What is the recommended management of congenital adrenal hyperplasia (21‑hydroxylase deficiency) from infancy through adulthood?

Management of Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency)

All patients with congenital adrenal hyperplasia require lifelong dual hormone replacement with hydrocortisone for glucocorticoid deficiency and fludrocortisone for mineralocorticoid deficiency, with dosing titrated to suppress adrenal androgens while avoiding glucocorticoid overexposure. 1, 2

Glucocorticoid Replacement

Pediatric Dosing

• Administer hydrocortisone 6–10 mg/m² body surface area daily in split doses 3
• Give the first dose immediately upon waking and ensure the last dose is taken at least 6 hours before bedtime to mimic physiologic cortisol rhythm 3
• Divide total daily dose into 2-3 administrations to maintain more stable cortisol levels throughout the day 2, 4

Adult Dosing

• Prescribe hydrocortisone 15–25 mg daily (or cortisone acetate 18.75–31.25 mg daily) in split doses 3
• Use the lowest dose compatible with health and sense of well-being to minimize long-term glucocorticoid complications 3
• The goal is to balance adequate androgen suppression against the risks of chronic glucocorticoid overexposure, which include obesity, diabetes, hypertension, and decreased bone mineral density 5, 6

Critical Pitfall in Glucocorticoid Dosing

Supraphysiological glucocorticoid doses are commonly employed to suppress adrenal androgens, but this creates significant long-term cardiometabolic complications, impaired growth in children, and reduced quality of life 2, 5. Titrate to the minimum effective dose using both clinical assessment (growth velocity in children, menstrual regularity in females, signs of virilization) and biochemical monitoring 2, 6.

Mineralocorticoid Replacement

Standard Dosing

• Administer fludrocortisone 50–200 µg as a single daily dose 3
• Children and younger adults typically require higher doses within this range 3, 2
• The FDA-approved dosing for salt-losing adrenogenital syndrome is 0.1–0.2 mg (100–200 µg) daily 1

Salt Supplementation

• Advise patients to consume salt and salty foods ad libitum to support blood pressure and prevent salt-wasting crises 3
• Specifically instruct patients to avoid liquorice and grapefruit juice, which interfere with mineralocorticoid metabolism 3

Monitoring and Dose Adjustment

• If essential hypertension develops, reduce the fludrocortisone dose but do not discontinue it entirely 3, 2
• Monitor blood pressure, serum electrolytes (sodium and potassium), and plasma renin activity to guide fludrocortisone titration 3

Stress Dosing for Acute Illness and Procedures

Minor to Moderate Illness

• Patients must receive education to double or triple their oral hydrocortisone dose during febrile illnesses, vomiting, diarrhea, or other physiologic stressors 3, 7
• Provide all patients with supplies for self-injection of parenteral hydrocortisone for emergencies 3

Surgery and Invasive Procedures

• Administer intravenous or intramuscular hydrocortisone 100 mg immediately before surgery, followed by 100 mg every 6–8 hours until the patient recovers 3
• Increase oral doses postoperatively as the patient transitions back to maintenance therapy 3

Pregnancy and Delivery

• Make small adjustments to hydrocortisone and fludrocortisone doses during pregnancy, particularly in the last trimester 3
• Give parenteral hydrocortisone during labor and delivery to prevent adrenal crisis 3, 6

Management of Adrenal Crisis

Treat suspected adrenal crisis immediately—never delay treatment for diagnostic procedures, as mortality occurs in 0.5 per 100 patient-years 7

Immediate Treatment Protocol

• Administer intravenous or intramuscular hydrocortisone 100 mg immediately, followed by 100 mg every 6–8 hours until recovery 3
• Infuse isotonic (0.9%) sodium chloride solution at an initial rate of 1 L/hour until hemodynamic improvement is achieved 3
• Secure blood samples for cortisol and ACTH measurement prior to treatment if possible, but do not delay therapy 3
• Once treatment is initiated, investigate the underlying precipitant (most commonly infection) 3, 4

Biochemical Monitoring to Guide Therapy

Steroid Biomarkers

• Measure 17-hydroxyprogesterone (17-OHP) and androstenedione to assess adequacy of androgen suppression 2, 4
• Elevated 17-OHP indicates undertreatment with glucocorticoids, while suppressed levels may indicate overtreatment 2
• Interpretation of biomarkers must account for age, sex, clinical context, and time of day due to circadian variation 2

Electrolytes and Renin

• Check serum sodium and potassium at baseline and at least annually to ensure adequate mineralocorticoid replacement 3
• Plasma renin activity helps guide fludrocortisone dosing: elevated renin suggests inadequate mineralocorticoid replacement 3, 2

Age-Specific Treatment Goals

Infancy and Childhood

• Prevent adrenal crisis and sudden death 7, 4
• Achieve normal linear growth velocity and bone maturation without premature epiphyseal closure 6, 4
• Suppress adrenal androgens to prevent premature adrenarche and growth acceleration 6, 4

Adolescence

• Ensure normal timing of puberty and prevent symptoms of hyperandrogenism (hirsutism, acne, menstrual irregularities) 6
• Address treatment adherence issues that commonly arise during adolescence due to increasing independence 6
• Monitor for complications from previous genital surgery in females with classic CAH 6

Adulthood

• Preserve menstrual regularity and fertility in females 6
• Prevent long-term cardiometabolic complications including obesity, diabetes, hypertension, and decreased bone mineral density 5, 6
• Provide education and support regarding sexuality, atypical genitalia, and gender identity issues 6

Androgen Replacement

There is insufficient evidence of benefit to recommend routine replacement of adrenal androgens (DHEA) in patients with congenital adrenal hyperplasia 3

Long-Term Follow-Up

Annual Assessment

• Review patients at least annually with assessment of health, well-being, weight, blood pressure, and serum electrolytes 3
• Monitor for development of new autoimmune disorders, particularly hypothyroidism, which commonly coexists with autoimmune adrenal insufficiency 3

Bone Health Monitoring

• Assess bone mineral density every 3–5 years to detect complications of chronic glucocorticoid therapy 3
• This is particularly important given the lifelong exposure to glucocorticoids in CAH patients 5, 6

Additional Monitoring in CAH

• Screen for adrenal rest tumors, especially in males with inadequate androgen suppression 6, 4
• Assess for cardiometabolic risk factors including insulin resistance, dyslipidemia, and hypertension 5, 6, 4

Patient Education and Safety Measures

All patients with congenital adrenal hyperplasia must wear medical alert identification jewelry and carry a steroid emergency card at all times 3, 7

• Provide comprehensive education on managing daily medications and recognizing situations requiring stress dosing 3, 7
• Ensure patients and caregivers can recognize early signs of adrenal crisis (severe hypotension, confusion, vomiting, collapse) 3, 7
• Supply emergency hydrocortisone injection kits with clear instructions for self-administration 3