Novel treatment approaches: prepubertal adrenal steroid blockade in children with congenital adrenal hyperplasia

Clinical Center

Investigators

Abstract

Despite decades of study, the growth and development of most children with CAH remain sub-optimal. Retrospective studies indicate that the adult height of treated CAH patients is relatively independent of the degree of adrenal androgen control suggesting that both hyperandrogenism and hypercortisolism contribute to the observed adult short stature. The investigational regimen of an antiandrogen (flutamide), an aromatase inhibitor (letrozole), and reduced hydrocortisone dose vs. conventional treatment was shown short-term (2 year) to normalize linear growth rate and bone maturation. A prospective long-term randomized parallel study to adult height of an antiandrogen (flutamide) and an aromatase inhibitor (letrozole), and reduced hydrocortisone dose vs. conventional treatment is completed and no differences were found between the investigational and control groups in final adult height, the primary outcome. However, growth rate and rate of bone maturation were reduced in the investigational group prior to puberty, despite lower hydrocortisone dose (7.6 [1.5] vs 15.0 [3.6] mg/m2/day, P < .001), and improvement in predicted adult height appeared greater at pubertal onset (P = .049) compared to standard therapy, reflecting the importance of obtaining adult height in studies of growth enhancing therapies, which is usually not done. Pubertal height gain accounts for approximately 20% of adult height in healthy individuals. Despite clinical trials, aromatase inhibitors are commonly used in children with CAH in an attempt to optimize adult height. Our data does not support this. In addition, our study provides evidence that physiologic glucocorticoid replacement (approximately 8 mg/m2/day) is safe in growing children and even moderate increases in glucocorticoid dosing may play a role in growth suppression during puberty. Exploratory data analysis of secondary outcomes is underway.