Treatment of Cushing's Syndrome
Surgical resection of the causative tumor is the first-line treatment for all forms of endogenous Cushing's syndrome, with medical therapy reserved for cases where surgery is not an option or has not been curative. 1
Diagnostic Approach
Before initiating treatment, proper diagnosis is essential:
- Confirm hypercortisolism using 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), or overnight 1 mg dexamethasone suppression test (DST) 1
- Determine ACTH dependency status to identify the source 1
- For ACTH-dependent cases, perform pituitary MRI and potentially inferior petrosal sinus sampling (IPSS) to differentiate pituitary from ectopic sources 1
- For ACTH-independent cases, adrenal imaging is required to identify adrenal adenomas, carcinomas, or bilateral hyperplasia 1
Treatment Algorithm
1. ACTH-Dependent Cushing's Syndrome (Cushing's Disease)
First-line: Surgical Treatment
- Transsphenoidal surgery (TSS) for pituitary adenomas 1
- Surgical resection of ectopic ACTH-producing tumors when identified and accessible 1
Second-line: Medical Therapy (if surgery fails or is not an option)
Adrenal Steroidogenesis Inhibitors:
- Ketoconazole: 400-1200 mg/day in divided doses; ~65% UFC normalization; monitor for hepatotoxicity and drug interactions 1
- Metyrapone: 500 mg/day to 6 g/day in divided doses every 6-8 hours; ~70% UFC normalization; monitor for hirsutism, hypertension, and hypokalemia 1
- Osilodrostat: 2-7 mg twice daily (maximum 30 mg twice daily); 86% UFC normalization in phase 3 trials; FDA approved for CD when surgery is not an option 1
- Mitotane: 250-500 mg/day up to 8 g/day; ~80% UFC normalization; slow onset of action; teratogenic 1
Pituitary-Directed Therapy:
Glucocorticoid Receptor Antagonist:
- Mifepristone: Starting dose 300 mg once daily, can be increased to maximum of 1200 mg/day based on weight and response; improves glucose control and clinical features 3
Third-line Options:
- Pituitary radiation therapy with concurrent medical therapy 4
- Bilateral adrenalectomy for refractory cases 1, 4
2. ACTH-Independent Cushing's Syndrome
Adrenal Adenoma or Unilateral Disease:
- Laparoscopic adrenalectomy of the affected gland 1
- Postoperative glucocorticoid supplementation until HPA axis recovery 1
Adrenal Carcinoma:
- Open adrenalectomy with lymph node dissection 1
- Consider adjuvant mitotane therapy and radiation for high-grade tumors 1
Bilateral Adrenal Hyperplasia:
- If cortisol production is asymmetric: unilateral adrenalectomy of the most active side 1
- If cortisol production is symmetric: medical management with steroidogenesis inhibitors 1
Special Considerations
Acute Severe Hypercortisolism
- Etomidate: 0.04-1 mg/kg/h IV for rapid control in ICU setting; requires careful monitoring 1
Hypertension Management in Cushing's Syndrome
- Mineralocorticoid receptor antagonists (spironolactone, eplerenone) are particularly effective 1
- Multiple antihypertensive agents often required due to multiple pathways of hypertension in Cushing's syndrome 1
Pediatric Considerations
- Surgical approach is still first-line, but thromboprophylaxis should be used more selectively 1
- For medical therapy, ketoconazole or metyrapone are preferred; pasireotide is not recommended 1
- Growth hormone deficiency assessment within 3-6 months post-surgery 1
Monitoring and Follow-up
- Regular assessment of cortisol levels (UFC, morning serum cortisol) to evaluate treatment efficacy 1
- Monitor for specific medication side effects (liver function with ketoconazole, electrolytes with metyrapone) 1
- Address comorbidities: diabetes, hypertension, osteoporosis, and psychiatric symptoms 1
Common Pitfalls
- Failure to recognize cyclical Cushing's syndrome, which may require repeated testing 1
- Inadequate treatment of comorbidities, which contribute significantly to morbidity and mortality 1
- Drug interactions with ketoconazole and other steroidogenesis inhibitors 1
- Adrenal insufficiency risk with medical therapy, requiring careful dose titration 1