrome

• Adrenal adenoma: Laparoscopic adrenalectomy 1
• Adrenal carcinoma: Surgical resection with consideration of adjuvant radiation therapy 1
• Bilateral adrenal hyperplasia:
  • If cortisol production is asymmetric: unilateral adrenalectomy of the most active side 1
  • If cortisol production is symmetric: medical management 1

3. Ectopic ACTH Syndrome

• Surgical removal of the ACTH-secreting tumor when possible 2
• If unresectable: bilateral adrenalectomy or medical management 1

Combination Therapy Strategies

For inadequate response to monotherapy, consider combinations 2:

• Ketoconazole + metyrapone
• Ketoconazole + osilodrostat
• Pasireotide + cabergoline

Monitoring Treatment Efficacy

• 24-hour urinary free cortisol (UFC)
• Morning serum cortisol
• Late-night salivary cortisol
• Clinical symptoms and comorbidities 2

Important Considerations

• Lifelong follow-up is essential as recurrence can occur up to 15 years after apparent surgical cure 1
• Rapid cortisol normalization should be prioritized in severe disease 2
• For patients with poorly controlled diabetes, optimize anti-diabetic therapy before starting medical treatment for Cushing's 3
• Monitor for adrenal insufficiency after successful treatment 1

Common Pitfalls to Avoid

1. Undertreatment leading to persistent complications of hypercortisolism
2. Overtreatment causing adrenal insufficiency
3. Inadequate monitoring of treatment response
4. Failing to recognize cyclical Cushing's syndrome 2
5. Discontinuing medical therapy prematurely, as recurrence typically follows 5