What is the recommended treatment and dosage of Metyrapone (metypyrapone) for Cushing's syndrome?

Metyrapone for Cushing's Syndrome

For Cushing's syndrome, initiate metyrapone at 1000-1500 mg/day in divided doses (typically 250-750 mg every 4-6 hours), then titrate upward based on urinary free cortisol levels to a typical maintenance dose of 1500-2250 mg/day, with maximum doses reaching 4000-6000 mg/day in severe cases. 1, 2

Dosing Algorithm

Initial Dosing Strategy

• Start at 1000-1040 mg/day divided into 2-4 doses for most patients with Cushing's syndrome 1
• For severe hypercortisolism (>5-fold elevated UFC), consider starting at 1500 mg/day 3
• The Endocrine Society recommends 15 mg/kg every 4 hours in pediatric patients 2

Dose Titration

• Escalate dose every 1-2 weeks based on urinary free cortisol (UFC) measurements until normalization occurs 1
• Target mean serum cortisol of 150-300 nmol/L (5.4-10.9 μg/dL) or UFC normalization 4
• Typical effective doses range from 1425-2127.5 mg/day (median 1500 mg/day) 1
• Maximum doses may reach 4000-6000 mg/day in refractory cases, particularly ectopic ACTH syndrome 5, 4

Disease-Specific Dosing

• Cushing's disease: Median effective dose 1375-2250 mg/day 5, 4
• Ectopic ACTH syndrome: Higher doses typically required, median 1500-4000 mg/day 5, 4
• Adrenal adenoma: Lower doses often sufficient, median 750-1750 mg/day 5, 4
• Adrenocortical carcinoma: Median 1250 mg/day 4

Clinical Efficacy and Timeline

Biochemical Response

• UFC normalization occurs in 47-75% of patients, with most studies showing 70-71% response rates 1
• Rapid onset: 67% reduction in UFC within the first month of treatment 1, 3
• Late-night salivary cortisol decreases by 57% within first month 3
• Sustained control maintained in 43-70% at 8-9 months 1, 3

Loss of Control ("Escape")

• Up to 18-23% of initially responsive patients lose biochemical control despite continued therapy 1
• Escape typically occurs at 6-9 months despite initial normalization 1
• Requires dose escalation or alternative therapy 1

Clinical Improvements

• 66-75% of patients show general clinical improvement including reduced blood pressure, improved glucose metabolism, decreased psychiatric symptoms, and improved muscle weakness 1
• Body weight reduction of approximately 4 kg after UFC normalization 3
• Clinical benefits typically follow biochemical control 5

Monitoring Requirements

Biochemical Monitoring

• Measure UFC and/or late-night salivary cortisol monthly during dose titration 3
• Check serum cortisol levels (9 AM or mean day-curve) to guide dosing 5, 4
• Critical caveat: 11-deoxycortisol (metyrapone's precursor metabolite) causes clinically significant cross-reactivity with cortisol in immunoassays, potentially falsely elevating cortisol measurements 1
• Use liquid chromatography-tandem mass spectrometry when available for accurate cortisol measurement 3

Safety Monitoring

• Monitor for signs of adrenal insufficiency (reported in 12% of patients) 1
• Check potassium levels regularly due to hypokalemia risk 1
• Assess for hyperandrogenic effects, particularly in women 1

Adverse Effects Profile

Common Side Effects (Manageable)

• Hirsutism: Most common in women, occurs in approximately 50% with prolonged use, may limit long-term therapy in females 1, 3
• Dizziness, arthralgia, fatigue: Frequently reported, typically mild 1
• Hypokalemia: Monitor and supplement as needed 1
• Nausea and gastrointestinal upset: Occurs in approximately 25% of patients, usually within 2 weeks of initiation or dose increase, reversible 1, 4

Less Common Side Effects

• Adrenal insufficiency: Reported in 12% of patients, manageable with dose reduction 1
• Abdominal pain and atopic dermatitis: Less frequently reported 1
• In children: Hyperandrogenism with advanced bone age 2

Important Safety Note

• Severe side effects are rare; most adverse events are mild and reversible with dose adjustment or discontinuation 3, 4
• No hepatotoxicity concerns (unlike ketoconazole) 1

Clinical Context and Treatment Role

When to Use Metyrapone

• Bridge therapy while awaiting definitive treatment (surgery or radiotherapy) 2, 6
• After surgical failure or when surgery is contraindicated 2, 6
• Preoperative medical therapy to reduce cortisol burden 6
• Long-term management after pituitary irradiation (83% adequate control over median 27 months) 5

Pharmacokinetics Considerations

• Rapid onset: Peak plasma concentration at 1 hour, clinical effect within 2 hours 7, 5
• Short half-life of 1.9 hours (active metabolite metyrapol: 4 hours) requires multiple daily doses 7
• Divided dosing (every 4-6 hours) maintains consistent enzyme inhibition 7, 5

Practical Implementation

Start with 250-500 mg three times daily (750-1500 mg/day total), measure UFC after 2-4 weeks, then increase by 250-500 mg/day increments every 1-2 weeks until UFC normalizes or maximum tolerated dose is reached. 1, 3 Monitor closely for adrenal insufficiency during titration, and warn female patients about potential hirsutism with prolonged use. 1