Endocrine Abstracts

Since the pioneering work of Lawson Wilkins in the 1950s, glucocorticoids have been the cornerstone of therapy for patients with congenital adrenal hyperplasia, particularly classic 21-hydroxylase deficiency (21OHD). Glucocorticoids are used both to replace the cortisol deficiency and to provide the missing negative feedback to the hypothalamic-pituitary-adrenal (HPA) axis, to lower the production of unwanted precursors, which are metabolized to androgens. Substantially higher than physiologic glucocorticoid dosing with late-day dosing is often required to correct the adrenal-derived androgen excess, allow normal growth and development, and maintain fertility. This glucocorticoid exposure, however, leads to long-term complications in adults, such as obesity, mood disorders, bone loss, and cardiometabolic dysfunction. Alterative pharmacologic targets have been explored to reduce glucocorticoid exposure in 21OHD. Crinecerfont, a corticotropin-releasing factor type 1 receptor (CRF1) antagonist was trialed in placebo-controlled studies for children and adults with 21OHD. The pediatric trial showed a reduction in androstenedione (A4) of ~50% after 4 weeks, which allowed glucocorticoid dose reduction of 18%, with ~25% A4 reduction by week 28. In the adult trial, A4 also fell ~50% after 4 weeks, which enabled a 27.3% (17% placebo-controlled) glucocorticoid dose reduction, while maintaining A4 at or below baseline. Additional therapeutics targeting the HPA axis are in trials, particularly atumelnant, an orally administered MC2R (ACTH receptor) antagonist, and Lu AG13909, an antibody to ACTH. These treatments might allow simplified and less toxic glucocorticoid regimens for children and adults with 21OHD, to improve short- and long-term outcomes.