Alternative Strategies for the Treatment of Classical Congenital Adrenal Hyperplasia: Pitfalls and Promises

Appropriate treatment of children with congenital adrenal hyperplasia (CAH) is challenging because it requires the simultaneous and continuous control of a number of physiologic mechanisms. The molecular defect, usually in the enzyme 21-hydroxylase (21-OH), leads to a decreased production of cortisol that removes the normal negative feedback to pituitary corticotrophs [1, 2]. Consequently, adrenocorticotropic hormone (ACTH) secretion is increased and drives the shunting of cortisol precursors to androgen synthetic pathways [3]. To control CAH, therefore, it is necessary both to adequately replace glucocorticoids (and mineralocorticoids in salt-wasting forms) and to prevent the production of excess androgens.Adequate control of CAH requires life-long glucocorticoid (GC) replacement sufficient to maintain adrenal androgen suppression. Determining the "optimal level" of GC replacement, however, can be elusive. Undertreatment leads to adrenal insufficiency and androgen excess, while over-treatment leads to obesity, iatrogenic Cushing's syndrome, and osteoporosis [4–10]. Both under- and over-treatment of CAH can result in diminished adult height [11–14]. The final effect on bone age (BA) maturation will reflect the integrated effect of GCs and adrenal androgens over time, especially in the prepubertal child.We present an overview of new/potential treatment strategies aimed at improving the outcome in patients with CAH. Included are strategies, such as GnRH analogs, antiandrogens, and aromatase inhibitors, for which there are clinical studies completed and/or ongoing to support their use in CAH. For other approaches, such as bilateral adrenalectomy and circadian hydrocortisone treatment, the treatment strategies have already been implemented in the clinical arena albeit in a small number of cases, but formal trials are lacking. Finally, we have included several regimens that have been utilized in other conditions and extrapolated for use in CAH.Corticotropin releasing hor