Treatment of Cushing's Syndrome
First-Line Treatment: Surgery
Transsphenoidal selective surgery is the definitive first-line treatment for Cushing's syndrome, particularly for Cushing's disease (pituitary-dependent), with the goal of removing the adenoma while preserving normal pituitary tissue. 1 This approach achieves remission in approximately 75-80% of patients, though 20-25% experience persistent disease and a similar proportion may relapse within 2-4 years post-operatively. 2, 3
Surgical Approach by Etiology:
- Cushing's disease (pituitary adenoma): Transsphenoidal selective surgery performed by an experienced neurosurgeon 1
- Adrenal adenoma: Laparoscopic adrenalectomy when feasible, with mandatory postoperative corticosteroid supplementation until HPA axis recovery 4
- Adrenal carcinoma: Open adrenalectomy if tumor is >5 cm, inhomogeneous, has irregular margins, or shows local invasion 4
- Ectopic ACTH: Surgical removal of the ectopic tumor if resectable 4
Critical post-operative consideration: After unilateral adrenalectomy for cortisol-secreting adenoma, stress-dose hydrocortisone coverage is mandatory because the contralateral adrenal has been chronically suppressed and cannot mount an adequate stress response. 5
Second-Line Treatment Options
When surgery fails, is not feasible, or disease recurs, treatment follows this hierarchy:
1. Repeat Surgery
- Reintervention can be considered for persistent or recurrent disease, achieving remission in up to 93% of pediatric patients with early recurrence 1
2. Medical Therapy (Primary Options)
For chronic medical management, ketoconazole (400-1200 mg/day) is the most commonly used agent due to its easy availability and relatively tolerable toxicity profile. 4 However, newer evidence supports additional options:
Adrenal Steroidogenesis Inhibitors:
- Ketoconazole: 400-1200 mg/day; monitor for hepatotoxicity, gastrointestinal disturbances, and adrenal insufficiency 4, 1
- Metyrapone: Effective alternative to ketoconazole, though can increase androgen and mineralocorticoid production; side effects include hirsutism, dizziness, artralgia, fatigue, and hypokalemia 1, 6
- Mitotane: Adrenostatic agent with longer onset of action 4
- Osilodrostat: Oral 11β-hydroxylase inhibitor showing efficacy across all etiologies of Cushing's syndrome, including ectopic and adrenal causes; requires monitoring for hypocortisolism and QT prolongation 7
Glucocorticoid Receptor Antagonist:
- Mifepristone: FDA-approved for Cushing's syndrome associated with glucose intolerance when surgery is not an option 8, 3
- Dosing: Start 300 mg daily, escalate by 300 mg increments every 2-4 weeks up to 900 mg (<60 kg) or 1200 mg (>60 kg) 8
- Critical warning: Does NOT reduce cortisol levels; blocks cortisol action at receptor level 8
- Most effective for controlling glucose metabolism and diabetes in Cushing's syndrome 3
- Major adverse effects: Hypokalemia (44% of patients), endometrial hypertrophy (38%), vaginal bleeding, QT prolongation 8
- Contraindicated with strong CYP3A inhibitors or limit dose to 900 mg/day if combination necessary 8
Pituitary-Directed Agents:
- Pasireotide: Approved for Cushing's disease when surgery fails or is not an option; achieves remission in a consistent subgroup 3
- Cabergoline: Dopamine agonist with efficacy in select patients 3
3. Pituitary Radiotherapy
- Indicated for recurrent disease not amenable to curative surgery 1
- Options include stereotactic radiotherapy, fractionated proton beam, or gamma knife radiosurgery 1
- Can be combined with ketoconazole during the latency period (months to years) before radiation takes effect 6
- Major limitation: Considerable risk of hypopituitarism 3
4. Bilateral Adrenalectomy
- Provides immediate and definitive control of hypercortisolism 6
- Reserved for severe, refractory disease or life-threatening complications 1, 6
- Requires lifelong glucocorticoid AND mineralocorticoid replacement 6
- Consider for unresectable ectopic tumors 4
Management of Complications and Comorbidities
Hypertension Management:
Mineralocorticoid receptor antagonists (spironolactone or eplerenone) are the most effective antihypertensive agents in Cushing's syndrome because they block mineralocorticoid receptor activation by excess cortisol. 6
Hypokalemia:
- Occurs in 44% of patients on mifepristone and can occur at any time during treatment 8
- Correct hypokalemia BEFORE initiating mifepristone 8
- Treat with IV or oral potassium supplementation; if persistent despite supplementation, add mineralocorticoid antagonists 8
Opportunistic Infections:
- Patients are at risk for Pneumocystis jiroveci pneumonia, particularly shortly after initiating treatment 8
- Maintain high clinical suspicion if respiratory distress develops 8
Monitoring During Treatment
For Medical Therapy:
- Measure urinary free cortisol, late-night salivary cortisol, and/or assess clinical symptoms to evaluate efficacy 1
- Consider changing treatment if cortisol levels remain elevated after 2-3 months at maximum tolerated doses 1
- Serial cortisol monitoring essential for guiding steroid tapering after adrenalectomy 5
For Mifepristone Specifically:
- Monitor potassium levels regularly (hypokalemia in 44%) 8
- Monitor for QT prolongation 8
- Premenopausal women: Monitor endometrial thickness (mean increase from 6.14 mm to 15.7 mm); refer to gynecology if vaginal bleeding occurs 8
- Monitor HDL-cholesterol (reductions observed) 8
- Monitor TSH (19% develop asymptomatic elevations) 8
Diagnostic Adjuncts to Guide Treatment
Bilateral inferior petrosal sinus sampling (BIPSS) should be performed to confirm pituitary source versus ectopic ACTH production, as this test can lateralize the tumor and improve surgical outcomes even when imaging is negative. 6 This is particularly critical when plasma ACTH levels are mid-normal to elevated, distinguishing Cushing's disease from ectopic ACTH syndrome. 9
Long-Term Follow-Up
- Lifelong surveillance is necessary for Cushing's disease, as recurrence can occur up to 15 years after apparent surgical cure 1
- For adrenal adenoma, lifelong surveillance is NOT required 5
- Assess for growth hormone deficiency after definitive therapy in patients who have not completed linear growth 1
- Regular endocrine follow-up during HPA axis recovery phase to monitor for adrenal insufficiency, assess growth velocity and bone density recovery, and confirm HPA axis recovery before discontinuing replacement therapy 5
Critical Pitfalls to Avoid
- Do NOT discontinue steroids rapidly after adrenalectomy—abrupt withdrawal can precipitate adrenal crisis; taper must be gradual and biochemically guided 5
- Do NOT forget stress-dose coverage during intercurrent illness until HPA axis recovery is confirmed 5
- Do NOT use mifepristone in patients on lifesaving corticosteroid therapy (e.g., organ transplant immunosuppression)—it will antagonize desired glucocorticoid effects 8
- Do NOT combine mifepristone with strong CYP3A inhibitors without dose limitation to 900 mg/day 8
- Do NOT assume cortisol levels will decrease with mifepristone—it blocks receptor action but does not lower cortisol; elevated cortisol may still activate mineralocorticoid receptors in cardiac tissue 8