What is the medical treatment for a 40-year-old female patient with iatrogenic or endogenous Cushing syndrome, with a history of estrogen replacement therapy?

Medical Treatment for Cushing Syndrome

Iatrogenic (Exogenous) Cushing Syndrome

For iatrogenic Cushing syndrome, immediately discontinue the causative glucocorticoid if medically feasible, followed by gradual tapering to prevent adrenal insufficiency. 1

Initial Management

• Stop all sources of exogenous glucocorticoids including oral, injectable, inhaled, and topical preparations 1
• Taper gradually rather than abrupt cessation to avoid precipitating adrenal crisis, as the hypothalamic-pituitary-adrenal (HPA) axis remains suppressed 1
• Consider switching to lower-dose inhaled steroids or alternative medications for the underlying condition if complete discontinuation is not possible 1

Management of Complications During Tapering

• Hypertension: Use spironolactone 25-50 mg daily or eplerenone 50-100 mg daily as first-line therapy, as these mineralocorticoid receptor antagonists directly counteract cortisol's mechanism of causing hypertension 1, 2
• Hyperglycemia: Initiate metformin as first-line, or consider GLP-1 receptor agonists or DPP-4 inhibitors; monitor blood glucose closely during taper as insulin requirements will decrease 1
• Osteoporosis prevention: Prescribe calcium 1000-1500 mg daily and vitamin D 800-1000 IU daily immediately for patients who received prednisone >7.5 mg daily for >3 months; initiate bisphosphonate therapy based on risk factors 1
• GI protection: Prescribe proton pump inhibitors (omeprazole 20 mg daily or equivalent) for patients on concomitant NSAIDs 1

Monitoring During Tapering

• Assess body weight to track resolution of central obesity 1
• Blood pressure at each visit 1
• Fasting glucose or HbA1c every 4-8 weeks 1
• Serum potassium if on mineralocorticoid antagonists, at each dose reduction (every 2-4 weeks) 1
• Morning cortisol level once daily dose reaches physiologic range (≤5 mg prednisone) to assess HPA axis recovery 1
• Monitor for clinical features of adrenal insufficiency including fatigue, weakness, nausea, hypotension, and hypoglycemia 3, 1

Special Considerations for Severe Cases

• Mifepristone (glucocorticoid receptor blocker) can be considered for severe cases of hypercortisolism with complications, though it requires careful monitoring as cortisol levels remain elevated and only clinical features can assess treatment response 3, 1
• Continue stress-dose coverage until HPA axis recovery is confirmed, which may take up to 12 months after prolonged high-dose therapy 1

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Endogenous Cushing Syndrome

For endogenous Cushing syndrome, adrenal steroidogenesis inhibitors are the first-line medical therapy, with ketoconazole, osilodrostat, or metyrapone as preferred agents. 3

First-Line Medical Therapy: Adrenal Steroidogenesis Inhibitors

Ketoconazole

• Dosing: 400-1200 mg/day orally, divided twice daily 3
• Efficacy: Approximately 65% achieve urinary free cortisol (UFC) normalization initially 3
• Advantages: Most commonly used due to easy availability and relatively tolerable toxicity profile 3
• Monitoring: Regular liver function tests required due to risk of serious hepatotoxicity; monitor for QTc prolongation 3
• Key considerations: Needs gastric acid for absorption (avoid proton pump inhibitors); careful review of other medications for drug-drug interactions is essential 3

Osilodrostat

• Dosing: 2-7 mg twice daily orally; maximum 30 mg twice daily 3
• Efficacy: 86% achieve UFC normalization in Phase 3 studies 3
• Advantages: Rapid decrease in UFC; FDA approved for Cushing's disease when pituitary surgery is not an option or has not been curative 3
• Monitoring: Risk for hypocortisolism, hypokalemia, and QTc prolongation; careful monitoring for hyperandrogenism in women (hirsutism, hypertension, hypokalemia) 3

Metyrapone

• Dosing: 500 mg/day to 6 g/day; dosing every 6-8 hours 3, 4
• Efficacy: Approximately 70% achieve UFC normalization; rapid decrease in UFC typically within first month 3, 2
• Monitoring: Monitor for hyperandrogenism with long-term use in women; possible cross-reactivity with 11-deoxycortisol in cortisol immunoassays 3

Treatment Selection Based on Disease Severity

Mild Disease

• Ketoconazole, osilodrostat, or metyrapone are typically preferred 3
• Cabergoline (0.5-7 mg weekly) may be used for mild Cushing's disease; approximately 40% achieve UFC normalization, though it is less effective and has slower onset 3

Moderate Disease with Residual Tumor

• Cabergoline or pasireotide may be preferred due to potential for tumor shrinkage 3
• Pasireotide (0.3-0.9 mg twice daily subcutaneously or 10-30 mg monthly LAR): 15-26% achieve UFC normalization with twice-daily dosing, 40% with monthly LAR 3
• Critical caveat: High rate of hyperglycemia with pasireotide requires careful patient selection 3

Severe Disease

• Rapid normalization of cortisol is the most important goal 3
• Osilodrostat and metyrapone provide response within hours; ketoconazole within a few days 3
• Etomidate (0.04-1 mg/kg/h IV) works rapidly for acute treatment in ICU settings; 100% achieve serum cortisol control (10-20 μg/dL) 3
• Combination therapy with multiple steroidogenesis inhibitors may be necessary 3
• Bilateral adrenalectomy should be considered if hypercortisolism is very severe and not responsive to optimized medical therapy to avoid worsening outcomes 3, 2

Glucocorticoid Receptor Blocker

Mifepristone

• Mechanism: Blocks cortisol action at the glucocorticoid receptor regardless of etiology 3
• Efficacy: After 24 weeks, 60% with concurrent diabetes or impaired glucose tolerance had ≥25% reduction in glucose area under the curve; 38% with hypertension had ≥5 mm Hg reduction in diastolic blood pressure 3
• Critical monitoring: Cortisol levels remain high; only clinical features can assess treatment response and adrenal insufficiency 3
• Adverse effects: Increased blood pressure with hypokalemia (may require spironolactone); endometrial hypertrophy and irregular menstrual bleeding; potential drug-drug interactions 3

Adjunctive Therapies

• Mineralocorticoid receptor antagonists (spironolactone or eplerenone) are the most effective antihypertensive agents, as they block mineralocorticoid receptor activation by excess cortisol 2
• Pituitary radiotherapy (fractionated or stereotactic) can be effective for presumed occult pituitary disease, particularly when combined with ketoconazole during the latency period 2

Monitoring Treatment Outcomes

• Multiple serial tests of both UFC and late-night salivary cortisol (LNSC) are used to monitor treatment outcomes 3
• UFC average: 2-3 collections 3
• LNSC: ≥2 on consecutive days 3

Special Patient Considerations

• Young women desiring pregnancy: Metyrapone may be preferred, though none of these drugs is specifically approved for use in pregnancy 3
• History of bipolar or impulse control disorder: Cabergoline should not be used 3
• Estrogen replacement therapy: Dexamethasone suppression test is not useful in women on estrogen-containing oral contraceptives; measuring dexamethasone level along with cortisol improves test interpretability 3

Common Pitfalls

• Do not assume all Cushing syndrome is exogenous; rule out endogenous causes before attributing symptoms solely to medication 1
• Avoid concomitant azole antifungals (itraconazole, voriconazole) with inhaled budesonide or fluticasone, as this significantly increases risk of exogenous Cushing syndrome 1
• Avoid methylprednisolone when combined with oral itraconazole due to higher risk of exogenous Cushing syndrome and subsequent adrenal insufficiency 1