Endocrine Abstracts

The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (21OHD). The treatment for classic (severe) 21OHD differs from treatment of most other types of adrenal insufficiency in that not only must one replace the glucocorticoid and mineralocorticoid deficiency but also attenuate the high adrenal-derived androgen production. In order to reduce the adrenocorticotropin (ACTH) driven androgen production, supraphysiologic doses of glucocorticoid and/or long-acting synthetic glucocorticoids are often used, to compensate for the short half-life of oral hydrocortisone. In particular, the early morning rise in ACTH and adrenal steroids is difficult to manage in 21OHD. Consequently, adults with 21OHD suffer from high rates of obesity, low bone density, and cushingoid features.

Several strategies have been employed recently to improve the control of androgen excess in 21OHD while limiting the dose of glucocorticoid to the physiologic replacement range. Modified-release forms of hydrocortisone have been developed to prolong its half-life, and hydrocortisone has been delivered via a continuous subcutaneous infusion system, to match the dosage and timing to the clinical need. Abiraterone acetate, the prodrug for the potent 17-hydroxylase/17,20-lyase (CYP17A1) inhibitor abiraterone, markedly lowered androgens in six adult women with 21OHD in a short-term study of 100–250 mg/day. The non-steroidal antagonist of the corticotropin-releasing factor receptor type 1 (CRFR1), NBI-77860, lowered ACTH and 17OHP in eight adult women with 21OHD. These therapies are all under further study to determine safety and efficacy in children and adults.

In addition, the pathways of androgen excess in 21OHD have been unclear, and the best biomarkers for diagnosis and titration of therapy are debated. Recent work suggests that the alternate or ‘backdoor’ pathway to dihydrotestosterone via 5α-reduced precursors significantly contributes to the androgen excess of infants with 21OHD. Specific 21- and 19-carbon steroids of adrenal origin might be better biomarkers of 21OHD than 17-hydroxyprogesterone and testosterone.