What is the primary treatment for Cushing's disease?

Treatment for Cushing's Disease

Selective transsphenoidal adenomectomy performed by an experienced pituitary surgeon is the first-line treatment for Cushing's disease. 1, 2

Primary Treatment Approach

• Transsphenoidal surgery aims to remove the ACTH-secreting pituitary adenoma while preserving normal pituitary tissue 1
• Surgical success is significantly influenced by surgeon experience, making it essential to refer patients to centers with specialized expertise in pituitary surgery 1
• Early post-operative remission is associated with successful identification of the adenoma during surgery, while factors predicting long-term remission include younger age, smaller adenoma size, and absence of cavernous sinus or dural invasion 1
• Remission rates following transsphenoidal surgery range from approximately 50% to 90%, depending on tumor characteristics and surgical expertise 3
• Pure endoscopic endonasal approaches have shown promising results with remission rates comparable to traditional approaches and potentially lower rates of major postoperative complications 4

Management of Persistent or Recurrent Disease

When initial surgery fails to achieve remission or when disease recurs, a stepwise approach is recommended:

Second-Line Options:

1. Repeat Transsphenoidal Surgery

   • Indicated when tumor is still visible on MRI 1
   • Early biochemical remission rates of up to 93% have been reported in pediatric patients 1, 2

2. Radiation Therapy

   • Appropriate for recurrent disease not amenable to curative surgery 1
   • Options include stereotactic radiotherapy, fractionated proton beam therapy, and gamma knife radiosurgery 1, 3
   • May take months to years to achieve full effect 3

3. Medical Therapy

   • Used to reduce cortisol burden while awaiting definitive surgery or the effect of radiotherapy 1, 2
   • Options include:
     • Adrenal steroidogenesis inhibitors (metyrapone, ketoconazole) 1, 2, 5
     • Metyrapone works by inhibiting 11-beta-hydroxylation in the adrenal cortex, reducing cortisol production 5
     • Potential side effects of medical therapy must be monitored: metyrapone can cause hirsutism, dizziness, hypokalemia, and possible hyperandrogenism; ketoconazole may cause hepatotoxicity 2

4. Bilateral Adrenalectomy

   • Considered for patients with severe refractory Cushing's disease or life-threatening emergencies 2, 3
   • Provides definitive treatment to eliminate hypercortisolemia but results in permanent adrenal insufficiency requiring lifelong glucocorticoid and mineralocorticoid replacement 3

Monitoring and Follow-up

• Lifelong follow-up is essential as recurrence can occur up to 15 years after apparent surgical cure 1, 2
• Regular monitoring for development of hypopituitarism following surgery or radiotherapy is necessary 1
• Evaluation for growth hormone deficiency 3-6 months postoperatively in patients who have not completed linear growth 1, 2
• Treatment efficacy should be assessed through measurement of urinary free cortisol, late-night salivary cortisol, and clinical symptoms 2

Clinical Considerations and Pitfalls

• Cushing's disease is associated with significant morbidity and premature death if left untreated, with complications including cardiovascular disease, metabolic disorders, skeletal problems, infections, and neuropsychiatric disturbances 6
• Even after successful treatment and biochemical "cure," patients may continue to experience negative physical and psychosocial sequelae of chronic hypercortisolism 6
• Bilateral inferior petrosal sinus sampling (BIPSS) may help lateralize pituitary ACTH secretion when no lesion is visible on MRI, with predictive value for lateralization of 75-80% 1
• Consider changing treatment approach if cortisol levels remain elevated after 2-3 months with maximum tolerated doses of medical therapy 2