What is the initial approach to treating Cushing syndrome?

Initial Treatment Approach to Cushing Syndrome

Surgical resection of the underlying tumor causing hypercortisolism is the first-line treatment for Cushing syndrome, regardless of etiology. 1, 2

Immediate First Step: Exclude Iatrogenic Causes

• Before any treatment or further testing, you must exclude exogenous glucocorticoid use (oral, injections, inhalers, topical preparations), as this is the most common cause of Cushing syndrome and failure to identify it leads to unnecessary interventions without patient benefit. 3
• If exogenous steroids are identified, discontinue them if medically feasible rather than pursuing treatment for endogenous disease. 3

Primary Treatment: Surgery Based on Etiology

For Cushing Disease (Pituitary ACTH-Secreting Adenoma)

• Transsphenoidal surgery (TSS) to remove the pituitary adenoma is the definitive first-line treatment, representing 60-70% of endogenous Cushing syndrome cases. 1, 2
• This approach is critical in children and adolescents to normalize growth and puberty. 1
• Postoperative corticosteroid supplementation is required until recovery of the hypothalamus-pituitary-adrenal axis, which typically occurs within approximately 12 months. 1, 3
• In children, evaluate for growth hormone deficiency by 3-6 months postoperatively and provide immediate replacement if needed to ensure proper growth. 3

For Adrenal Causes (ACTH-Independent)

• Adrenalectomy is the primary treatment for cortisol-secreting adrenal adenomas or carcinomas. 1, 4
• Unilateral laparoscopic adrenalectomy for adenomas; extended adrenalectomy by an expert surgeon for adrenal cortex carcinoma. 4
• For select younger patients with mild autonomous cortisol secretion (MACS) and progressive metabolic comorbidities attributable to cortisol excess, adrenalectomy should be considered. 1

For Ectopic ACTH Syndrome

• Surgical resection of the ACTH-producing tumor (commonly bronchial carcinoid or small cell lung cancer) when feasible. 3
• When the primary tumor is irresecable, bilateral adrenalectomy is recommended. 5

Medical Therapy: When Surgery Fails or Is Not Possible

Medical therapy is reserved for cases where surgery is not possible, has failed, or while awaiting definitive treatment. 1

Steroidogenesis Inhibitors (Most Effective Pharmacological Option)

• Ketoconazole normalizes cortisol in approximately 64% of patients and is the medical treatment of choice. 1, 6

  • Monitor liver function regularly to minimize hepatotoxicity risk. 1
  • Men may experience hypogonadism and gynecomastia, which can limit prolonged treatment. 3
  • Mean effective dose is 600-673.9 mg/d, though 15-23% of initially responsive patients may escape control. 3

• Metyrapone is an alternative steroidogenesis inhibitor, particularly useful in children. 3

  • Block-and-replace regimens with metyrapone may be considered. 3

• Osilodrostat is a recently approved option for Cushing syndrome. 1, 3

Adjunctive Medical Management

• Mineralocorticoid receptor antagonists (spironolactone or eplerenone) for hypertension associated with Cushing syndrome. 1
• Monitor treatment response using 24-hour urinary free cortisol (UFC) as the most commonly used measure, along with clinical improvement in symptoms and signs. 1

Last-Resort Options for Severe Refractory Cases

• Bilateral adrenalectomy should be reserved for severe refractory cases or life-threatening emergencies. 1

  • This carries a higher risk of corticotroph tumor progression (Nelson syndrome) in children compared to adults. 1

• Radiation therapy may be appropriate for patients not responsive to surgery and medication. 2

• Repeat TSS can be considered in patients with biochemical evidence of recurrent Cushing disease if tumor is visible on MRI, especially if the first surgery was not performed at a high-volume pituitary center. 3

Critical Pitfalls to Avoid

• Never begin treatment without first excluding iatrogenic Cushing syndrome—this is a strong recommendation based on high-quality evidence. 3
• Do not use pasireotide in children with Cushing disease. 3
• Avoid routine thromboprophylaxis in pediatric patients undergoing surgery due to bleeding risk; reserve for selected cases only. 3
• Be aware that ectopic Cushing syndrome associated with small cell lung cancer carries a very poor prognosis. 3, 4
• Recognize that clinical improvement after treatment may be incomplete despite spectacular initial results, emphasizing the need for timely multidisciplinary management. 4