Nocturnal Dexamethasone versus Hydrocortisone for the Treatment of Children with Congenital Adrenal Hyperplasia

Abstract

Classic congenital adrenal hyperplasia affects approximately 1 in 15,000 children. Current treatment strategies using multiple daily doses of hydrocortisone lead to suboptimal outcomes. We tested the hypothesis that nocturnal administration of dexamethasone will suppress the hypothalamic-pituitary-adrenal axis more effectively than standard hydrocortisone treatment by blocking the inherent diurnal secretion of ACTH. We performed a pilot study of five prepubertal patients comparing CAH control during two 24-hour hospitalizations, one on hydrocortisone and the other on dexamethasone. The patterns of adrenal suppression differed markedly between hydrocortisone and nocturnal dexamethasone, with significant suppression of the morning rise in ACTH, 17-hydroxyprogesterone, and androstenedione while on dexamethasone. On hydrocortisone therapy, there is a marked variation in ACTH and adrenal hormones depending on time of day and timing of hydrocortisone administration. Longer-term studies are needed to investigate the lowest effective dose and potential toxicity of nocturnal dexamethasone to determine its utility as a therapy for CAH.

A follow-up history of young man with apparent cortisone reductase deficiency (ACRD) – several years after diagnosis

“…In prepubertal children hydrocortisone as physiological cortisol is chosen as the first-line treatment. It has the least impact on growth suppression as a short-acting glucocorticoid [14]. In our case, administration of oral hydrocortisone (17.5 mg daily) was discontinued after two months due to the lack of significant improvement of suppression of adrenal androgen production.…”

Twice Daily Compared to Three Times Daily Hydrocortisone in Prepubertal Children with Congenital Adrenal Hyperplasia

“…Pharmacokinetics of hydrocortisone and diurnal variation of adrenal products are also essential to consider when understanding optimal dosing intervals. There is remarkable synchronicity in the patterns of ACTH, 17OHP, and androstenedione production, peaking at about 4–10 a.m. [19]. There tends to be a decline in hormones in the afternoon regardless of when hydrocortisone is given [13].…”

“…Furthermore, studies of diurnal variation show lowest natural 17OHP levels between the hours of 1,600–2,000 [13, 15]. Dauber et al [19] has shown that some patients have a natural decline of 17OHP in the afternoon prior to any dose of HC being given. Therefore, adding another hydrocortisone dose at this time with another peak may be physiologically unnecessary [15].…”

“…It is also important to note that there is significant variability in adrenal hormone production depending on time of day, physical activity, daily stressors, and individual patient variability [16, 19]. As it is impractical to obtain multiple blood draws throughout the day in clinical practice, there must be some acknowledgment of fluctuation in 17OHP and androgen levels [19, 21]. In fact, levels may fluctuate through the day as much as 40-fold [19], and steady state cortisol levels are not only very difficult to obtain [22] but are also not physiologic.…”

Novel insights into glucocorticoid replacement therapy for pediatric and adult adrenal insufficiency

“…81 Nocturnal administration efficacy was investigated by Dauber and colleagues in five prepubertal children. 82 Dexamethasone given at 1/50 total HC daily dose proved to suppress more efficiently both morning ACTH and adrenal steroids than conventional HC replacement.…”