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 hyperplasia (CAH) is adjustment of glucocorticoid doses to suppress ACTH and androgens without causing iatrogenic hypercortisolism. The possibility that structural alterations of the adrenal or a dysfunction of the hypothalamic pituitary adrenal (HPA) axis caused by glucocorticoid deficiency during fetal life contribute to this problem was studied in 21-hydroxylase deficient mice caused by deletion of the cytochrome P-450 21-hydroxylase gene. Homozygotes showed about 200-fold elevations in plasma progesterone, hyperplastic adrenal cortices lacking zonation, and structural alterations of adrenocortical 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 in parvicellular terminals of the median eminence was increased in homozygotes. Prenatal dexamethasone treatment (0.5 to 2 microg/day) prevented the increases in CRH mRNA, whereas dexamethasone only partially decreased POMC mRNA levels, and had no effect on serum progesterone levels. The data suggest that intrauterine glucocorticoid deficiency in CAH causes hyperactivity of the hypothalamic-pituitary-corticotroph axis and insensitivity to glucocorticoid feedback. These studies in 21-hydroxylase deficient mice may provide new insights on the mechanism, clinical manifestations and management of some types of human CAH.
Tajima
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Section on Endocrine Physiology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1862, USA.
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Bornstein
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Aguilera
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D000311:Adrenal Glands / Q000473:pathology; D000312:Adrenal Hyperplasia, Congenital; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005333:Fetus / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism* / Q000473:pathology*; D007031:Hypothalamus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010902:Pituitary Gland / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism* / Q000473:pathology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D011374:Progesterone / Q000097:blood; D014667:Vasopressins / Q000378:metabolism
D005938:Glucocorticoids; D014667:Vasopressins; D011374:Progesterone; D011333:Pro-Opiomelanocortin; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone