What are the treatment options for Cushing's syndrome?

Treatment of Cushing's Syndrome

First-Line Treatment: Surgery

Transsphenoidal selective surgery is the definitive first-line treatment for Cushing's disease (pituitary adenoma), achieving remission in approximately 75-80% of patients, and should be performed by an experienced neurosurgeon at a high-volume center. 1

• For adrenal adenomas, laparoscopic adrenalectomy is the recommended approach, with mandatory postoperative stress-dose hydrocortisone coverage because the contralateral adrenal has been chronically suppressed. 1

• For adrenal carcinoma, open adrenalectomy is indicated if the tumor is >5 cm, inhomogeneous, has irregular margins, or shows local invasion. 1

• For ectopic ACTH syndrome, surgical removal of the ectopic tumor should be pursued if resectable. 1

Second-Line Treatment Options

Repeat Surgery

Repeat transsphenoidal surgery can be considered for biochemical recurrence if tumor is visible on MRI, especially if the first surgery was not performed at a pituitary tumor center of excellence. 2

• Remission rates after reoperation range from 37% to 88%, though surgical and endocrinological complications may be higher with repeat procedures. 2

• If MRI does not show tumor, reoperation may still be appropriate at high-volume centers if positive pathology or central ACTH gradient on inferior petrosal sinus sampling was documented at initial operation. 2

Medical Therapy

Medical therapy targets adrenal steroidogenesis, pituitary receptors, or glucocorticoid receptors and is used for persistent/recurrent disease, surgical non-candidates, or while awaiting radiation effects. 2, 3

Adrenal Steroidogenesis Inhibitors (Most Commonly Used)

Ketoconazole (400-1200 mg/day) is the most commonly used agent for chronic medical management due to easy availability and relatively tolerable toxicity profile. 1

• Normalizes urinary free cortisol in 64.3% of patients (median 50%; range 44.7-92.9%), though 15-23% of initially responsive patients may escape biochemical control. 2

• Key adverse effects: hepatotoxicity (monitor liver function tests), gastrointestinal disturbances, hypogonadism and gynecomastia in men, and risk of adrenal insufficiency with overtreatment. 2, 4

Metyrapone is an effective alternative to ketoconazole. 1

• Important caveat: Can increase androgen and mineralocorticoid production proximal to the blockade, causing hirsutism, hypokalemia, dizziness, artralgia, and fatigue. 1, 4

Osilodrostat is a recently approved steroidogenesis inhibitor that blocks multiple adrenal enzymes. 2

Mitotane is an adrenostatic agent with longer onset of action, typically reserved for adrenocortical carcinoma. 1

Etomidate can be used intravenously for severe, life-threatening hypercortisolism requiring rapid control. 2

Pituitary-Targeted Therapy

Pasireotide (somatostatin analog) is FDA-approved for Cushing's disease at 0.6-0.9 mg subcutaneously twice daily. 5

• Critical warning: Nearly all patients develop hyperglycemia within the first two weeks, requiring intensive glycemic monitoring weekly for 2-3 months and optimization of anti-diabetic therapy. 5

• Other adverse effects include bradycardia, QT prolongation, hypocortisolism, and cholelithiasis—baseline ECG, gallbladder ultrasound, and electrolytes are mandatory before initiation. 5

• Maximum urinary free cortisol reduction typically occurs by two months of treatment. 5

Cabergoline (dopamine agonist) has been used in limited trials but is less established. 6

Glucocorticoid Receptor Antagonist

Mifepristone blocks cortisol action at the receptor level and is being tested for persistent/recurrent Cushing's disease and ectopic ACTH syndrome. 6

Radiation Therapy

Pituitary radiation is indicated for recurrent Cushing's disease not amenable to curative surgery, with options including stereotactic radioterapy, fractionated proton beam, or gamma knife radiosurgery. 4

• Medical therapy is typically needed while awaiting radiation effects, which can take months to years. 2

Bilateral Adrenalectomy

Bilateral adrenalectomy is reserved for severe, refractory Cushing's disease or life-threatening emergencies when other treatments have failed. 4

• Results in permanent adrenal insufficiency requiring lifelong glucocorticoid and mineralocorticoid replacement. 7

• Risk of Nelson's syndrome (aggressive pituitary tumor growth) in 8-29% of patients after bilateral adrenalectomy for Cushing's disease. 7

Treatment Algorithm by Etiology

Cushing's Disease (Pituitary Adenoma)

1. Transsphenoidal surgery by experienced neurosurgeon 1
2. If persistent/recurrent: Repeat surgery (if tumor visible on MRI) OR medical therapy OR radiation 2, 4
3. If refractory: Bilateral adrenalectomy 4

Adrenal Adenoma

1. Laparoscopic adrenalectomy with mandatory postoperative hydrocortisone 1

Adrenal Carcinoma

1. Open adrenalectomy ± adjuvant mitotane 1

Ectopic ACTH Syndrome

1. Surgical removal of ectopic tumor if resectable 1
2. If unresectable: Bilateral adrenalectomy or medical management with steroidogenesis inhibitors 1

Monitoring During Medical Therapy

Measure urinary free cortisol, late-night salivary cortisol, and/or clinical symptoms to evaluate efficacy. 1

• Consider changing treatment if cortisol levels remain elevated after 2-3 months at maximum tolerated doses. 1

• Critical for adrenal steroidogenesis inhibitors: Monitor for adrenal insufficiency (weakness, fatigue, anorexia, nausea, hypotension, hyponatremia, hypoglycemia) as overtreatment can occur. 2

Management of Hypertension

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. 1

Long-Term Surveillance

Lifelong surveillance is necessary for Cushing's disease, as recurrence can occur up to 15 years after apparent surgical cure. 1

• Regular endocrine follow-up during HPA axis recovery to monitor for adrenal insufficiency and confirm axis recovery before discontinuing replacement therapy. 1

• Serial cortisol monitoring is essential for guiding steroid tapering after adrenalectomy. 1

Common Pitfalls to Avoid

• Do not delay treatment in patients with severe hypercortisolism—significant morbidity and mortality occur with untreated disease. 7, 8

• Do not forget stress-dose steroids after unilateral adrenalectomy for cortisol-secreting adenoma—the contralateral adrenal cannot mount adequate stress response. 1

• Do not start pasireotide without intensive diabetes management plan—hyperglycemia is nearly universal and can be severe. 5

• Do not use ketoconazole without monitoring liver function—hepatotoxicity is a significant risk. 2, 4

• Do not assume surgical cure is permanent—biochemical recurrence occurs in 20-25% within 2-4 years. 6, 7