What are the treatment options and doses for Cushing syndrome?

Cushing Syndrome: Symptoms and Treatment Options

Transsphenoidal surgery is the first-line treatment for Cushing syndrome, with medical therapy primarily used when surgery fails or is contraindicated, using medications like metyrapone (15 mg/kg every 4h) or ketoconazole (400-600 mg/day initially) to control hypercortisolism. 1

Clinical Manifestations of Cushing Syndrome

• Central obesity, moon face, buffalo hump, and supraclavicular fat pads are hallmark physical manifestations 2
• Skin changes including facial plethora, thin skin, easy bruising, and purple striae 2
• Proximal muscle weakness due to protein catabolism 2
• Metabolic disturbances including glucose intolerance or diabetes mellitus, hypertension, and dyslipidemia 2, 3
• Psychiatric manifestations including depression, anxiety, irritability, and cognitive impairment 2
• Growth failure and short stature in children and adolescents 1

Treatment Algorithm

First-Line Treatment

• Transsphenoidal surgery is the treatment of choice for Cushing's disease (pituitary-dependent Cushing syndrome) 1
• Surgical excision is successful in 75-80% of patients, but 20-25% show persistence and similar proportion may experience recurrence within 2-4 years 4
• For adrenal-dependent Cushing syndrome, laparoscopic unilateral adrenalectomy for adenomas or extended adrenalectomy for carcinomas 5

Second-Line Options When Surgery Fails

1. Radiotherapy

   • Focal external beam radiotherapy is more rapidly effective in children than adults 1
   • Fractionated treatment with total dose of 45 Gy in 25 fractions over 35 days 1
   • Gamma knife stereotactic radiosurgery using maximum dose of 50 Gy and margin dose of 25 Gy 1
   • Typically achieves cure within 9-18 months 1

2. Medical Therapy

   • Steroidogenesis Inhibitors:

     • Metyrapone: 15 mg/kg every 4 hours for 6 doses (alternatively 300 mg/m² every 4h), usual dose 250-750 mg every 4h 1
     • Ketoconazole: For patients over 12 years, initially 400-600 mg/day in 2-3 divided doses, increased to 800-1,200 mg/day until cortisol normalizes, then maintenance dose of 400-800 mg/day 1
     • Osilodrostat: Highest efficacy based on clinical trials, currently being evaluated in phase II trial for children and adolescents 2, 1

   • Pituitary-directed drugs:

     • Pasireotide: Initial dose 0.6 mg or 0.9 mg subcutaneously twice daily, with dose range of 0.3-0.9 mg twice daily 6
     • Cabergoline: Limited data in children but effective in a subgroup of adult patients 1, 3

3. Bilateral Adrenalectomy

   • Reserved only for severe refractory Cushing's disease or life-threatening emergencies 1
   • Risk of Nelson syndrome (corticotroph tumor progression) is higher in children than adults 1

Treatment Approach for Cyclic Cushing's Syndrome

• Multiple, periodic, sequential late-night salivary cortisol measurements for surveillance 2
• Block-and-replace regimen may be useful to maintain stable cortisol levels 2
• Combination therapy recommended for persistent hypercortisolism 2

Medication Monitoring and Side Effects

• Metyrapone:

  • Monitor for hirsutism, dizziness, arthralgia, fatigue, hypokalemia, and nausea 1
  • Prolonged use can lead to hyperandrogenism and advanced bone age in children 1

• Ketoconazole:

  • Regular liver function monitoring required due to hepatotoxicity risk 1, 2
  • Watch for gastrointestinal disturbance and adrenal insufficiency 1

• Pasireotide:

  • Monitor for hyperglycemia and diabetes (occurs with initiation) 6
  • Check for bradycardia and QT prolongation 6
  • Evaluate for gallstones and complications of cholelithiasis 6

Follow-up and Surveillance

• Consider growth hormone (GH) deficiency testing after definitive therapy in children who have not completed linear growth 1
• Prompt initiation of GH replacement for those who are GH deficient or fail to show catch-up growth 1
• Monitor pubertal progression to identify hypogonadotropic hypogonadism 1
• Consider bone mineral density assessment prior to adult transition in patients at high risk for bone fragility 1

Treatment Pitfalls to Avoid

• Medical therapy should not replace definitive treatment (surgery/radiotherapy) in children and adolescents 1
• Avoid prolonged use of steroidogenesis inhibitors in children due to effects on growth and development 1
• Monitor for adrenal insufficiency when using higher doses of steroidogenesis inhibitors 2
• Be aware of potential QTc prolongation with combination therapy 2
• Lifelong follow-up is essential as recurrence can occur up to 15 years after apparent surgical cure 1