How should Cushing syndrome be treated?

Treatment of Cushing Syndrome

Surgical resection of the causative tumor is the first-line definitive treatment for all forms of Cushing syndrome, with medical therapy reserved for preoperative optimization, surgical failures, or patients who are not surgical candidates. 1

Treatment Algorithm by Etiology

Cushing's Disease (Pituitary ACTH-Secreting Adenoma)

Primary Treatment:

• Transsphenoidal selective removal of the corticotroph adenoma achieves remission in approximately 80% of patients, though long-term relapse occurs in up to 30% of cases 2
• This remains the optimal initial approach for all patients with confirmed pituitary disease 3, 1

Second-Line Options After Surgical Failure:

• Repeat surgery if residual tumor is visible on MRI, though this carries high risk of hypopituitarism 2
• Bilateral adrenalectomy is preferred for patients without visible residual tumors, particularly women desiring fertility, as it provides immediate and definitive control of hypercortisolism 4, 5, 2
• Pituitary radiotherapy (fractionated or stereotactic) combined with ketoconazole during the latency period before radiation takes effect 4, 2
• Pasireotide LAR (FDA-approved) at 10 mg intramuscularly every 28 days, with dose escalation up to 40 mg for patients who fail to normalize 24-hour urinary free cortisol after 4 months 6

Adrenal Cushing Syndrome

Treatment:

• Surgical resection of cortisol-secreting adrenal tumors (adenomas or carcinomas) 3, 1
• Unilateral adrenalectomy for unilateral adenomas results in tertiary adrenal insufficiency requiring temporary glucocorticoid replacement until HPA axis recovery 7
• Following adrenalectomy, patients require stress-dose hydrocortisone coverage (2 mg/kg at induction, then continuous IV infusion based on weight) because the contralateral adrenal has been chronically suppressed 7

Ectopic ACTH Syndrome

Treatment:

• Surgical removal of the ectopic ACTH or CRH-secreting tumor when feasible 3, 1, 2
• Medical therapy or bilateral adrenalectomy for unresectable tumors 1

Medical Management

Indications for Medical Therapy:

• Preoperative optimization to reduce surgical risk 8, 2
• Patients who are not surgical candidates or decline surgery 8
• Residual or recurrent disease not amenable to repeat resection 8
• While awaiting effects of radiotherapy (latency period) 4, 2

Steroidogenesis Inhibitors (All Etiologies)

Ketoconazole (First-Line Medical Therapy):

• Most effective medical treatment for chronic management 3, 2
• Dosing in adults: initially 400-600 mg daily in 2-3 divided doses, increased to 800-1,200 mg daily until cortisol normalizes, then maintenance 400-800 mg daily 9
• Critical monitoring: Liver function tests due to hepatotoxicity risk 9
• In children >12 years, use same dosing but reserve for short-term preoperative use or while awaiting radiotherapy effects, not long-term therapy due to effects on growth and puberty 9

Metyrapone (Alternative to Ketoconazole):

• Effective alternative recommended by the Endocrine Society, though increases androgen and mineralocorticoid production 4
• Dosing in children: 15 mg/kg every 4 hours for 6 doses, or 300 mg/m² every 4 hours (usual adult dose 250-750 mg every 4 hours) 9
• Adverse effects include hirsutism, hypokalaemia, and hyperandrogenism with prolonged use 9
• Limited role for long-term treatment in children due to adverse effects on growth 9

Other Steroidogenesis Inhibitors:

• Aminoglutethimide, mitotane, and etomidate available for specific situations 2, 10
• These agents can be used alone or in combination for rapid control of severe hypercortisolism 2

Pituitary-Directed Therapy (Cushing's Disease Only)

Pasireotide LAR (FDA-Approved):

• Indicated for Cushing's disease when surgery is not an option or has failed 6
• Initial dose: 10 mg IM every 28 days, escalate to maximum 40 mg if UFC not normalized after 4 months 6
• Critical baseline evaluations required: Fasting glucose, HbA1c, liver tests, ECG, potassium, and magnesium 6
• Patients with poorly controlled diabetes must optimize glycemic control before starting 6

Cabergoline:

• Dopamine agonist with potential benefit in ACTH-secreting tumors, though limited evidence 10

Glucocorticoid Receptor Antagonist

Mifepristone:

• Blocks cortisol action at the glucocorticoid receptor level 8, 10
• Currently tested for persistent/recurrent Cushing's disease and metastatic adrenal carcinoma 10

Management of Hypertension in Cushing Syndrome

Mineralocorticoid receptor antagonists are the most effective antihypertensive agents:

• Spironolactone or eplerenone block mineralocorticoid receptor activation by excess cortisol, which increases renal sodium absorption 9, 4
• Hypercortisolism promotes hypertension through multiple pathways (activating renin-angiotensin system, sensitizing vasculature to catecholamines, impairing nitric oxide bioavailability), so combination therapy is often needed 9

Bilateral Adrenalectomy for Severe/Refractory Disease

Indications:

• Severe, refractory Cushing's disease with life-threatening complications (e.g., left ventricular hypertrophy, cirrhosis) requiring rapid cortisol normalization 4, 5
• Life-threatening emergencies 9, 5
• Failed pituitary surgery without visible residual tumor, especially in women desiring fertility 2

Critical Considerations:

• Provides immediate and definitive control of hypercortisolism 4, 5
• Requires lifelong glucocorticoid and mineralocorticoid replacement 4, 5
• Nelson syndrome risk: Corticotroph tumor progression after bilateral adrenalectomy is more frequent in children than adults, often requiring pituitary surgery or radiotherapy 9, 5
• Regular pituitary MRI monitoring required post-adrenalectomy 5

Pediatric-Specific Considerations

Treatment Priorities:

• Definitive treatments (surgery and/or radiotherapy) are strongly preferred to allow rapid normalization of growth and puberty 9
• Medical therapies should be confined to normalizing cortisol preoperatively or while awaiting radiotherapy response, not long-term management 9
• Reserve bilateral adrenalectomy only for severe refractory disease or life-threatening emergencies due to higher Nelson syndrome risk 9

Post-Treatment Monitoring in Children:

• Dynamic testing for GH deficiency soon after definitive therapy in all children in remission who have not completed linear growth 9
• Close monitoring of pubertal progression to identify hypogonadotrophic hypogonadism 9
• Prompt GH replacement when deficiency confirmed 9

Critical Pitfalls to Avoid

Diagnostic Pitfalls:

• Do not pursue imaging before biochemical confirmation of hypercortisolism 9
• Perform bilateral inferior petrosal sinus sampling (BSIPSS) to confirm pituitary versus ectopic ACTH source, as this improves surgical outcomes even when imaging is negative 4

Treatment Pitfalls:

• Do not use long-term medical therapy in children when definitive treatment is possible, as it impairs growth and puberty 9
• Do not discontinue steroids rapidly after adrenalectomy; gradual taper guided by biochemical monitoring is essential to prevent adrenal crisis 7
• Do not forget stress-dose glucocorticoid coverage during intercurrent illness until HPA axis recovery is confirmed 7
• Monitor liver function on ketoconazole due to hepatotoxicity risk 9
• Optimize diabetes control before starting pasireotide and monitor glucose closely 6

Post-Treatment Surveillance

All Patients:

• Adequate glucocorticoid and other hormone replacement 2
• Treatment of osteoporosis 2
• Long-term monitoring for recurrence of Cushing syndrome 2

After Bilateral Adrenalectomy:

• Regular pituitary MRI to monitor for Nelson syndrome 5
• Close monitoring for adrenal insufficiency 5
• Assessment of cardiac function (LVH regression) and liver function if cirrhosis present 5

After Adrenalectomy for Adrenal Adenoma:

• Serial morning cortisol levels to guide steroid tapering and assess HPA axis recovery 7
• Regular endocrine follow-up during recovery phase to monitor growth velocity, bone density, and guide eventual discontinuation of replacement therapy 7
• Lifelong surveillance NOT required for adrenal adenoma (unlike Cushing's disease where recurrence can occur up to 15 years later) 7