How is classic congenital adrenal hyperplasia (21‑hydroxylase deficiency) managed, including glucocorticoid and mineralocorticoid dosing for infants, children, adolescents, and adults, and stress‑dose adjustments?

Management of Classic Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency)

Classic CAH requires lifelong glucocorticoid and mineralocorticoid replacement, with hydrocortisone as the preferred glucocorticoid at age-specific doses and fludrocortisone for mineralocorticoid replacement, adjusted by clinical and biochemical monitoring.

Glucocorticoid Replacement

Infants and Young Children

• Start hydrocortisone at 15 mg/m²/day divided into three doses (e.g., upon awakening, midday, and late afternoon—at least 6 hours before bedtime) 1, 2
• Infants require lower doses than older children due to the predominance of non-aromatizable androgens 3
• Critical pitfall: The glucocorticoid activity of fludrocortisone contributes to total glucocorticoid exposure in infants and must be factored into dosing to avoid growth suppression 3
• Titrate based on growth velocity, 17-hydroxyprogesterone levels, and androgen profiles 1, 2

Adolescents and Adults

• Hydrocortisone 15–25 mg/day remains the preferred regimen, divided into 2–3 doses 4, 5
• Three-dose schedule: 10 mg at 07:00,5 mg at 12:00, and 2.5–5 mg at 16:00 4
• Two-dose schedule (for adherence): 15 mg at 07:00 + 5 mg at 12:00, or 10 mg + 10 mg 4
• Adolescents may require dose adjustments due to altered hydrocortisone clearance during puberty 1
• Avoid exceeding 25–30 mg/day as this enters the supraphysiological range and increases risk of iatrogenic Cushing's syndrome 5

Alternative Glucocorticoids

• Cortisone acetate 25–37.5 mg/day in divided doses may substitute when hydrocortisone is unavailable (requires hepatic conversion) 4
• Prednisolone 4–5 mg/day is reserved for adherence problems or hydrocortisone intolerance 4, 5
• Dexamethasone must be avoided due to prolonged activity and high risk of overtreatment 4

Mineralocorticoid Replacement

Dosing by Age

• Infants and children: Start fludrocortisone at 150 µg/m²/day (up to 500 µg/day may be needed) 1, 4
• Adolescents and adults: 50–200 µg once daily in the morning 4, 6
• Taken as a single morning dose upon awakening 4, 6

Monitoring and Adjustment

• Titrate to plasma renin activity (target upper half of reference range), serum sodium, potassium, and blood pressure 4, 6, 1
• Under-replacement is common and leads clinicians to inappropriately increase glucocorticoids, raising adrenal crisis risk 4, 6
• Signs of under-replacement: orthostatic hypotension, salt cravings, lightheadedness 6
• Signs of over-replacement: peripheral edema, hypertension 6
• If hypertension develops, reduce (never stop) fludrocortisone and add a vasodilator 4, 6

Special Considerations

• Third trimester of pregnancy: Increase fludrocortisone due to progesterone's anti-mineralocorticoid effects 4, 6
• Advise unrestricted salt intake; avoid potassium-containing salt substitutes 4, 6
• Avoid liquorice and grapefruit juice (potentiate mineralocorticoid effect) 6

Stress-Dose Adjustments

Minor Illness or Physical Stress

• Double or triple the usual hydrocortisone dose during febrile illness, gastroenteritis, or minor procedures 4

Major Stress, Surgery, or Adrenal Crisis

• Immediate hydrocortisone 100 mg IV bolus, followed by 100 mg every 6–8 hours (or 200 mg/24h continuous infusion) 7, 4
• Concurrent rapid IV fluid resuscitation: 1 L/hour isotonic saline initially, then 3–4 L over 24 hours with hemodynamic monitoring 7
• Taper parenteral hydrocortisone over 1–3 days to oral maintenance once stable 7
• Resume fludrocortisone when hydrocortisone dose falls below 50 mg/day 7
• All patients must carry emergency injectable hydrocortisone and be trained in self-administration 4

Perioperative Management

• Hydrocortisone 100 mg IV at induction, followed by 200 mg/24h infusion during surgery 7
• Double the oral replacement dose for 48 hours to 1 week postoperatively depending on recovery (e.g., if usual dose is 10-5-5 mg, give 20-10-10 mg) 7

Monitoring Adequacy of Replacement

Clinical Assessment (Primary Tool)

• Plasma ACTH and serum cortisol are NOT useful for dose titration 7, 4
• Over-replacement: weight gain, insomnia, peripheral edema 7, 4
• Under-replacement: lethargy, nausea, poor appetite, weight loss, increased/uneven pigmentation 7, 4
• Assess energy patterns throughout the day, mental concentration, daytime somnolence 4

Biochemical Monitoring

• Children: Monitor 17-hydroxyprogesterone and androgen profiles to titrate glucocorticoid dose 1, 2
• Adults: Serum sodium, potassium, and plasma renin activity for mineralocorticoid adequacy 4, 6
• Growth velocity in children is the most sensitive indicator of appropriate dosing 1, 3

Annual Follow-Up

• Measure weight, blood pressure (supine and standing), serum electrolytes 4, 6
• Bone density every 3–5 years to detect chronic glucocorticoid excess 5

Drug Interactions Requiring Dose Adjustment

Medications Increasing Hydrocortisone Requirements

• Anti-epileptics/barbiturates, rifampin, etomidate, topiramate (induce CYP3A4) 7, 4

Medications Decreasing Hydrocortisone Requirements

• Grapefruit juice and liquorice (inhibit metabolism) 4, 6

Medications Affecting Fludrocortisone

• Diuretics, acetazolamide, NSAIDs, carbenoxolone: avoid or use cautiously (blunt mineralocorticoid effect) 4, 6
• Drospirenone-containing contraceptives: may require increased fludrocortisone 4, 6

Patient Education and Safety

• Wear Medic-Alert identification jewelry and carry a steroid emergency card 7, 4
• Train in self-administration of intramuscular hydrocortisone for emergencies 7, 4
• Educate on recognizing adrenal crisis symptoms and when to seek immediate care 7
• Delays in emergency hydrocortisone administration can be fatal 7

Duration of Treatment

• Lifelong replacement is required for all patients with classic CAH 7, 1

Common Pitfalls to Avoid

• Masking inadequate mineralocorticoid replacement with excessive glucocorticoids increases adrenal crisis risk and iatrogenic Cushing's syndrome 4, 5, 6
• Failing to account for fludrocortisone's glucocorticoid activity in infants, leading to growth suppression 3
• Abruptly stopping fludrocortisone when hypertension develops (reduce dose instead and add vasodilator) 4, 6
• Using dexamethasone for maintenance therapy 4
• Inadequate stress-dosing during illness or surgery, precipitating adrenal crisis 7