Effects of maternal dexamethasone treatment in early pregnancy on pituitary-adrenal axis in fetal sheep.
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 P450C(17) and 3beta-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 11beta-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.
Department of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Thorsten
T
Braun
Shaofu
S
Li
Deborah M
DM
Sloboda
Wei
W
Li
Melanie C
MC
Audette
Timothy J M
TJ
Moss
Stephen G
SG
Matthews
Graeme
G
Polglase
Ilias
I
Nitsos
John P
JP
Newnham
John R G
JR
Challis
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics; D000311:Adrenal Glands / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D047109:Fetal Development / Q000187:drug effects*; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005865:Gestational Age; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology; D017403:In Situ Hybridization; D008297:Male; D009097:Multienzyme Complexes / Q000235:genetics; D010902:Pituitary Gland / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000196:embryology; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011375:Progesterone Reductase / Q000235:genetics; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D012756:Sheep; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D013251:Steroid Isomerases / Q000235:genetics
C021425:3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase; D005938:Glucocorticoids; D009097:Multienzyme Complexes; D011333:Pro-Opiomelanocortin; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D011375:Progesterone Reductase; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D013254:Steroid 17-alpha-Hydroxylase; D013251:Steroid Isomerases