Purpose of Steroid Replacement in Congenital Adrenal Hyperplasia
Steroid replacement therapy in CAH serves three critical functions: replacing deficient cortisol to prevent life-threatening adrenal crises, suppressing excess ACTH-driven androgen production that causes virilization, and replacing mineralocorticoids (in salt-wasting forms) to maintain blood pressure and electrolyte balance. 1, 2, 3
Primary Therapeutic Goals
1. Glucocorticoid Replacement for Cortisol Deficiency
CAH results from enzyme deficiencies (most commonly 21-hydroxylase) that block cortisol synthesis, creating absolute glucocorticoid deficiency that requires lifelong replacement. 4, 5
Glucocorticoids are essential for survival—they enable the body to respond to physiological stress, maintain blood pressure, regulate glucose metabolism, and modulate immune responses. 1
Without adequate replacement, patients face adrenal crises characterized by severe hypotension, shock, electrolyte abnormalities, and potentially death. 6
Standard maintenance dosing uses hydrocortisone 15-25 mg daily in divided doses (typically 10 mg morning, 5 mg midday, 2.5-5 mg afternoon) to approximate physiological cortisol secretion patterns. 6
2. Suppression of Excess Androgen Production
The enzyme block in CAH causes accumulation of steroid precursors that are shunted into androgen synthesis pathways, producing excess testosterone and androstenedione. 3, 5
Glucocorticoid therapy suppresses ACTH secretion from the pituitary, which in turn reduces the drive for adrenal steroid production and decreases androgen excess. 3, 5
In females, uncontrolled androgen excess causes virilization including ambiguous genitalia at birth, premature pubic hair, accelerated bone maturation, short final adult height, irregular menses, and infertility. 4, 7
In males, excess androgens cause premature sexual development, accelerated bone age, and compromised final height. 4
The therapeutic challenge is achieving androgen suppression without causing iatrogenic hypercortisolism—strict normalization of 17-hydroxyprogesterone and androstenedione often requires glucocorticoid doses that cause metabolic complications. 3
3. Mineralocorticoid Replacement in Salt-Wasting Forms
Approximately 75% of patients with classic CAH have complete 21-hydroxylase deficiency affecting both cortisol and aldosterone synthesis, requiring fludrocortisone replacement. 2, 6
Fludrocortisone 50-200 µg daily (sometimes up to 500 µg in children and young adults) replaces deficient aldosterone to maintain sodium retention, blood pressure, and potassium excretion. 6
Mineralocorticoid replacement is evaluated by assessing salt cravings, orthostatic blood pressure, peripheral edema, and plasma renin activity. 6
Patients require unrestricted sodium salt intake as a third essential component of therapy alongside glucocorticoid and mineralocorticoid replacement. 6
Critical Treatment Principles
Stress Dosing Requirements
During illness, injury, or surgery, cortisol requirements increase up to five-fold (approximately 100 mg/day) compared to normal production of 20 mg/day. 8
For major stress or surgery: hydrocortisone 100 mg IV bolus followed by 50-100 mg every 6 hours or continuous infusion of 200 mg over 24 hours. 8
For minor illness or fever: double the regular oral maintenance dose. 8
All patients must carry emergency injectable hydrocortisone 100 mg with self-injection training and wear medical alert identification. 6, 8
Monitoring and Adjustment Challenges
Current glucocorticoid regimens cannot optimally replicate normal physiological cortisol rhythms, and both over-treatment and under-treatment are commonly reported. 7
Modified-release hydrocortisone formulations (Plenadren, Efmody) attempt to better mimic circadian cortisol patterns, but recent evidence suggests they may provide suboptimal androgen control in CAH despite improving metabolic profiles. 9, 5
Biochemical monitoring uses 17-hydroxyprogesterone, androstenedione, and testosterone levels, though newer biomarkers like 11-ketotestosterone may prove more specific. 3
Long-Term Complications Requiring Vigilance
Important long-term health issues affect both disease control and treatment side effects: compromised final adult height, fertility problems, cardiometabolic risk, bone metabolism abnormalities, and reduced quality of life. 4
Glucocorticoid over-replacement causes weight gain, hypertension, glucose intolerance, osteoporosis, and increased cardiovascular risk. 9, 4
Under-replacement leads to poor androgen control, virilization progression, accelerated bone maturation, and recurrent adrenal crises. 6, 4
Patients require lifelong multidisciplinary follow-up with regular monitoring of growth parameters, bone age, metabolic markers, fertility assessment, and psychological support. 4