What is the treatment for Cushing's syndrome?

Treatment for Cushing's Syndrome

The first-line treatment for Cushing's syndrome is surgical resection of the underlying cause, with transsphenoidal surgery for pituitary adenomas (Cushing's disease), laparoscopic adrenalectomy for adrenal adenomas, and resection of ectopic ACTH-secreting tumors when identified. 1, 2

Diagnostic Approach to Guide Treatment

Before initiating treatment, proper diagnosis and classification is essential:

1. Confirm hypercortisolism using:

   • 24-hour urinary free cortisol (UFC) measurements (at least 2-3 samples)
   • Late-night salivary cortisol (LNSC)
   • 1mg overnight dexamethasone suppression test (DST)

2. Determine ACTH status:

   • ACTH-dependent (elevated/normal ACTH): Suggests pituitary or ectopic source
   • ACTH-independent (suppressed ACTH): Suggests adrenal source

3. Localize the source with appropriate imaging:

   • Pituitary MRI for suspected Cushing's disease
   • Adrenal CT/MRI for suspected adrenal cause
   • Chest/abdominal imaging for suspected ectopic source
   • Bilateral inferior petrosal sinus sampling (BIPSS) when imaging is inconclusive

Treatment Algorithm Based on Etiology

1. Cushing's Disease (Pituitary ACTH-secreting Adenoma) - 60-70% of cases

First-line treatment:

• Transsphenoidal surgery (TSS) 1, 2
  • Remission rates: 65-90% for microadenomas, 50-65% for macroadenomas
  • Postoperative glucocorticoid replacement until HPA axis recovery (typically 12 months)

For persistent/recurrent disease:

• Repeat transsphenoidal surgery if feasible
• Medical therapy:
  • Pituitary-directed: Pasireotide (first FDA-approved for Cushing's disease) 3
  • Adrenal steroidogenesis inhibitors: Ketoconazole (600-800mg/day), metyrapone (1-4.5g/day), or osilodrostat 1
  • Glucocorticoid receptor antagonist: Mifepristone 4
• Radiation therapy (conventional or stereotactic)
• Bilateral adrenalectomy as last resort 1, 2

2. Adrenal Causes (ACTH-independent)

For adrenal adenoma:

• Laparoscopic unilateral adrenalectomy 1, 2
• Postoperative glucocorticoid replacement until HPA axis recovery

For adrenal carcinoma:

• Open adrenalectomy with extended resection 1
• Consider adjuvant mitotane therapy

For bilateral adrenal hyperplasia:

• Medical therapy or bilateral adrenalectomy depending on severity 1, 2

3. Ectopic ACTH Syndrome

For localized tumors:

• Surgical resection of the tumor 1, 2

For occult or metastatic tumors:

• Medical therapy to control hypercortisolism:
  • Steroidogenesis inhibitors (ketoconazole, metyrapone, osilodrostat)
  • Consider bilateral adrenalectomy for severe, uncontrollable hypercortisolism 1

Medical Therapy Options

Medical therapy is used when surgery fails, is contraindicated, or while awaiting definitive treatment:

1. Steroidogenesis inhibitors:

   • Ketoconazole: 400-1200mg/day (most commonly used) 1
   • Metyrapone: Starting at 1g/day divided into four doses, up to 4.5g/day 1
   • Osilodrostat: Newer agent with high efficacy 1
   • Mitotane: Used primarily for adrenal carcinoma 1

2. Pituitary-directed therapy:

   • Pasireotide: Somatostatin analog specifically approved for Cushing's disease 3
   • Cabergoline: Dopamine agonist (less effective, used as adjunct)

3. Glucocorticoid receptor antagonist:

   • Mifepristone: Blocks cortisol action at receptor level; useful for controlling hyperglycemia in Cushing's syndrome 4

4. Combination therapy:

   • Consider when monotherapy is insufficient
   • Common combinations: ketoconazole + metyrapone, ketoconazole + osilodrostat, or pasireotide + cabergoline 1

Monitoring Treatment Response

• Clinical improvement (weight, blood pressure, glucose metabolism, quality of life)
• Biochemical normalization:
  • 24-hour UFC
  • Morning serum cortisol
  • Late-night salivary cortisol
  • Note: Cortisol monitoring not useful when using mifepristone 1, 4

Special Considerations

• Cushing's syndrome in children: Surgical resection is first-line; thromboprophylaxis should be reserved for selected cases due to bleeding risk; evaluate for growth hormone deficiency within 3-6 months post-surgery 1

• Preoperative medical therapy: Consider in severe cases with life-threatening complications (psychiatric, infectious, cardiovascular) or when surgery is delayed 1

• Carcinoid syndrome: May occur with ectopic ACTH-secreting tumors; somatostatin analogs can help control symptoms 1

Pitfalls and Caveats

1. Adrenal insufficiency: Most common complication after successful treatment; requires careful glucocorticoid replacement and patient education

2. Recurrence: Can occur years after initial remission; requires lifelong monitoring

3. Nelson's syndrome: Progressive pituitary tumor growth after bilateral adrenalectomy; monitor ACTH levels and perform regular pituitary imaging

4. Drug interactions: Monitor for interactions with ketoconazole and other medications that affect CYP3A4

5. Thromboembolic risk: Consider prophylaxis in adults with severe hypercortisolism

By following this structured approach to diagnosis and treatment, mortality and morbidity from Cushing's syndrome can be significantly reduced, with improved quality of life for patients.