Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of Disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology

Nature Clinical Practice Endocrinology & Metabolism volume 3, pages 479–488 (2007)Cite this article

Abstract

Epidemiological evidence suggests that an adverse prenatal environment permanently 'programs' physiology and increases the risk of cardiovascular, metabolic, neuroendocrine and psychiatric disorders in adulthood. Prenatal stress or exposure to excess glucocorticoids might provide the link between fetal maturation and adult pathophysiology. In a variety of animal models, prenatal stress, glucocorticoid exposure and inhibition (or knockout of) 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)—the fetoplacental barrier to maternal glucocorticoids—reduce birth weight and cause increases in adult blood pressure, glucose levels, hypothalamic–pituitary–adrenal (HPA) axis activity and anxiety-related behaviors. In humans, mutations in the gene that encodes 11β- hydroxysteroid dehydrogenase type 2 are associated with low birth weight. Babies with low birth weight have higher plasma cortisol levels throughout life, which indicates HPA-axis programming. In human pregnancy, severe maternal stress affects the offspring's HPA axis and is associated with neuropsychiatric disorders; moreover, maternal glucocorticoid therapy alters offspring brain function. The molecular mechanisms that underlie prenatal programming might reflect permanent changes in the expression of specific transcription factors, including the glucocorticoid receptor; tissue specific effects reflect modification of one or more of the multiple alternative first exons or promoters of the glucocorticoid receptor gene. Intriguingly, some of these effects seem to be inherited by subsequent generations that are unexposed to exogenous glucocorticoids at any point in their lifespan from fertilization, which implies that these epigenetic effects persist.

Key Points

  • Maternal stress or glucocorticoid treatment alters fetal growth and has permanent effects on offspring structure and function that predispose to cardiovascular, metabolic and neuropsychiatric disease

  • Placental 11β-hydroxysteroid dehydrogenase type 2 normally inactivates almost all maternal cortisol; its deficiency has similar effects to those of maternal glucocorticoid administration

  • The mechanisms of fetal programming are being elucidated and involve epigenetic changes that affect the expression of specific genes, including the glucocorticoid receptor gene

  • Some changes persist into at least a second generation, which implies the existence of epigenetic inheritance

  • Whilst the evolutionary purpose of fetal programming might be to optimize fitness of the offspring to its probable environment, in modern societies such programming frequently results in misprediction and an increased risk of disease

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The concept of developmental programming
Figure 2: The placental barrier to fetal glucocorticoid exposure

Similar content being viewed by others

References

  1. Cameron NM et al. (2005) The programming of individual differences in defensive responses and reproductive strategies in the rat through variations in maternal care. Neurosci Biobehav Rev 29: 843–865

    Article  Google Scholar 

  2. Gluckman P and Hanson M (2004) Living with the past: evolution, development, and patterns of disease. Science 305: 1733–1736

    Article  CAS  Google Scholar 

  3. Agrawal AA et al. (1999) Transgenerational induction of defences in animals and plants. Nature 401: 60–63

    Article  CAS  Google Scholar 

  4. Gluckman PD and Hanson MA (2006) Mismatch: Why our World No Longer Fits Our Bodies. Oxford: Oxford University Press

    Google Scholar 

  5. Goland RS et al. (1995) Concentrations of corticotropin-releasing hormone in the umbilical-cord blood of pregnancies complicated by preeclampsia. Reprod Fertil Dev 7: 1227–1230

    Article  CAS  Google Scholar 

  6. McTernan CL et al. (2001) Reduced placental 11β-hydroxysteroid dehydrogenase type 2 mRNA levels in human pregnancies complicated by intrauterine growth restriction: an analysis of possible mechanisms. J Clin Endocrinol Metab 86: 4979–4983

    CAS  PubMed  Google Scholar 

  7. Langley-Evans SC (1997) Hypertension induced by foetal exposure to a maternal low-protein diet, in the rat, is prevented by pharmacological blockade of maternal glucocorticoid synthesis. J Hypertens 15: 537–544

    Article  CAS  Google Scholar 

  8. Barker DJP (2004) The developmental origins of adult disease. J Am Coll Nutr 23 (Suppl 6): 588S–595S

    Article  CAS  Google Scholar 

  9. Cooper C et al. (1996) Childhood growth and age at menarche. Br J Obstet Gynaecol 103: 814–817

    Article  CAS  Google Scholar 

  10. Gluckman PD and Hanson MA (2006) Evolution, development and timing of puberty. Trends Endocrinol Metab 17: 7–12

    Article  CAS  Google Scholar 

  11. Barker DJP et al. (1993) Fetal nutrition and cardiovascular disease in adult life. Lancet 341: 938–941

    Article  CAS  Google Scholar 

  12. Gustafsson J-A et al. (1983) Sex steroid-induced changes in hepatic enzymes. Ann Rev Physiol 45: 51–60

    Article  CAS  Google Scholar 

  13. Edwards CRW et al. (1993) Dysfunction of the placental glucocorticoid barrier: a link between the foetal environment and adult hypertension? Lancet 341: 355–357

    Article  CAS  Google Scholar 

  14. Seckl J (2004) Prenatal glucocorticoids and long-term programming. Eur J Endocrinol 151 (Suppl 3): U49–U62

    Article  CAS  Google Scholar 

  15. Benediktsson R et al. (1993) Glucocorticoid exposure in utero: a new model for adult hypertension. Lancet 341: 339–341

    Article  CAS  Google Scholar 

  16. Nyirenda MJ et al. (1998) Glucocorticoid exposure in late gestation permanently programmes rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J Clin Invest 101: 2174–2181

    Article  CAS  Google Scholar 

  17. Dodic M et al. (1998) An early prenatal exposure to excess glucocorticoid leads to hypertensive offspring in sheep. Clin Sci 94: 149–155

    Article  CAS  Google Scholar 

  18. Liu L et al. (2001) Maternal glucocorticoid treatment programs HPA regulation in adult offspring: sex-specific effects. Am J Physiol Endocrinol Metab 280: E729–E739

    Article  CAS  Google Scholar 

  19. O'Regan D et al. (2004) Glucocorticoid exposure in late gestation in the rat permanently programs gender-specific differences in adult cardiovascular and metabolic physiology. Am J Physiol Endocrinol Metab 287: E863–E870

    Article  CAS  Google Scholar 

  20. Clifton VL and Murphy VE (2004) Maternal asthma as a model for examining fetal sex-specific effects on maternal physiology and placental mechanisms that regulate human fetal growth. Placenta 25: S45–S52

    Article  CAS  Google Scholar 

  21. Celsi G et al. (1998) Prenatal dexamethasone causes oligonephronia, sodium retention, and higher blood pressure in the offspring. Pediatr Res 44: 317–322

    Article  CAS  Google Scholar 

  22. Beitens IZ et al. (1973) The metabolic clearance rate, blood production, interconversion and transplacental passage of cortisol and cortisone in pregnancy near term. Pediatr Res 7: 509–519

    Article  Google Scholar 

  23. Brown RW et al. (1996) Isolation and cloning of human placental 11β-hydroxysteroid dehydrogenase-2 cDNA. Biochem J 313: 1007–1017

    Article  CAS  Google Scholar 

  24. Benediktsson R et al. (1997) Placental 11β-hydroxysteroid dehydrogenase type 2 is the placental barrier to maternal glucocorticoids: ex vivo studies. Clin Endocrinol 46: 161–166

    Article  CAS  Google Scholar 

  25. Stewart PM et al. (1995) Type 2 11β-hydroxysteroid dehydrogenase messenger RNA and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal steroidogenesis. J Clin Endocrinol Metab 80: 885–890

    CAS  PubMed  Google Scholar 

  26. Murphy VE et al. (2002) Reduced 11β-hydroxysteroid dehydrogenase type 2 activity is associated with decreased birth weight centile in pregnancies complicated by asthma. J Clin Endocrinol Metab 87: 1660–1668

    CAS  PubMed  Google Scholar 

  27. Mune T et al. (1995) Human hypertension caused by mutations in the kidney isozyme of 11β-hydroxysteroid dehydrogenase. Nat Genet 10: 394–399

    Article  CAS  Google Scholar 

  28. Lindsay RS et al. (1996) Inhibition of 11β-hydroxysteroid dehydrogenase in pregnant rats and the programming of blood pressure in the offspring. Hypertension 27: 1200–1204

    Article  CAS  Google Scholar 

  29. Lindsay RS et al. (1996) Programming of glucose tolerance in the rat: role of placental 11β-hydroxysteroid dehydrogenase. Diabetologia 39: 1299–1305

    Article  CAS  Google Scholar 

  30. Welberg LAM et al. (2000) Inhibition of 11β-hydroxysteroid dehydrogenase, the feto-placental barrier to maternal glucocorticoids, permanently programs amygdala glucocorticoid receptor mRNA expression and anxiety-like behavior in the offspring. Eur J Neurosci 12: 1047–1054

    Article  CAS  Google Scholar 

  31. Holmes M et al. (2006) The mother or the fetus? 11β-hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behaviour by endogenous glucocorticoids. J Neurosci 26: 3840–3844

    Article  CAS  Google Scholar 

  32. Agarwal AK et al. (1995) Gene structure and chromosomal localization of the human HSD11K gene encoding the kidney (type 2) isozyme of 11β-hydroxysteroid dehydrogenase. Genomics 29: 195–199

    Article  CAS  Google Scholar 

  33. Hardy DB and Yang K (2002) The expression of 11β-hydroxysteroid dehydrogenase type 2 is induced during trophoblast differentiation: effects of hypoxia. J Clin Endocrinol Metab 87: 3696–3701

    CAS  PubMed  Google Scholar 

  34. Alfaidy N et al. (2002) Oxygen regulation of placental 11β-hydroxysteroid dehydrogenase 2: Physiological and pathological implications. J Clin Endocrinol Metab 87: 4797–4805

    Article  CAS  Google Scholar 

  35. Johnstone JF et al. (2005) The effects of chorioamnionitis and betamethasone on 11 β hydroxysteroid dehydrogenase types 1 and 2 and the glucocorticoid receptor in preterm human placenta. J Soc Gynecol Investig 12: 238–245

    Article  CAS  Google Scholar 

  36. van Beek JP et al. (2004) Glucocorticoids stimulate the expression of 11 β-hydroxysteroid dehydrogenase type 2 in cultured human placental trophoblast cells. J Clin Endocrinol Metab 89: 5614–5621

    Article  CAS  Google Scholar 

  37. Ma XH et al. (2003) Gestation-related and betamethasone-induced changes in 11 β-hydroxysteroid dehydrogenase types 1 and 2 in the baboon placenta. Am J Obstet Gynecol 188: 13–21

    Article  Google Scholar 

  38. Yang KP et al. (2006) Cadmium reduces 11 β-hydroxysteroid dehydrogenase type 2 activity and expression in human placental trophoblast cells. Am J Physiol Endocrinol Metab 290: E135–E142

    Article  CAS  Google Scholar 

  39. Atanasov AG et al. (2005) Organotins disrupt the 11 β-hydroxysteroid dehydrogenase type 2-dependent local inactivation of glucocorticoids. Environ Health Perspect 113: 1600–1606

    Article  CAS  Google Scholar 

  40. Langley-Evans SC et al. (1996) Maternal dietary protein restriction, placental glucocorticoid metabolism and the programming of hypertension. Placenta 17: 169–172

    Article  CAS  Google Scholar 

  41. McMullen S et al. (2004) Alterations in placental 11 β-hydroxysteroid dehydrogenase (11 β HSD) activities and fetal cortisol: cortisone ratios induced by nutritional restriction prior to conception and at defined stages of gestation in ewes. Reproduction 127: 717–725

    Article  CAS  Google Scholar 

  42. Stocker C et al. (2004) Modulation of susceptibility to weight gain and insulin resistance in low birth weight rats by treatment of their mothers with leptin during pregnancy and lactation. Int J Obes 28: 129–136

    Article  CAS  Google Scholar 

  43. Vickers MH et al. (2005) Neonatal leptin treatment reverses developmental programming. Endocrinology 146: 4211–4216

    Article  CAS  Google Scholar 

  44. Whittle WL et al. (2001) Glucocorticoid regulation of human and ovine parturition: the relationship between fetal hypothalamic–pituitary–adrenal axis activation and intrauterine prostaglandin production. Biol Reprod 64: 1019–1032

    Article  CAS  Google Scholar 

  45. Karalis K et al. (1996) Cortisol blockade of progesterone: a possible molecular mechanism involved in the initiation of human labor. Nat Med 2: 556–560

    Article  CAS  Google Scholar 

  46. Sun K and Myatt L (2003) Enhancement of glucocorticoid-induced 11 β-hydroxysteroid dehydrogenase type 1 expression by proinflammatory cytokines in cultured human amnion fibroblasts. Endocrinology 144: 5568–5577

    Article  CAS  Google Scholar 

  47. Brown RW et al. (1996) The ontogeny of 11β-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor gene expression reveal intricate control of glucocorticoid action in development. Endocrinology 137: 794–797

    Article  CAS  Google Scholar 

  48. Stewart PM et al. (1995) Type 2 11β-hydroxysteroid dehydrogenase in foetal and adult life. J Steroid Biochem Mol Biol 55: 465–471

    Article  CAS  Google Scholar 

  49. Liu D et al. (1997) Maternal care, hippocampal glucocorticoid receptors, and hypothalamic–pituitary–adrenal responses to stress. Science 277: 1659–1662

    Article  CAS  Google Scholar 

  50. Weaver I et al. (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7: 847–854

    Article  CAS  Google Scholar 

  51. Kotelevtsev Y et al. (1999) Hypertension in mice lacking 11β-hydroxysteroid dehydrogenase type 2. J Clin Invest 103: 683–689

    Article  CAS  Google Scholar 

  52. Drake AJ et al. (2005) Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats. Am J Physiol Regul Integr Comp Physiol 288: R34–R38

    Article  CAS  Google Scholar 

  53. Drake AJ and Walker BR (2004) The intergenerational effects of fetal programming: non-genomic mechanisms for the inheritance of low birth weight and cardiovascular risk. J Endocrinol 180: 1–16

    Article  CAS  Google Scholar 

  54. Rakyan VK et al. (2003) Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci USA 100: 2538–2543

    Article  CAS  Google Scholar 

  55. Nyirenda M et al. (2006) Prenatal programming of hepatocyte nuclear factor (HNF)4 α in the rat: a key mechanism in the 'fetal origins of hyperglycemia'? Diabetologia 49: 1412–1420

    Article  CAS  Google Scholar 

  56. McCormick J et al. (2000) 5′-heterogeneity of glucocorticoid receptor mRNA is tissue-specific; differential regulation of variant promoters by early life events. Mol Endocrinol 14: 506–517

    CAS  PubMed  Google Scholar 

  57. Chen FH et al. (1999) Multiple glucocorticoid receptor transcripts in membrane glucocorticoid receptor-enriched S-49 mouse lymphoma cells. J Cell Biochem 74: 418–429

    Article  CAS  Google Scholar 

  58. Thomassin H et al. (2001) Glucocorticoid-induced DNA demethylation and gene memory during development. EMBO J 20: 1974–1983

    Article  CAS  Google Scholar 

  59. Doyle LW et al. (2000) Antenatal corticosteroid therapy and blood pressure at 14 years of age in preterm children. Clin Sci 98: 137–142

    Article  CAS  Google Scholar 

  60. Dalziel SR et al. (2005) Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial. Lancet 365: 1856–1862

    Article  CAS  Google Scholar 

  61. MacArthur BA et al. (1982) School progress and cognitive development of 6-year-old children whose mothers were treated antenatally with betamethasone. Pediatrics 70: 99–105

    CAS  PubMed  Google Scholar 

  62. Trautman PD et al. (1995) Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study. Psychoneuroendocrinology 20: 439–449

    Article  CAS  Google Scholar 

  63. French NP et al. (1998) Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol 180: 114–121

    Article  Google Scholar 

  64. Yeh T et al. (2004) Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 350: 1304–1313

    Article  CAS  Google Scholar 

  65. Crowther CA et al. (2006) Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet 367: 1913–1919

    Article  CAS  Google Scholar 

  66. de Vries A et al. (2007) Prenatal dexamethasone exposure induces changes in nonhuman primate offspring cardiometabolic and hypothalamic–pituitary–adrenal axis function. J Clin Invest 117: 1058–1067

    Article  CAS  Google Scholar 

  67. Clark PM et al. (1996) Size at birth and adrenocortical function in childhood. Clin Endocrinol 45: 721–726

    Article  CAS  Google Scholar 

  68. Phillips DI et al. (1998) Elevated plasma cortisol concentrations: an explanation for the relationship between low birth weight and adult cardiovascular risk factors. J Clin Endocrinol Metab 83: 757–760

    CAS  PubMed  Google Scholar 

  69. Phillips DIW et al. (2000) Low birth weight predicts elevated plasma cortisol concentrations in adults from 3 populations. Hypertension 35: 1301–1306

    Article  CAS  Google Scholar 

  70. Levitt NS et al. (2000) Impaired glucose tolerance and elevated blood pressure in low birth weight, non-obese young South African adults: early programming of the cortisol axis. J Clin Endocrinol Metab 85: 4611–4618

    CAS  PubMed  Google Scholar 

  71. Reynolds RM et al. (2001) Altered control of cortisol secretion in adult men with low birth weight and cardiovascular risk factors. J Clin Endocrinol Metab 86: 245–250

    CAS  PubMed  Google Scholar 

  72. Turner JD and Muller CP (2005) Structure of the glucocorticoid receptor (NR3C1) gene 5′ untranslated region: identification, and tissue distribution of multiple new human exon 1. J Mol Endocrinol 35: 283–292

    Article  CAS  Google Scholar 

  73. Yehuda R (2002) Current concepts—post-traumatic stress disorder. N Engl J Med 346: 108–114

    Article  CAS  Google Scholar 

  74. Yehuda R et al. (2004) Enhanced sensitivity to glucocorticoids in peripheral mononuclear leukocytes in posttraumatic stress disorder. Biological Psychiatry 55: 1110–1116

    Article  CAS  Google Scholar 

  75. Yehuda R et al. (2005) Transgenerational effects of posttraumatic stress disorder in babies of mothers exposed to the World Trade Center attacks during pregnancy. J Clin Endocrinol Metab 90: 4115–4118

    Article  CAS  Google Scholar 

  76. Berkowitz GS et al. (2003) The World Trade Center disaster and intrauterine growth restriction. JAMA 290: 595–596

    Article  Google Scholar 

  77. Engel SM et al. (2005) Psychological trauma associated with the World Trade Center attacks and its effect on pregnancy outcome. Paediatr Perinat Epidemiol 19: 334–341

    Article  Google Scholar 

Download references

Acknowledgements

Work in the authors' laboratory is supported by the Wellcome Trust, British Heart Foundation, Medical Research Council, European Union, Human Frontier Science Program and the Scottish Hospitals Endowments Research Trust.

Author information

Authors and Affiliations

  1. JR Seckl is Moncrieff-Arnott Professor of Molecular Medicine and Director of Research at the College of Medicine and Veterinary Medicine, University of Edinburgh. MC Holmes is a Reader, at the Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK.,

    Jonathan R Seckl & Megan C Holmes

Authors
  1. Jonathan R Seckl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Megan C Holmes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonathan R Seckl.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Seckl, J., Holmes, M. Mechanisms of Disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology. Nat Rev Endocrinol 3, 479–488 (2007). https://doi.org/10.1038/ncpendmet0515

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpendmet0515

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing