What is the treatment for Cushing's syndrome?

Treatment of Cushing's Syndrome

The first-line treatment for Cushing's syndrome is surgical resection of the causative tumor, with the specific approach determined by the underlying etiology (pituitary, adrenal, or ectopic source). 1

Diagnostic Confirmation and Classification

Before initiating treatment, proper diagnosis and classification are essential:

1. Confirm hypercortisolism using:

   • 24-hour urinary free cortisol measurements
   • Late-night salivary cortisol
   • 1mg overnight dexamethasone suppression test 1

2. Determine ACTH status to classify as:

   • ACTH-dependent (pituitary or ectopic source)
   • ACTH-independent (adrenal source) 1, 2

3. Localize the source with appropriate imaging:

   • Pituitary MRI for suspected Cushing's disease
   • Adrenal CT/MRI for suspected adrenal causes
   • Chest/abdominal imaging for ectopic sources 1

Treatment Algorithm Based on Etiology

1. Cushing's Disease (Pituitary Origin, 60-70% of cases)

• First-line: Transsphenoidal surgery (TSS) with remission rates of 65-90% for microadenomas and 50-65% for macroadenomas 1
• For persistent/recurrent disease:
  • Medical therapy with steroidogenesis inhibitors
  • Pituitary-directed radiation therapy
  • Bilateral adrenalectomy as a last resort 1, 3

2. Adrenal Cushing's Syndrome

• First-line: Laparoscopic unilateral adrenalectomy for benign adenomas 1
• For suspected malignancy: Open adrenalectomy 1
• Post-surgery: Glucocorticoid replacement until HPA axis recovery 1

3. Ectopic ACTH Syndrome

• First-line: Surgical resection of the tumor when localized 1
• If surgery not possible: Medical therapy to control cortisol production 1

Medical Therapy Options

Medical therapy is indicated when:

• Surgery is contraindicated or delayed
• Persistent/recurrent disease after surgery
• Awaiting effects of radiation therapy 1

Steroidogenesis Inhibitors

• Ketoconazole: 400-1200mg/day (monitor liver function)
• Metyrapone: 1-4.5g/day (monitor for hyperandrogenism)
• Osilodrostat: Newer agent with good efficacy 1

Pituitary-Directed Therapy

• Pasireotide: FDA-approved for Cushing's disease; initial dose 0.6-0.9mg twice daily by subcutaneous injection 4
  • Monitor for hyperglycemia, which occurs in most patients
  • Titrate dose based on response and tolerability
  • Maximum UFC reduction typically seen by two months 4
• Cabergoline: Can be used in combination with steroidogenesis inhibitors 1

Glucocorticoid Receptor Antagonist

• Mifepristone: Particularly useful for controlling hyperglycemia in Cushing's syndrome 1
  • Note: Cortisol monitoring is not useful during treatment

Special Considerations

Pediatric Patients

• Surgical resection is first-line treatment
• Medical therapies should be limited to normalizing cortisol levels before surgery or while awaiting response to radiotherapy 5
• Growth and pubertal development must be closely monitored 5

Severe or Refractory Cases

• Bilateral adrenalectomy should be reserved for severe refractory disease or life-threatening emergencies 5
• Risk of Nelson's syndrome (progressive pituitary tumor growth after bilateral adrenalectomy) is higher in children than adults 5

Monitoring and Follow-up

• Post-treatment monitoring: Assess for adrenal insufficiency, which is the most common complication after successful treatment 1
• Long-term follow-up: Lifelong monitoring for recurrence and management of persistent comorbidities 1
• Comorbidity management: Aggressive treatment of hypertension, diabetes, osteoporosis, and other metabolic complications 5, 1

Potential Complications to Monitor

• Hypocortisolism after treatment (requires glucocorticoid replacement)
• Hyperglycemia (particularly with pasireotide)
• Recurrence (can occur years after initial remission)
• Nelson's syndrome after bilateral adrenalectomy 1, 4

By following this treatment algorithm based on the specific etiology of Cushing's syndrome, clinicians can optimize outcomes and minimize complications for patients with this challenging endocrine disorder.