Effects of maternal dexamethasone treatment in early pregnancy on pituitary-adrenal axis in fetal sheep

Thorsten Braun, Shaofu Li, Deborah M Sloboda, Wei Li, Melanie C Audette, Timothy J M Moss, Stephen G Matthews, Graeme R Polglase, Ilias Nitsos, John P Newnham, John R G Challis

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 b1 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 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.
Original languageEnglish
Pages (from-to)5466 - 5477
Number of pages12
JournalEndocrinology
Volume150
Issue number12
DOIs
Publication statusPublished - 2009

Cite this

Braun, T., Li, S., Sloboda, D. M., Li, W., Audette, M. C., Moss, T. J. M., ... Challis, J. R. G. (2009). Effects of maternal dexamethasone treatment in early pregnancy on pituitary-adrenal axis in fetal sheep. Endocrinology, 150(12), 5466 - 5477. https://doi.org/10.1210/en.2009-0086
Braun, Thorsten ; Li, Shaofu ; Sloboda, Deborah M ; Li, Wei ; Audette, Melanie C ; Moss, Timothy J M ; Matthews, Stephen G ; Polglase, Graeme R ; Nitsos, Ilias ; Newnham, John P ; Challis, John R G. / Effects of maternal dexamethasone treatment in early pregnancy on pituitary-adrenal axis in fetal sheep. In: Endocrinology. 2009 ; Vol. 150, No. 12. pp. 5466 - 5477.
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title = "Effects of maternal dexamethasone treatment in early pregnancy on pituitary-adrenal axis in fetal sheep",
abstract = "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 b1 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 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.",
author = "Thorsten Braun and Shaofu Li and Sloboda, {Deborah M} and Wei Li and Audette, {Melanie C} and Moss, {Timothy J M} and Matthews, {Stephen G} and Polglase, {Graeme R} and Ilias Nitsos and Newnham, {John P} and Challis, {John R G}",
year = "2009",
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Braun, T, Li, S, Sloboda, DM, Li, W, Audette, MC, Moss, TJM, Matthews, SG, Polglase, GR, Nitsos, I, Newnham, JP & Challis, JRG 2009, 'Effects of maternal dexamethasone treatment in early pregnancy on pituitary-adrenal axis in fetal sheep' Endocrinology, vol. 150, no. 12, pp. 5466 - 5477. https://doi.org/10.1210/en.2009-0086

Effects of maternal dexamethasone treatment in early pregnancy on pituitary-adrenal axis in fetal sheep. / Braun, Thorsten; Li, Shaofu; Sloboda, Deborah M; Li, Wei; Audette, Melanie C; Moss, Timothy J M; Matthews, Stephen G; Polglase, Graeme R; Nitsos, Ilias; Newnham, John P; Challis, John R G.

In: Endocrinology, Vol. 150, No. 12, 2009, p. 5466 - 5477.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Effects of maternal dexamethasone treatment in early pregnancy on pituitary-adrenal axis in fetal sheep

AU - Braun, Thorsten

AU - Li, Shaofu

AU - Sloboda, Deborah M

AU - Li, Wei

AU - Audette, Melanie C

AU - Moss, Timothy J M

AU - Matthews, Stephen G

AU - Polglase, Graeme R

AU - Nitsos, Ilias

AU - Newnham, John P

AU - Challis, John R G

PY - 2009

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N2 - 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 b1 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 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.

AB - 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 b1 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 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.

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