What is the best management approach for Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency?

Management of Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

All patients with CAH due to 21-hydroxylase deficiency require lifelong dual hormone replacement with both glucocorticoids and mineralocorticoids, with hydrocortisone as the preferred glucocorticoid in children and most adults. 1, 2

Glucocorticoid Replacement

Dosing Strategy

• Hydrocortisone (HC) is the preferred glucocorticoid, dosed at 15-25 mg daily in adults (or 18.75-31.25 mg cortisone acetate equivalent) 1
• In children, use 6-10 mg/m² body surface area per day of hydrocortisone 1
• Administer in split doses: first dose immediately upon waking, last dose at least 6 hours before bedtime 1
• Use the lowest dose compatible with health and sense of well-being to minimize long-term glucocorticoid complications 1

The rationale for hydrocortisone over synthetic glucocorticoids is critical—HC more closely mimics physiological cortisol secretion and has a shorter half-life, reducing the risk of growth suppression in children and metabolic complications in adults 3, 4. While prednisolone and dexamethasone have been studied, evidence suggests prednisolone may lead to better bone maturation control in prepubertal children, but hydrocortisone remains first-line due to its superior safety profile 3.

Monitoring and Adjustment

• Titrate doses based on 17-hydroxyprogesterone (17-OHP) and androstenedione levels, though these markers have limitations and should be interpreted alongside clinical parameters 4, 5
• During puberty, clearance of hydrocortisone changes, requiring dose adjustments and potentially altered dosing schedules 4
• Avoid over-treatment: supraphysiological glucocorticoid doses lead to obesity, osteoporosis, cardiovascular disease, and reduced quality of life 6, 5, 7

Mineralocorticoid Replacement

Fludrocortisone is essential for all patients with classic CAH to prevent salt-wasting crises and maintain blood pressure 1, 2.

Dosing Protocol

• Standard adult dose: 50-200 µg daily as a single morning dose 1
• Children and young adults require higher doses, often 150 µg/m²/day initially 4
• For salt-losing adrenogenital syndrome specifically: 0.1-0.2 mg (100-200 µg) daily 2
• If essential hypertension develops, reduce (but do not stop) fludrocortisone dose to 0.05 mg daily 1

Monitoring Parameters

• Assess plasma renin activity (PRA) and blood pressure to guide fludrocortisone dosing 4
• Advise patients to consume salt and salty foods ad libitum 1
• Avoid liquorice and grapefruit juice, which potentiate mineralocorticoid effects 1
• Monitor serum electrolytes at least annually 1

Critical Safety Measures

Patient Education and Emergency Preparedness

Every patient must have the following in place 1:

• Medical alert identification jewelry (bracelet or necklace)
• Steroid emergency card carried at all times
• Injectable hydrocortisone supplies for self-administration during adrenal crisis
• Education on stress-dosing: double or triple oral doses during minor to moderate concurrent illnesses 1

Adrenal Crisis Management

Adrenal crisis is life-threatening and requires immediate treatment without delay 1, 8:

• Administer 100 mg hydrocortisone IV or IM immediately, followed by 100 mg every 6-8 hours until recovery 1
• Infuse 0.9% sodium chloride solution at 1 L/hour initially until hemodynamic improvement 1
• Never delay treatment for diagnostic procedures if adrenal crisis is suspected 1, 8
• Identify and treat the underlying precipitant (infection, trauma, surgery) once treatment is initiated 1

Stress Dosing for Surgery and Procedures

• Surgery and invasive procedures require IV or IM hydrocortisone and increased oral doses 1
• During pregnancy, small dose adjustments may be needed, particularly in the third trimester when progesterone's anti-mineralocorticoid effects increase fludrocortisone requirements 1
• During delivery, give 100 mg hydrocortisone IV bolus, repeated every 6 hours as needed 1

Diagnostic Confirmation

Before initiating lifelong treatment, confirm the diagnosis 1:

• Measure 21-hydroxylase autoantibodies if autoimmune etiology is suspected 1
• Obtain urine steroid profile and sequence steroidogenic genes (CYP21B) to confirm 21-hydroxylase deficiency 1
• In males, measure very long-chain fatty acids (VLCFA) to exclude adrenoleukodystrophy 1

Long-Term Follow-Up

Annual review is mandatory and should include 1:

• Assessment of health, well-being, weight, and blood pressure
• Serum electrolytes measurement
• Screening for new autoimmune disorders, particularly hypothyroidism
• Bone mineral density monitoring every 3-5 years to assess for glucocorticoid-induced osteoporosis
• Evaluation for testicular or ovarian adrenal rest tumors in adults, though specific screening intervals are not well-established 7

Common Pitfalls to Avoid

• Do not use topical or systemic glucocorticoid monotherapy without mineralocorticoid replacement in classic CAH—this leads to recurrent adrenal crises 1
• Do not stop fludrocortisone if hypertension develops—reduce the dose instead and add vasodilators if needed 1
• Do not rely solely on 17-OHP levels for monitoring—these are subject to variability and should be combined with clinical assessment and other androgens 5
• Avoid diuretics, acetazolamide, NSAIDs, and drospirenone-containing contraceptives as they interact with fludrocortisone 1
• Do not prescribe adrenal androgen (DHEA) replacement routinely—there is insufficient evidence of benefit 1

The evidence base for CAH management remains limited, with most trials being small, short-duration, and of moderate quality 3. Novel therapies including modified-release hydrocortisone formulations and adjunct agents to control androgens are under investigation but not yet standard of care 6, 5.