Advertisement

The Effects of Dexamethasone Treatment in Early Gestation on Hypothalamic–Pituitary–Adrenal Responses and Gene Expression at 7 Months of Postnatal Age in Sheep

Abstract

We determined the effects of prenatal dexamethasone administration in early gestation on development of the hypothalamic–pituitary–adrenal (HPA) axis up to 7 months of postnatal age with measurements of hormone levels and gene expression. Plasma adrenocorticotropic hormone and cortisol levels after corticotropin-releasing hormone (CRH)/arginine vasopressin challenge were lower in treatment females than in control females and treatment males. Calculation of cortisol to adrenocorticotropic hormone ratios indicated however that the adrenals of treatment females were more responsive to adrenocorticotropic hormone than control females or treatment males. Effects of treatment and sex dependence at 7 months of age were observed in levels of hypothalamic CRH messenger RNA (mRNA), hypothalamic arginine vasopressin mRNA, pituitary proopiomelanocortin mRNA, pituitary prohormone convertase 1 and prohormone convertase 2, glucocorticoid receptor and mineralocorticoid receptor in the hypothalamus and hippocampus, adrenal adrenocorticotropic hormone receptor, steroidogenic acute regulatory, 3β hydroxysteroid dehydrogenase, and 11β hydroxysteroid dehydrogenase type 2 mRNA. The results indicate that exposure to glucocorticoids in early pregnancy produces persisting and sex-dependent effects on the hypothalamic–pituitary–adrenal axis at 7 months of age.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 510

This is the net price. Taxes to be calculated in checkout.

References

  1. 1.

    Challis JRG, Matthews SG, Gibb W, Lye SJ. Endocrine and paracrine regulation of birth at term and preterm 1. Endocr Rev. 2000;21(5):514–550.

  2. 2.

    Ikegami M, Jobe AH, Newnham J, Polk DH, Willet KE, Sly P. Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs. Am J Respir Crit Care Med. 1997;156(1):178–184.

  3. 3.

    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(6): 309–313.

  4. 4.

    Sloboda DM, Newnham JP. Effects of repeated maternal betamethasone administration on growth and hypothalamicpituitary-adrenal function of the ovine fetus at term. J Endocrinol. 2000;165(1):79–91.

  5. 5.

    Challis JRG, Sloboda D, Matthews SG, et al. The fetal placental hypothalamic–pituitary–adrenal (HPA) axis, parturition and post natal health. Mol Cell Endocrinol. 2001;185(1–2): 135–144.

  6. 6.

    Sloboda DM, Moss TJ, Gurrin LC, Newnham JP. The effect of prenatal betamethasone administration on postnatal ovine hypothalamic-pituitary-adrenal function. J Endocrinol. 2002; 172(1):71–81.

  7. 7.

    Sloboda DM, Challis JRG, Moss TJM, Newnham JP. Synthetic glucocorticoids: antenatal administration and long-term implications. Curr Pharm Des. 2005;11(11):1459–1472.

  8. 8.

    Sloboda DM, Moss TJM, Li S, et al. Hepatic glucose regulation and metabolism in adult sheep: effects of prenatal betamethasone. Am J Physiol Endocrinol Metab. 2005;289(4):721–728.

  9. 9.

    Sloboda DM, Moss TJM, Li S, et al. Prenatal betamethasone exposure results in pituitary-adrenal hyporesponsiveness in adult sheep. Am J Physiol Endocrinol Metab. 2007;292(1):E61–E70.

  10. 10.

    Braun T, Li S, Moss TJM, et al. Maternal betamethasone administration reduces binucleate cell number and placental lactogen in sheep. J Endocrinol. 2007;194(2):337–347.

  11. 11.

    Sloboda DM, Moss TJM, Li S, Matthews SG, Challis JRG, Newnham JP. Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11 {beta}-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: ontogeny and effects of prenatal glucocorticoid exposure. J Endocrinol. 2008;197(2): 213–220.

  12. 12.

    David M, Forest MG. Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. J Pediatr. 1984;105(5):799–803.

  13. 13.

    Pang SY, Pollack MS, Marshall RN, Immken L. Prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med. 1990;322(2):111–115.

  14. 14.

    Dorr HG, Sippell WG. Prenatal dexamethasone treatment in pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: effect on midgestational amniotic fluid steroid levels. J Clin Endocrinol Metab. 1993;76(1):117–120.

  15. 15.

    Hirvikoski T, Nordenström A, Lindholm T, et al. Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone. Obstet Gynecol Surv 2007;62: 382–384.

  16. 16.

    Dodic M, Abouantoun T, O’Connor A, Wintour EM, Moritz KM. Programming effects of short prenatal exposure to dexamethasone in sheep. Hypertension. 2002;40(5):729–734.

  17. 17.

    Moritz K, Butkus A, Hantzis V, Peers A, Wintour EM, Dodic M. Prolonged low-dose dexamethasone, in early gestation, has no long-term deleterious effect on normal ovine fetuses. Endocrinology. 2002;143(4):1159–1165.

  18. 18.

    Dodic M, Hantzis V, Duncan J, et al. Programming effects of short prenatal exposure to cortisol. FASEB J. 2002;16(9):1017–1026.

  19. 19.

    Dodic M, McAlinden AT, Jefferies AJ, et al. Differential effects of prenatal exposure to dexamethasone or cortisol on circulatory control mechanisms mediated by angiotensin II in the central nervous system of adult sheep. J Physiol. 2006;571(pt 3):651–660.

  20. 20.

    Hantzis V, Albiston A, Matsacos D, et al. Effect of early glucocorticoid treatment on MR and GR in late gestation ovine kidney. Kidney Int. 2002;61(2):405–413.

  21. 21.

    Dodic M, Peers A, Moritz K, Hantzis V, Wintour EM. No evidence for HPA reset in adult sheep with high blood pressure due to short prenatal exposure to dexamethasone. Am J Physiol Regul Integr Comp Physiol 2002;282(2):R343–R350.

  22. 22.

    De Blasio MJ, Dodic M, Jefferies AJ, et al. Maternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring. Am J Physiol Endocrinol Metab. 2007;293(1):E75–E82.

  23. 23.

    Roghair RD, Lamb FS, Miller FJ, Scholz TD, Segar JL. Early gestation dexamethasone programs enhanced postnatal ovine coronary artery vascular reactivity. Am J Physiol Regul Integr Comp Physiol 2005;288(1):46–53.

  24. 24.

    Roghair RD, Segar JL, Sharma RV, et al. Newborn lamb coronary artery reactivity is programmed by early gestation dexamethasone before the onset of systemic hypertension. Am J Physiol Regul Integr Comp Physiol 2005;289(4):R1169–R1176.

  25. 25.

    Lim GB, Jeyaseelan K, Wintour EM. Ontogeny of erythropoietin gene expression in the sheep fetus: effect of dexamethasone at 60 days of gestation. Blood. 1994;84(2):460–466.

  26. 26.

    Glickman JA, Challis JR. The changing response pattern of sheep fetal adrenal cells throughout the course of gestation. Endocrinology. 1980;106(5):1371–1376.

  27. 27.

    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(12):5466–5477.

  28. 28.

    Moss TJM, Sloboda DM, Gurrin LC, et al. Programming effects in sheep of prenatal growth restriction and glucocorticoid exposure. Am J Physiol Regul Integr Compar Physiol. 2001;281(3): 960–970.

  29. 29.

    Moss TJM, Doherty DA, Nitsos I, Sloboda DM, Harding R, Newnham JP. Effects into adulthood of single or repeated antenatal corticosteroids in sheep. Am J Obstet Gynecol. 2005;192(1):146–152.

  30. 30.

    Jaquiery AL, Oliver MH, Bloomfield FH. Fetal exposure to excess glucocorticoid is unlikely to explain the effects of periconceptional undernutrition in sheep. J Physiol. 2006;572(pt 1): 109–118.

  31. 31.

    Ballard PL, Kitterman JA, Bland RD, et al. Ontogeny and regulation of corticosteroid binding globulin capacity in plasma of fetal and newborn lambs. Endocrinology. 1982;110(2):359–366.

  32. 32.

    Challis JR, Nancekievill EA, Lye SJ. Possible role of cortisol in the stimulation of cortisol-binding capacity in the plasma of fetal sheep. Endocrinology. 1985;116(3): 1139–1144.

  33. 33.

    Phillips DIW, Barker DJP, Fall CHD, et al. Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome? J Clin Endocrinol Metab. 1998;83(3): 757–760.

  34. 34.

    Matthews SG, Heavens RP, Sirinathsingji DJS. Cellular localization of corticotropin releasing factor mRNA in the ovine brain. Brain Res Mol Brain Res. 1991;11(2):171–176.

  35. 35.

    Matthews SG, Challis JR. Regulation of CRH and AVP mRNA in the developing ovine hypothalamus: effects of stress and glucocorticoids. Am J Physiol. 1995;268(6 pt 1): 1096–1107.

  36. 36.

    Yang K, Hammond GL, Challis JR. Characterization of an ovine glucocorticoid receptor cDNA and developmental changes in its mRNA levels in the fetal sheep hypothalamus, pituitary gland and adrenal. J Mol Endocrinol 1992;8(2):173–180.

  37. 37.

    Matthews SG, Han X, Lu F, Challis JR. Developmental changes in the distribution of pro-opiomelanocortin and prolactin mRNA in the pituitary of the ovine fetus and lamb. J Mol Endocrinol. 1994;13(2):175–185.

  38. 38.

    Dai G, Smeekens SP, Steiner DF, McMurtry JP, Kwok SCM. Characterization of multiple prohormone convertase PC1/3 transcripts in porcine ovary. Biochim Biophys Acta. 1995;1264(1):1–6.

  39. 39.

    Seidah NG, Fournier H, Boileau G, Benjannet S, Rondeau N, Chretien M. The cDNA structure of the porcine pro-hormone convertase PC 2 and the comparative processing by PC 1 and PC 2 of the N-terminal glycopeptide segment of porcine POMC. FEBS Lett. 1992;310(3):235–239.

  40. 40.

    Zhao HF, Simard J, Labrie C, Breton N, Rheaume E. Molecular cloning, cDNA structure and predicted amino acid sequence of bovine 3 beta-hydroxy-5-ene steroid dehydrogenase/delta 5-delta 4 isomerase. FEBS Lett. 1989;259(1):153–157.

  41. 41.

    Van Harmelen V, Ariapart P, Hoffstedt J, Lundkvist I, Bringman S, Arner P. Increased adipose angiotensinogen gene expression in human obesity. Obes Res. 2000;8(4):337–341.

  42. 42.

    Gyomory S, Gupta S, Lye SJ, Gibb W, Labrie F, Challis JRG. Temporal expression of prostaglandin H synthase type 2 (PGHS-2) and P45OC17 in ovine placentomes with the natural onset of labour. Placenta. 2000;21(5–6):478–486.

  43. 43.

    Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–254.

  44. 44.

    Ritzén EM. Prenatal dexamethasone treatment of fetuses at risk for congenital adrenal hyperplasia: benefits and concerns. Semin Neonatol. 2001;6(4):357–362.

  45. 45.

    Newnham JP, Moss TJ. Antenatal glucocorticoids and growth: single versus multiple doses in animal and human studies. Semin Neonatol. 2001;6(4):285–292.

  46. 46.

    Moss TJ, Harding R, Newnham JP. Lung function, arterial pressure and growth in sheep during early postnatal life following single and repeated prenatal corticosteroid treatments. Early Hum Dev. 2002;66(1):11–24.

  47. 47.

    Currie IS, Brooks AN. Corticotrophin-releasing factors in the hypothalamus of the developing fetal sheep. J Dev Physiol. 1992;17(5):241–246.

  48. 48.

    Pradier P, Tournaire C, Dalle M, Delost P. Plasma concentrations of adrenocorticotropin-related peptides in lambs injected with ovine corticotropin releasing factor or vasopressin. J Dev Physiol. 1989;11(2):103–109.

  49. 49.

    Lu F, Yang K. Regulation of ovine fetal pituitary function by corticotrophin-releasing hormone, arginine vasopressin and cortisol in vitro. J Endocrinol. 1994;143(1):199–208.

  50. 50.

    Almeida OF, Canoine V, Ali S, Holsboer F, Patchev VK. Activational effects of gonadal steroids on hypothalamopituitary-adrenal regulation in the rat disclosed by response to dexamethasone suppression. J Neuroendocrinol. 1997;9(2):129–134.

  51. 51.

    Whittle WL, Patel FA, Alfaidy N, et al. Glucocorticoid regulation of human and ovine parturition: the relationship between fetal hypothalamic-pituitary-adrenal axis activation and intrauterine prostaglandin production. Biol Reprod. 2001;64(4):1019–1032.

  52. 52.

    Dong W, Seidel B, Marcinkiewicz M, Chretien M, Seidah NG, Day R. Cellular localization of the prohormone convertases in the hypothalamic paraventricular and supraoptic nuclei: selective regulation of PC1 in corticotrophin-releasing hormone parvocellular neurons mediated by glucocorticoids. J Neurosci. 1997; 17(2):563–575.

  53. 53.

    Stevens A, Begum G, Cook A, et al. Epigenetic changes in the hypothalamic proopiomelanocortin and glucocorticoid receptor genes in the ovine fetus after periconceptional undernutrition. Endocrinology. 2010;151(8):3652–3664.

  54. 54.

    Connor KL, Challis JR, van Zijl P, et al. Do alterations in placental 11beta-hydroxysteroid dehydrogenase (11betaHSD) activities explain differences in fetal hypothalamic-pituitary-adrenal (HPA) function following periconceptional undernutrition or twinning in sheep? Reprod Sci. 2009;16(12):1201–1212.

Download references

Author information

Correspondence to Shaofu Li BSc.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Li, S., Nitsos, I., Polglase, G.R. 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. 19, 260–270 (2012) doi:10.1177/1933719111418374

Download citation

Keywords

  • hypothalamic–pituitary–adrenal
  • dexamethasone
  • fetal programming
  • steroidogenic enzymes