What are the treatment options for Cushing's syndrome?

Treatment Options for Cushing's Syndrome

The first-line treatment for Cushing's syndrome is surgical resection of the underlying tumor, with specific surgical approaches determined by the etiology of cortisol excess. 1

Etiology-Specific Treatment Approaches

1. Cushing's Disease (Pituitary-Dependent)

• First-line: Transsphenoidal surgery (TSS)
  • Remission rates: 65-90% for microadenomas, 50-65% for macroadenomas 1
• For persistent/recurrent disease:
  • Radiation therapy (RT), particularly stereotactic radiosurgery (SRS)
    • SRS achieves biochemical control in 80% of patients 2
    • Conventional RT typically delivers 45-50 Gy in <2 Gy fractions 2
  • Medical therapy (see below)
  • Bilateral adrenalectomy as last resort 2

2. Adrenal Causes

• Adrenal adenoma: Laparoscopic unilateral adrenalectomy 1
• Adrenal carcinoma: Open adrenalectomy 1
• Bilateral adrenal hyperplasia: Bilateral adrenalectomy 2

3. Ectopic ACTH Syndrome

• Localized tumors: Surgical resection of the ACTH-secreting tumor 1
• Unidentified or metastatic source: Medical therapy to control cortisol production 1

Medical Therapy Options

Medical therapy is indicated when:

1. Surgery is contraindicated or delayed
2. Persistent/recurrent disease after surgery
3. Severe hypercortisolism requiring rapid control before surgery
4. Adjunctive treatment while awaiting radiation effects 2, 1

Steroidogenesis Inhibitors

• Ketoconazole: 400-1200 mg/day 1
• Metyrapone: 1-4.5 g/day 1
  • Mechanism: Inhibits 11-beta-hydroxylation in adrenal cortex 3
  • Pharmacokinetics: Peak concentration at 1 hour, half-life of 1.9 hours 3
• Osilodrostat: Potent 11β-hydroxylase inhibitor 1
• Mitotane: For adrenocortical carcinoma or severe hypercortisolism 1

Pituitary-Directed Therapies

• Pasireotide: Somatostatin analog effective for Cushing's disease 1
• Cabergoline: Dopamine agonist, often used in combination with steroidogenesis inhibitors 1

Special Considerations

Preoperative Medical Therapy

• Consider for patients with severe disease and life-threatening complications 2, 1
• May improve metabolic, cardiovascular, and coagulation parameters 2
• Note: Makes postoperative assessment of surgical cure more challenging 2

Radiation Therapy Considerations

• Monitoring: Lifelong monitoring for pituitary hormone deficiencies (occurs in 25-50% of patients) 2
• Spacing: Maintain at least 3-5 mm between tumor and optic chiasm; chiasm dose <8 Gy 2
• Adjuvant medical therapy: Required during latency period until RT takes effect 2

Bilateral Adrenalectomy (BLA) Considerations

• Results in immediate control of cortisol excess 2
• Requires lifelong glucocorticoid and mineralocorticoid replacement 2
• Risk of Nelson's syndrome (25-40% after 5-10 years) requiring monitoring 2
• May be preferred earlier in women desiring pregnancy 2

Post-Treatment Monitoring

• After successful treatment: Monitor for adrenal insufficiency (most common complication) 1
• After BLA: Monitor plasma ACTH and pituitary imaging starting 6 months post-surgery 2
• After RT: Lifelong monitoring for pituitary hormone deficiencies and tumor recurrence 2
• For all patients: Regular screening for comorbidities (diabetes, hypertension, osteoporosis, dyslipidemia) 1

Treatment Algorithm

1. Confirm diagnosis using at least two different tests (24-hour UFC, LNSC, 1mg DST)
2. Determine etiology (ACTH-dependent vs. independent)
3. Proceed to first-line surgical treatment based on etiology
4. For surgical failures or non-surgical candidates:
   • Consider RT for pituitary disease
   • Implement medical therapy based on disease severity and comorbidities
   • Consider BLA for severe, refractory cases

Medical therapy should be carefully monitored with regular assessment of cortisol levels and potential side effects, with dose adjustments as needed to maintain normal cortisol levels.