Prenatal dexamethasone treatment does not prevent alterations of the hypothalamic pituitary adrenal axis in steroid 21-hydroxylase deficient mice

A major difficulty in the clinical management of congenital adrenal hyperpl asia (CAH) is adjustment of glucocorticoid doses to suppress ACTH and andro gens without causing iatrogenic hypercortisolism. The possibility that stru ctural alterations of the adrenal or a dysfunction of the hypothalamic pitu itary adrenal (HPA) axis caused by glucocorticoid deficiency during fetal L ife contribute to this problem was studied in 2 l-hydroxylase deficient mic e caused by deletion of the cytochrome P-450 21-hydroxylase gene. Homozygot es showed about 200-fold elevations in plasma progesterone, hyperplastic ad renal cortices lacking zonation, and structural alterations of adrenocortic al mitochondria. Histochemical studies showed increases in hypothalamic CRH messenger RNA (mRNA) and immunoreactive (ir) CRH, and pituitary POMC mRNA in homozygous mice. VP mRNA levels in PVN perikarya were normal, but irVP i n parvicellular terminals of the median eminence was increased in homozygot es. Prenatal dexamethasone treatment (0.5 to 2 mu g/day) prevented the incr eases in CRH mRNA, whereas dexamethasone only partially decreased POMC mRNA levels, and had no effect on serum progesterone levels. The data suggest t hat intrauterine glucocorticoid deficiency in CAH causes hyperactivity of t he hypothalamic-pituitary-corticotroph aids and insensitivity to glucocorti coid feedback. These studies in 21-hydroxylase deficient mice may provide n ew insights on the mechanism, clinical manifestations and management of som e types of human CAH.