Hostname: page-component-78c5997874-v9fdk Total loading time: 0 Render date: 2024-11-19T15:17:20.650Z Has data issue: false hasContentIssue false
  • English
  • Français

Effects of glucocorticoid treatment given in early or late gestation on growth and development in sheep

Published online by Cambridge University Press:  23 January 2013

S. Li ,
D. M. Sloboda ,
T. J. M. Moss ,
I. Nitsos ,
G. R. Polglase ,
D. A. Doherty ,
J. P. Newnham ,
J. R. G. Challis  and
T. Braun
S. Li*
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, Perth, Western Australia, Australia Women and Infants Research Foundation of Western Australia, Perth, Western Australia, Australia
D. M. Sloboda
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada
T. J. M. Moss
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, Perth, Western Australia, Australia The Ritchie Centre, Monash Institute of Medical Research and Department of Obstetrics and Gynaecology, Monash University, Victoria, Australia
I. Nitsos
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, Perth, Western Australia, Australia The Ritchie Centre, Monash Institute of Medical Research and Department of Obstetrics and Gynaecology, Monash University, Victoria, Australia
G. R. Polglase
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, Perth, Western Australia, Australia The Ritchie Centre, Monash Institute of Medical Research and Department of Obstetrics and Gynaecology, Monash University, Victoria, Australia
D. A. Doherty
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, Perth, Western Australia, Australia Women and Infants Research Foundation of Western Australia, Perth, Western Australia, Australia
J. P. Newnham
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, Perth, Western Australia, Australia Women and Infants Research Foundation of Western Australia, Perth, Western Australia, Australia
J. R. G. Challis
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, Perth, Western Australia, Australia Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto, Canada
T. Braun
Affiliation:
Department of Obstetrics, Charité University Berlin, Berlin, Germany
*
*Address for correspondence: Mr S. Li, School of Women's and Infants’ Health, The University of Western Australia, M550, Crawley, WA 6009, Australia. (Email [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

Antenatal corticosteroids are used to augment fetal lung maturity in human pregnancy. Dexamethasone (DEX) is also used to treat congenital adrenal hyperplasia of the fetus in early pregnancy. We previously reported effects of synthetic corticosteroids given to sheep in early or late gestation on pregnancy length and fetal cortisol levels and glucocorticoids alter plasma insulin-like growth factor (IGF) and insulin-like growth factor binding protein (IGFBP) concentrations in late pregnancy and reduce fetal weight. The effects of administering DEX in early pregnancy on fetal organ weights and betamethasone (BET) given in late gestation on weights of fetal brain regions or organ development have not been reported. We hypothesized that BET or DEX administration at either stage of pregnancy would have deleterious effects on fetal development and associated hormones. In early pregnancy, DEX was administered as four injections at 12-hourly intervals over 48 h commencing at 40–42 days of gestation (dG). There was no consistent effect on fetal weight, or individual fetal organ weights, except in females at 7 months postnatal age. When BET was administered at 104, 111 and 118 dG, the previously reported reduction in total fetal weight was associated with significant reductions in weights of fetal brain, cerebellum, heart, kidney and liver. Fetal plasma insulin, leptin and triiodothyronine were also reduced at different times in fetal and postnatal life. We conclude that at the amounts given, the sheep fetus is sensitive to maternal administration of synthetic glucocorticoid in late gestation, with effects on growth and metabolic hormones that may persist into postnatal life.

Keywords

antenatal steroidsbetamethasonedexamethasonefetal brainIGF-insulin axis
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 4 , Issue 2 , April 2013 , pp. 146 - 156
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1.Dunlop, SA, Archer, MA, Quinlivan, JA, Beazley, LD, Newnham, JP. Repeated prenatal corticosteroids delay myelination in the ovine central nervous system. J Matern Fetal Med. 1997; 6, 309–313.Google Scholar
2.Abbasi, S, Hirsch, D, Davis, J, et al. Effect of single versus multiple courses of antenatal corticosteroids on maternal and neonatal outcome. Am J Obstet Gynecol. 2000; 182, 1243–1249.Google Scholar
3.Walfisch, A, Hallak, M, Mazor, M. Multiple courses of antenatal steroids: risks and benefits. Obstet Gynecol. 2001; 98, 491–497.Google ScholarPubMed
4.Thorp, JA, Jones, AM, Hunt, C, Clark, R. The effect of multidose antenatal betamethasone on maternal and infant outcomes. Am J Obstet Gynecol. 2001; 184, 196–202.Google Scholar
5.Newnham, JP, Moss, TJ. Antenatal glucocorticoids and growth: single versus multiple doses in animal and human studies. Semin Neonatol. 2001; 6, 285–292.Google Scholar
6.Li, S, Moss, TJM, Nitsos, I, et al. The impact of maternal synthetic glucocorticoid administration in late pregnancy on fetal and early neonatal hypothalamic–pituitary–adrenal axes regulatory genes is dependent upon dose and gestational age at exposure. J Dev Orig Health Dis 2013; 4(1), 77–89.Google Scholar
7.Gatford, KL, Owens, JA, Li, S, et al. Repeated betamethasone treatment of pregnant sheep programs persistent reductions in circulating IGF-I and IGF-binding proteins in progeny. Am J Physiol Endocrinol Metab. 2008; 295, E170–E178.Google Scholar
8.Jobe, AH, Newnham, J, Willet, K, Sly, P, Ikegami, M. Fetal versus maternal and gestational age effects of repetitive antenatal glucocorticoids. Pediatrics. 1998; 102, 1116–1125.Google Scholar
9.Newnham, JP, Evans, SF, Godfrey, M, et al. Maternal, but not fetal, administration of corticosteroids restricts fetal growth. J Matern Fetal Med. 1999; 8, 81–87.Google Scholar
10.Sloboda, DM, Moss, TJ, Li, S, et al. Prenatal betamethasone exposure results in pituitary–adrenal hyporesponsiveness in adult sheep. Am J Physiol Endocrinol Metab. 2007; 292, E61–E70.Google Scholar
11.Li, S, Nitsos, I, Polglase, GR, et al. The effects of dexamethasone treatment in early gestation on hypothalamic–pituitary–adrenal responses and gene expression at 7 months of postnatal age in sheep. Reprod Sci. 2012; 19, 260–270.Google Scholar
12.Braun, T, Li, S, Sloboda, DM, et al. Effects of maternal dexamethasone treatment in early pregnancy on pituitary–adrenal axis in fetal sheep. Endocrinology. 2009; 150, 5466–5477.Google Scholar
13.Moss, TJ, Doherty, DA, Nitsos, I, et al. Effects into adulthood of single or repeated antenatal corticosteroids in sheep. Am J Obstet Gynecol. 2005; 192, 146–152.CrossRefGoogle ScholarPubMed
14.Sloboda, DM, Newnham, JP, Challis, JR. Repeated maternal glucocorticoid administration and the developing liver in fetal sheep. J Endocrinol. 2002; 175, 535–543.Google Scholar
15.Winikor, J, Schlaerth, C, Rabaglino, MB, et al. Complex actions of estradiol-3-sulfate in late gestation fetal brain. Reprod Sci. 2012; 18, 654–665.Google Scholar
16.Gluckman, PD, Johnson-Barrett, JJ, Butler, JH, Edgar, BW, Gunn, TR. Studies of insulin-like growth factor-I and -II by specific radioligand assays in umbilical cord blood. Clin Endocrinol (Oxf). 1983; 19, 405–413.Google Scholar
17.Blache, D, Tellam, RL, Chagas, LM, et al. Level of nutrition affects leptin concentrations in plasma and cerebrospinal fluid in sheep. J Endocrinol. 2000; 165, 625–637.Google Scholar
18.Dawson, A, Deeming, DC, Dick, AC, Sharp, PJ. Plasma thyroxine concentrations in farmed ostriches in relation to age, body weight, and growth hormone. Gen Comp Endocrinol. 1996; 103, 308–315.Google Scholar
19.Zhang, S, Blache, D, Blackberry, MA, Martin, GB. Body reserves affect the reproductive endocrine responses to an acute change in nutrition in mature male sheep. Anim Reprod Sci. 2005; 88, 257–269.Google Scholar
20.Bergmeyer, HU, Bernt, E. Determination of glucose with glucose oxidase and peroxidase. In Methods of Enzymatic Analysis, 2, 1974; pp. 1205–1215. Academic Press: New York and London.Google Scholar
21.Liggins, GC, Howie, RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972; 50, 515–525.Google Scholar
22.Dean, F, Yu, C, Lingas, RI, Matthews, SG. Prenatal glucocorticoid modifies hypothalamo–pituitary–adrenal regulation in prepubertal guinea pigs. Neuroendocrinology. 2001; 73, 194–202.Google Scholar
23.Moss, TJ, Sloboda, DM, Gurrin, LC, et al. Programming effects in sheep of prenatal growth restriction and glucocorticoid exposure. Am J Physiol Regul Integr Comp Physiol. 2001; 281, R960–R970.Google Scholar
24.Novy, MJ, Walsh, SW. Dexamethasone and estradiol treatment in pregnant rhesus macaques: effects on gestational length, maternal plasma hormones, and fetal growth. Am J Obstet Gynecol. 1983; 145, 920–931.Google Scholar
25.Huang, WL, Beazley, LD, Quinlivan, JA, et al. Effect of corticosteroids on brain growth in fetal sheep. Obstet Gynecol. 1999; 94, 213–218.Google Scholar
26.French, NP, Hagan, R, Evans, SF, Mullan, A, Newnham, JP. Repeated antenatal corticosteroids: effects on cerebral palsy and childhood behavior. Am J Obstet Gynecol. 2004; 190, 588–595.Google Scholar
27.Challier, JC, Hauguel, S, Desmaizieres, V. Effect of insulin on glucose uptake and metabolism in the human placenta. J Clin Endocrinol Metab. 1986; 62, 803–807.Google Scholar
28.Desoye, G, Shafrir, E. Placental metabolism and its regulation in health and diabetes. Mol Aspects Med. 1994; 15, 505–682.Google Scholar
29.Hahn, T, Barth, S, Weiss, U, Mosgoeller, W, Desoye, G. Sustained hyperglycemia in vitro down-regulates the GLUT1 glucose transport system of cultured human term placental trophoblast: a mechanism to protect fetal development? FASEB J. 1998; 12, 1221–1231.Google Scholar
30.Smith, JT, Waddell, BJ. Leptin receptor expression in the rat placenta: changes in ob-ra, ob-rb, and ob-re with gestational age and suppression by glucocorticoids. Biol Reprod. 2002; 67, 1204–1210.Google Scholar
31.Sugden, MC, Langdown, ML, Munns, MJ, Holness, MJ. Maternal glucocorticoid treatment modulates placental leptin and leptin receptor expression and materno–fetal leptin physiology during late pregnancy, and elicits hypertension associated with hyperleptinaemia in the early-growth-retarded adult offspring. Eur J Endocrinol. 2001; 145, 529–539.Google Scholar
32.Amico, JA, Thomas, A, Crowley, RS, Burmeister, LA. Concentrations of leptin in the serum of pregnant, lactating, and cycling rats and of leptin messenger ribonucleic acid in rat placental tissue. Life Sci. 1998; 63, 1387–1395.Google Scholar
33.Kawai, M, Yamaguchi, M, Murakami, T, et al. The placenta is not the main source of leptin production in pregnant rat: gestational profile of leptin in plasma and adipose tissues. Biochem Biophys Res Commun. 1997; 240, 798–802.Google Scholar
34.Blazer, S, Moreh-Waterman, Y, Miller-Lotan, R, Tamir, A, Hochberg, Z. Maternal hypothyroidism may affect fetal growth and neonatal thyroid function. Obstet Gynecol. 2003; 102, 232–241.Google Scholar
35.Chattergoon, NN, Giraud, GD, Thornburg, KL. Thyroid hormone inhibits proliferation of fetal cardiac myocytes in vitro. J Endocrinol. 2007; 192, R1–R8.Google Scholar
36.Meaney, MJ, Diorio, J, Francis, D, et al. Postnatal handling increases the expression of cAMP-inducible transcription factors in the rat hippocampus: the effects of thyroid hormones and serotonin. J Neurosci. 2000; 20, 3926–3935.Google Scholar
37.Challis, JRG, Matthews, SG, Gibb, W, Lye, SJ. Endocrine and paracrine regulation of birth at term and preterm. Endocr Rev. 2000; 21, 514–550.Google Scholar
38.de Escobar, GM, Obregon, MJ, del Rey, FE. Maternal thyroid hormones early in pregnancy and fetal brain development. Best Pract Res Clin Endocrinol Metab. 2004; 18, 225–248.Google Scholar
39.Jacobson, L, Sapolsky, R. The role of the hippocampus in feedback regulation of the hypothalamic–pituitary–adrenocortical axis. Endocr Rev. 1991; 12, 118–134.Google Scholar
40.Matthews, SG. Antenatal glucocorticoids and the developing brain: mechanisms of action. Semin Neonatol. 2001; 6, 309–317.Google Scholar
41.De Kloet, ER, Vreugdenhil, E, Oitzl, MS, Joels, M. Brain corticosteroid receptor balance in health and disease. Endocr Rev. 1998; 19, 269–301.Google Scholar
42.Challis, JRG, Patrick, JE, Cross, J, et al. Short-term fluctuations in the concentration of cortisol and progesterone in fetal plasma, maternal plasma, and amniotic and allantoic fluids from sheep during late pregnancy. Can J Physiol Pharmacol. 1981; 59, 261–267.Google Scholar
43.Liggins, GC, Fairclough, RJ, Grieves, SA, Kendall, JZ, Knox, BS. The mechanism of initiation of parturition in the ewe. Recent Prog Horm Res. 1973; 29, 111–159.Google Scholar
44.Bloomfield, FH, Oliver, MH, Giannoulias, CD, et al. Brief undernutrition in late-gestation sheep programs the hypothalamic–pituitary–adrenal axis in adult offspring. Endocrinology. 2003; 144, 2933–2940.Google Scholar
45.Sloboda, DM, Moss, TJ, Li, S, et al. Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11beta-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: ontogeny and effects of prenatal glucocorticoid exposure. J Endocrinol. 2008; 197, 213–220.Google Scholar
46.Sloboda, DM, Newnham, JP, Challis, JR. Effects of repeated maternal betamethasone administration on growth and hypothalamic–pituitary–adrenal function of the ovine fetus at term. J Endocrinol. 2000; 165, 79–91.Google Scholar
47.Pena, CLJ, Champagne, FA. Epigenetic and neurodevelopmental perspectives on variation in parenting behavior. Parenting. 2012; 12, 202–211.Google Scholar
48.Wright, RJ. Epidemiology of stress and asthma: from constricting communities and fragile families to epigenetics. Immunol Allergy Clin North Am. 2011; 31, 19–39.CrossRefGoogle ScholarPubMed