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Effects of Maternal Dexamethasone Treatment in Early Pregnancy on Pituitary-Adrenal Axis in Fetal Sheep

Department of Physiology and Obstetrics and Gynecology (T.B., W.L., M.C.A., S.G.M., J.R.G.C.), University of Toronto, Toronto, Ontario M5S 1A8, Canada; Charité Campus Virchow-Klinikum (T.B.), Kliniken für Geburtsmedizin, 13353 Berlin, Germany; School of Women’s and Infants’ Health (S.L., D.M.S., T.J.M.M. G.P., I.N., J.P.N., J.R.G.C.) and Women and Infants Research Foundation (D.M.S., T.J.M.M., G.P., J.P.N.), The University of Western Australia, King Edward Memorial Hospital, Subiaco, Western Australia 6008, Australia; The Liggins Institute (D.M.S.), University of Auckland, and The National Research Centre for Growth and Development, Private Bag 92019, Auckland, New Zealand; and Department of Physiology (T.J.M.M.), Monash University, Clayton, Victoria 3800, Australia

Address all correspondence and requests for reprints to: Prof. J. R. G. Challis, President and CEO, Michael Smith Foundation for Health Research, Suite 200, 1285 West Broadway, Vancouver, British Columbia V6H 3X8, Canada. E-mail: jchallis{at}msfhr.org.

Fetal exposure to elevated levels of bioactive glucocorticoids early in gestation, as in suspected cases of congenital adrenal hyperplasia, may result in adverse neurological events. Fetal hypothalamic-pituitary-adrenal development and function may be involved. We investigated immediate and long-term effects of maternal dexamethasone (DEX) administration early in pregnancy on fetal growth and pituitary-adrenal activity in sheep. Pregnant ewes carrying singleton fetuses (total n = 119) were randomized to control (2 ml saline/ewe) or DEX-treated groups (im injections of 0.14 mg/kg ewe weight · 12 h) at 40–41 d gestation (dG). At 50, 100, 125, and 140 dG, fetal plasma and tissues were collected. DEX-exposed fetuses were lighter than controls at 100 dG (P < 0.05) but not at any other times. Fetal plasma ACTH levels and pituitary POMC and PC-1 mRNA levels were similar between groups. Fetal plasma cortisol levels were significantly reduced after DEX exposure in both male and female fetuses at 50 dG (P < 0.05), were similar at 100 and 125 dG, but were significantly higher than controls at 140 dG. At 140 dG, there was increased adrenal P450C₁₇ and 3β-HSD mRNA in female fetuses and reduced expression of ACTH-R mRNA in males. Fetal hepatic CBG mRNA levels mimicked plasma cortisol patterns. DEX exposure reduced CBG only in males at 50 dG (P < 0.05). Placental mRNA levels of 11β-HSD2 were increased after DEX in males (P < 0.05). Therefore, in sheep, early DEX may alter the developmental trajectory of the fetal hypothalamic-pituitary-adrenal axis, directly increasing fetal adrenal activation but not anterior pituitary function. In females, this effect may be attributed, in part, to increased fetal adrenal steroidogenic activity.