Advances in Pediatric Endocrinology

The most common form of congenital adrenal hyperplasia (CAH) is 21-hydroxylase deficiency, which causes insufficient mineralocorticoid and glucocorticoid production, leading to an increase in androgen production. Patients with classical CAH have a more severe enzyme deficiency while patients with nonclassical CAH have a milder enzyme defect. In children, hydrocortisone has been proven to optimize adrenal control while having the least impact on growth. The aims of treatment are to not only replace cortisol but to also minimize excess adrenal androgen production, thereby enhancing growth, adult height prognosis, appropriate onset of puberty, menstrual cycles, and fertility. However, chronically, high-dose glucocorticoid treatment in children may lead to a Cushingoid appearance and growth suppression. Therefore, it is vitally important that management of CAH be balanced with known risks of protracted steroid treatment in the pediatric population.

The Endocrine Society published updated CAH guidelines with proposed glucocorticoid dosing in 2018 cautioning providers against doses exceeding 20 mg/m2/day in infants or 15 to 17 mg/m2/day in children secondary to concerns of growth suppression. The guidelines state that hydrocortisone should be given three times daily (TID) in growing children and 2 to 3 times daily in fully grown patients. A recent study found that TID hydrocortisone is the most common pediatric CAH regimen, however, there is no cited evidence for the superiority of TID over two times daily (BID) dosing of hydrocortisone in children.

Karen Lin Su, MD, Medical Director, and Oksana Lekarev, DO, Associate Medical Director of the Comprehensive Care Center for Congenital Adrenal Hyperplasia at Weill Cornell Medicine, and their pediatric endocrinology colleagues at NewYork-Presbyterian Komansky Children’s Hospital, have used BID dosing of hydrocortisone as a therapeutic option for children with CAH for decades. They find that the convenience of this regimen helps ensure patient compliance and that biochemical CAH parameters as well as clinical parameters of growth, clinical hyperandrogenism, and metabolic risk are well controlled with this regimen. They hypothesized that dosing of BID rather than TID hydrocortisone could reduce the total daily steroid dose and, in turn, reduce metabolic risk factors while still maintaining adequate adrenal control.

“Our study is unique in its ability to highlight that BID dosing does not appear to impair any growth or metabolic parameters in children with congenital adrenal hyperplasia in comparison with TID dosing.” — Dr. Oksana Lekarev

To that end, they conducted a retrospective chart review of 128 visits by 36 individual patients of prepubertal children with classical CAH at NewYork-Presbyterian Komansky Children’s Hospital between March 2007 and February 2020. Adrenal control, growth, and metabolic data were extracted in those taking hydrocortisone BID versus TID. At each visit, the researchers compared testosterone levels, androstenedione levels, annualized growth velocity, bone age, blood pressure, BMI, and total daily steroid dose in those taking glucocorticoids BID (n = 77) versus TID (n = 51).

The results of their study, which were published in Hormone Research in Paediatrics, Issue 1, 2022, demonstrated that there was:

• No difference overall in adrenal control (8 percent versus 18 percent poor control) or testosterone levels (9.65 ng/dL versus 7.62 ng/dL) between the BID versus TID groups
• No difference in growth velocity (6.86 versus 6.32 cm/year) or bone age advancement (11.3 versus 5.91 months) between the groups
• No difference in daily steroid dose (12.1 versus 11.7 mg/m2/day), BMI Z- score (0.43 versus 0.31), or systolic blood pressure percentile (65.5 versus 61.7)

Drs. Lekarev and Su and their NewYork-Presbyterian Komansky Children's Hospital colleagues concluded that there is no clear advantage to TID over BID hydrocortisone dosing in the treatment of prepubertal children with CAH. Regarding adrenal control, BID dosing does not appear to detract from overall adrenal control biochemically nor does it appear to impact growth or bone age advancement. In addition, patients on TID dosing are not on a higher daily glucocorticoid dose compared to patients on BID dosing. In addition, prepubertal children on TID hydrocortisone do not have apparent adverse outcomes regarding metabolic parameters. Therefore, the study authors recommend that dosing regimens should be patient-centered with consideration of individual schedules and the family’s ability to regularly maintain the medication schedule as prescribed.