What is the treatment approach for pituitary Cushing's disease?

Treatment Approach for Pituitary Cushing's Disease

Selective adenomectomy by an experienced pituitary surgeon is the first-line treatment of choice for patients with pituitary Cushing's disease. 1

First-Line Treatment: Surgery

• Transsphenoidal selective adenomectomy is the optimal initial treatment, with the goal of removing the adenoma while preserving normal pituitary tissue 1
• Surgery should be performed by a surgeon experienced in pituitary surgery, as surgeon experience is a significant predictor of successful outcomes 1
• Early post-operative remission is associated with successful identification of the adenoma during surgery, while long-term remission correlates with younger age, smaller adenoma size, and absence of cavernous sinus or dural invasion 1
• A morning serum cortisol level <1 μg/dl (<28 nmol/l) after surgery is a positive predictor of long-term remission 1
• Surgical success rates in children and adolescents show early biochemical remission in approximately 93% of patients, though recurrence can occur 1
• Endoscopic approaches are increasingly used over microscopic techniques and may provide better visualization with fewer complications 1

Management of Persistent or Recurrent Disease

Second-Line Options:

1. Repeat Surgery

   • Consider repeat transsphenoidal surgery for patients with persistent or recurrent disease 1
   • Repeat surgery can achieve early biochemical remission in a high percentage of patients 1

2. Radiotherapy

   • Offer radiotherapy to patients with recurrent disease not amenable to curative surgery 1
   • Options include fractionated external beam radiotherapy, stereotactic radiotherapy, proton beam therapy, or gamma knife surgery 1
   • For fractionated treatment, a total radiation dose of 45 Gy in 25 fractions over 35 days is typically effective 1
   • Radiotherapy is more rapidly effective in children than adults, often showing results within 9-18 months 1
   • Consider potential long-term adverse effects, including hypopituitarism 1

3. Medical Therapy

   • Medical therapy can be used in several scenarios 1:
     • As presurgical treatment, particularly for severe disease
     • As postsurgical treatment in cases of surgical failure
     • As bridging therapy while awaiting effects of radiotherapy
     • As primary therapy when surgery is not an option

   Selection of medical therapy should consider:

   • Need for rapid cortisol normalization (adrenal steroidogenesis inhibitors work fastest) 1
   • Presence of residual tumor and potential for tumor shrinkage (pasireotide or cabergoline may be considered) 1
   • Patient comorbidities, particularly T2DM and hypertension 1
   • Drug tolerability, cost, and availability 1

   Medical therapy options:

   • Adrenal steroidogenesis inhibitors:

     • Osilodrostat and metyrapone have the fastest action and are orally available 1
     • Ketoconazole may be favored for ease of dose titration but requires liver enzyme monitoring 1
     • Etomidate can be used intravenously in very severe cases 1

   • Pituitary-directed drugs:

     • Pasireotide (somatostatin analog) - approved for treatment when surgery has failed 2
     • Cabergoline (dopamine agonist) - may be considered in mild disease 1, 2

   • Glucocorticoid receptor antagonist:

     • Mifepristone - particularly useful when Cushing's is associated with diabetes mellitus 2
     • Requires careful monitoring as cortisol cannot be used to assess treatment response 1

4. Bilateral Adrenalectomy

   • Reserve bilateral adrenalectomy only for severe refractory disease or life-threatening emergencies 1
   • Provides rapid and definitive control of cortisol excess but induces permanent adrenal insufficiency 2
   • Risk of Nelson syndrome (continued growth of pituitary tumor after adrenalectomy) appears higher in children than adults 1

Post-Treatment Follow-up and Management

• Monitoring for recurrence: Perform 6-monthly clinical examination, 24h UFC, electrolytes, and morning serum cortisol for at least 2 years, followed by lifelong annual clinical assessment 1

• Growth hormone deficiency assessment:

  • Wait at least 6-12 months after surgery before considering GH deficiency assessment 1
  • In children who have not completed linear growth, consider GH testing sooner (within 3-6 months) 1
  • Initiate GH replacement promptly if deficiency is confirmed, especially in children 1

• Other pituitary function monitoring:

  • Monitor for other pituitary hormone deficiencies, particularly after radiotherapy 1
  • Closely monitor pubertal progression to identify hypogonadotropic hypogonadism 1
  • Consider sex steroid replacement to enhance growth velocity when appropriate 1

• Bone health: Consider bone mineral density assessment, especially in patients at high risk for bone fragility 1

• Psychiatric and neurocognitive monitoring: Consider long-term monitoring for psychiatric and neurocognitive comorbidities, as these may persist even after biochemical remission 1

• Physical rehabilitation: Recommend physical rehabilitation for all patients, as CS-associated myopathy does not spontaneously resolve during remission 1

Common Pitfalls and Special Considerations

• Recurrence of Cushing's disease can occur up to 15 years after apparent surgical cure, necessitating lifelong follow-up 1
• Patients with macroadenomas and those requiring aggressive surgical resection are at higher risk for hypopituitarism 1
• Serum IGF-1 level alone is not a reliable indicator of GH deficiency 1
• When using medical therapy, monitor for tumor growth with MRI typically 6-12 months after initiating treatment 1
• Progressive elevations in ACTH during medical therapy may signal tumor growth and need for MRI 1
• In children, combined treatment with GH and other therapies (gonadotropin-releasing hormone analogs or aromatase inhibitors) may be needed to optimize growth potential 1