Congenital adrenal hyperplasia (CAH) is one of the most common genetic endocrine disorders. The classical form of the disease results from mutations in an enzyme called 21 hydroxylase, causing disrupted cortisol synthesis resulting in the release of ACTH from the pituitary gland and overproduction of 17-hydroxyprogesterone (17OHP), progesterone and adrenal androgens. The excess androgens can lead to virilization of females. In addition, many patients cannot synthesize sufficient aldosterone to maintain sodium balance resulting in a “salt wasting” form of the disease that can lead to hyponatremic dehydration. The most severe forms of the disease are life-threatening. CAH is an orphan disease that has an incidence estimated to be approximately 1 in 15,000 live births in North America (see Magic Foundation website). Corticosteroid replacement therapy is the standard of care in patients with CAH but is challenging, as excess glucocorticoid exposure is associated with complications, including short stature, obesity, hypertension, osteoporosis and an adverse metabolic profile. It has previously been suggested that CRF1 antagonists may provide a valuable therapeutic approach for the treatment of CAH32,33,34. In this regard, supporting evidence for CRF1 inhibition was provided by a non-peptide selective CRF1 antagonist that reduced ACTH and 17OHP in CAH patients35. Astressins offer an alternative means to treat CAH and maintain homeostasis in the stress axis with long-acting effects1.
1 Erchegyi et. al., (2016) J. Med. Chem., 59, 854-866
32 Merke et. al., (2002) Ann. Intern. Med., 136, 320-334
33 Zoumarkis et. al., (2006) Euro. J. of Endocrinol., 155, S85–S89
34 Grammatopoulo and Chrousos, (2002) Trends in Endocrinol. & Metab., 13, 346-444
35 Turcu et. al., (2016) J. Clin. Edocrinol. Metab., 101, 1174-1180