Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms

doi:10.1016/S0303-7207(01)00633-5

Molecular and Cellular Endocrinology

Volume 185, Issues 1–2, 20 December 2001, Pages 61-71

https://doi.org/10.1016/S0303-7207(01)00633-5 Get rights and content

Abstract

It has been long recognised that the glucocorticoid administration to pregnant mammals (including humans) reduces offspring birth weight. Epidemiologically, low weight or thinness at birth is associated with an increased risk of cardiovascular and metabolic disorders in adult life. So, does fetal exposure to glucocorticoids produce such ‘programming’ of adult disorders? Here data are reviewed which show, in rodents and other model species, that antenatal exposure to glucocorticoids reduces offspring birth weight and produces permanent hypertension, hyperglycaemia, hyperinsulinaemia, altered behaviour and neuroendocrine responses throughout the lifespan. This occurs with exogenous (dexamethasone) or endogenous glucocorticoids, the latter achieved by inhibiting 11β-hydroxysteroid dehydrogenase type 2, the feto-placental enzymic barrier to maternal glucocorticoids. Processes underlying fetal programming include determination of the ‘set point’ of the hypothalamic–pituitary–adrenal axis and of tissue glucocorticoid receptor expression. Detailed molecular mechanisms are being dissected. Analogous stress axis hyperreactivity occurs in lower birth weight humans and may be an early manifestation and indicate approaches to manipulation or prevention of the phenotype.

Section snippets

Introduction: the early life origins of adult disease

A plethora of epidemiological studies suggest that factors operating in early life are important determinants of the risk of common cardiovascular and metabolic disorders of adult life. Exploiting the preservation of detailed obstetric records in some hospitals in Britain, Barker and colleagues in Southampton uncovered a correlation between heart disease mortality and parameters of the early life environment, notably birth weight and early postnatal growth (Barker et al., 1989b, Barker et al.,

Programming

To explain these findings the idea of early life physiological ‘programming’ or ‘imprinting’ has been proposed (Barker et al., 1993a, Edwards et al., 1993, Seckl, 1998). Such programming occurs in a variety of systems and reflects the action of a factor during sensitive periods or ‘windows’ of development to exercise organisational effects that persist throughout life. It should be noted that environmental influences are not the only possible explanation of the epidemiological findings and the

Glucocorticoid programming

Long-term organisational effects are typically found with hormones, particularly steroids. For example, neonatal exposure to androgens programmes the expression steroid metabolising enzymes in the liver, the development of sexually dimorphic structures in the anterior hypothalamus as well as sexual behaviour (Arai and Gorski, 1968, Gustafsson et al., 1983). These effects can be exerted only during a specific perinatal period, but then persist throughout life, largely irrespective of any

Placental 11β-hydroxysteroid dehydrogenase type 2

Fetal glucocorticoid levels are lower than maternal levels (Beitens et al., 1973). This is ensured by placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) which catalyses the rapid metabolism of cortisol and corticosterone to inert 11-keto steroids, cortisone and 11-dehydrocorticosterone (Brown et al., 1996b) (Fig. 2). The enzyme is not a complete barrier to maternal glucocorticoids (Benediktsson et al., 1997) and dexamethasone is a poor substrate (Albiston et al., 1994). The

Liver

Glucocorticoids regulate several important hepatic processes, including key enzymes of carbohydrate and fat metabolism, such as phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting step in gluconeogenesis. Prenatal glucocorticoid administration programmes increased PEPCK transcription and hence enzyme activity (Nyirenda et al., 1998). This is confined to the gluconeogenic periportal region of the hepatic acinus. PEPCK is regulated by a variety of hormones, including glucocorticoids

Molecular mechanisms

Indications of the molecular mechanisms by which early life environmental factors may programme offspring physiology come from studies of the processes underpinning postnatal environmental programming of the HPA axis in the ‘neonatal handling’ paradigm (Levine, 1957, Levine, 1962, Meaney et al., 1988, Meaney et al., 1996); 15 min of daily ‘handling’ of rat pups during the first week or two of life (Meaney et al., 1988) permanently increases GR density in the hippocampus and prefrontal cortex,

Glucocorticoid programming in humans?

High-dose glucocorticoid treatment during human pregnancy reduces birth weight (Reinisch et al., 1978, Novy and Walsh, 1983). In rhesus monkeys, even brief dexamethasone administration in the last trimester affects the hippocampal structure and cortisol levels in the offspring, although the doses used are high (Uno et al., 1994, Sapolsky, 1992). There is scanty clinical evidence concerning the effects of low-dose glucocorticoids in utero. 11β-HSD-2 substrates, such as cortisol and prednisolone,

Acknowledgements

I am grateful to Drs Moffat Nyirenda, Karen Chapman, Megan Holmes, Brian Walker, Cheryl Docherty, Rebecca Reynolds and Leonie Welberg for enlightening discussions and interpretations of their data. Work performed at author's laboratory was generously supported by a Wellcome Trust Senior Clinical Fellowship, a Wellcome Trust Programme grant and project grants from the Wellcome Trust, the Medical Research Council, the Scottish Hospital Endowments Research Trust and the High Blood Pressure

References (112)

A.L. Albiston et al.
Cloning and tissue distribution of the human 11β-hydroxysteroid dehydrogenase type 2 enzyme
Molecular Cell Endocrinology
(1994)
D.J.P. Barker et al.
Fetal nutrition and cardiovascular disease in adult life
Lancet
(1993)
D.J.P. Barker et al.
Weight in infancy and death from ischaemic heart disease
Lancet
(1989)
R. Benediktsson et al.
Glucocorticoid exposure in utero: a new model for adult hypertension
Lancet
(1993)
A. Catalani et al.
Progeny of mothers drinking corticosterone during lactation has lower stress-induced corticosterone secretion and better cognitive performance
Brain Research
(1993)
T.J. Cole et al.
Molecular genetic analysis of glucocorticoid signaling during mouse development
Steroids
(1995)
R. Diaz et al.
Prenatal corticosterone treatment induces long-term changes in spontaneous and apomorphine-mediated motor activity in male and female rats
Neuroscience
(1997)
R. Diaz et al.
Prenatal corticosterone increases spontaneous and d-amphetamine induced locomotor activity and brain dopamine metabolism in prepubertal male and female rats
Neuroscience
(1995)
R. Diaz et al.
Codistribution of the dopamine D-3 receptor and glucocorticoid receptor mRNAs during striatal prenatal development in the rat
Neuroscience Letters
(1997)
A. Dunn et al.
Physiological and behavioral-responses to corticotropin-releasing factor administration—is crf a mediator of anxiety or stress responses
Brain Research Reviews
(1990)

C.R.W. Edwards et al.

Dysfunction of the placental glucocorticoid barrier: a link between the fetal environment and adult hypertension?

Lancet

(1993)

I.J. Encio et al.

The genomic structure of the human glucocorticoid receptor

Journal of Biological Chemistry

(1991)

M.G. Forest et al.

Prenatal diagnosis and treatment of 2l-hydroxylase deficiency

Journal of Steroid Biochemistry and Molecular Biology

(1993)

R.R. Holson et al.

Prenatal dexamethasone or stress but not ACTH or corticosterone alter sexual behavior in male rats

Neurotoxicology and Teratology

(1995)

D. Hsu et al.

Rapid stress-induced elevations in corticotropin-releasing hormone mRNA in rat central amygdala nucleus and hypothalamic paraventricular nucleus: an in situ hybridization analysis

Brain Research

(1998)

R.A. Huff et al.

Glucocorticoids regulate the ontogenic transition of adrenergic receptor subtypes in rat liver

Life Sciences

(1991)

R.J. Irving et al.

Adult cardiovascular risk factors in premature babies

Lancet

(2000)

S.C. Langley-Evans et al.

Maternal dietary protein restriction, placental glucocorticoid metabolism and the programming of hypertension

Placenta

(1996)

A. Lopez-Bernal et al.

Corticosteroid metabolism in vitro by human placenta, fetal membranes and decidua in early and late gestation

Placenta

(1981)

J.B. Mitchell et al.

Serotonergic regulation of type II corticosteroid receptor binding in cultured hippocampal cells: the role of serotonin-induced increases in cAMP levels

Neuroscience

(1992)

M.J. Novy et al.

Dexamethasone and estradiol treatment in pregnant rhesus macaques: effects on gestation length, maternal plasma hormones and fetal growth

American Journal of Obstetrics and Gynecology

(1983)

D. O'Donnell et al.

Postnatal handling alters glucocorticoid but not mineralocorticoid receptor mRNA expression in the hippocampus of adult rats

Molecular Brain Research

(1994)

T.A. Slotkin et al.

Programming of brainstem serotonin transporter development by prenatal glucocorticoids

Developmental Brain Research

(1996)

J.W. Smythe et al.

Neonatal handling alters serotonin (5-HT) turnover and 5-HT2 receptor binding in selected brain regions: relationship to the handling effect on glucocorticoid receptor expression

Developmental Brain Research

(1994)

Y. Arai et al.

Critical exposure time for androgenization of the developing hypothalamus in the female rat

Endocrinology

(1968)

J. Baird et al.

Testing the fetal origins hypothesis in twins: the Birmingham twin study

Diabetologia

(2001)

D.J.P. Barker

Fetal and Infant Origins of Adult Disease

(1991)

D.J.P. Barker

Mothers, Babies and Disease in Later Life

(1994)

D.J.P. Barker et al.

Fetal and placental size and risk of hypertension in adult life

British Medical Journal

(1990)

D.J.P. Barker et al.

Type 2 (non-insulin dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth

Diabetologia

(1993)

D.J.P. Barker et al.

Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease

British Medical Journal

(1989)

I.Z. Beitens et al.

The metabolic clearance rate, blood production, interconversion and transplacental passage of cortisol and cortisone in pregnancy near term

Pediatric Research.

(1973)

R. Benediktsson et al.

Fetal osteocalcin levels are related to placental 11β-hydroxysteroid dehydrogenase activity

Clinical Endocrinology

(1995)

R. Benediktsson et al.

Placental 11β-hydroxysteroid dehydrogenase type 2 is the placental barrier to maternal glucocorticoids: ex vivo studies

Clinical Endocrinology

(1997)

L.M. Berry et al.

Preterm newborn lamb renal and cardiovascular responses after fetal or maternal antenatal betamethasone

American Journal of Physiology-Regulatory Integrative and Comparative Physiology

(1997)

X.P. Bian et al.

Promotional role for glucocorticoids in the development of intracellular signalling: enhanced cardiac and renal adenylate cyclase reactivity to β-adrenergic and non-adrenergic stimuli after low-dose fetal dexamethasone exposure

Journal of Developmental Physiology

(1992)

X.P. Bian et al.

Fetal dexamethasone exposure interferes with establishment of cardiac noradrenergic innervation and sympathetic activity

Teratology

(1993)

R.W. Brown et al.

The ontogeny of 11β-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor gene expression reveal intricate control of glucocorticoid action in development

Endocrinology

(1996)

R.W. Brown et al.

Isolation and cloning of human placental 11β-hydroxysteroid dehydrogenase-2 cDNA

Biochemical Journal

(1996)

G. Celsi et al.

Prenatal dexamethasone causes oligonephronia, sodium retention, and higher blood pressure in the offspring

Pediatric Research

(1998)

G. Celsi et al.

Inhibition of renal growth by prenatal dexamethasone and the programming of blood pressure in the offspring

Journal of the American Society of Nephrology

(1997)

P.M. Clark et al.

Size at birth and adrenocortical function in childhood

Clinical Endocrinology

(1996)

G.C. Curhan et al.

Birth-weight and adult hypertension and obesity in women

Circulation

(1996)

G.C. Curhan et al.

Birth weight and adult hypertension, diabetes mellitus, and obesity in US men

Circulation

(1996)

S. Dave-Sharma et al.

Extensive personal experience-Examination of genotype and phenotype relationships in 14 patients with apparent mineralocorticoid excess

Journal of Clinical Endocrinology and Metabolism

(1998)

R. Diaz et al.

Ontogeny of mRNAs encoding glucocorticoid and mineralocorticoid receptors and 11β-hydroxysteroid dehydrogenases in prenatal rat brain development reveal complex control of glucocorticoid action

Journal of Neuroscience

(1998)

J. Diorio et al.

Postnatal handling induces changes in the hippocampal expression of cyclic nucleotide-dependent response element binding proteins in the rat

Society of Neuroscience Abstracts

(1996)

Docherty, C., Kalmar-Nagy, J., Engelen, M., Nathanielz, P.J., 2001. Effect of in vivo infusion of dexamethasone at 0.75...

M. Dodic et al.

An early prenatal exposure to excess glucocorticoid leads to hypertensive offspring in sheep

Clinical Science

(1998)

L.W. Doyle et al.

Antenatal corticosteroid therapy and blood pressure at 14 years of age in preterm children

Clinical Science

(2000)

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Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms

Abstract

Section snippets

Introduction: the early life origins of adult disease

Programming

Glucocorticoid programming

Placental 11β-hydroxysteroid dehydrogenase type 2

Liver

Molecular mechanisms

Glucocorticoid programming in humans?

Acknowledgements

Molecular Cell Endocrinology

Lancet

Lancet

Lancet

Brain Research

Steroids

Neuroscience

Neuroscience

Neuroscience Letters

Brain Research Reviews

Lancet

Journal of Biological Chemistry

Journal of Steroid Biochemistry and Molecular Biology

Neurotoxicology and Teratology

Brain Research

Life Sciences

Lancet

Placenta

Placenta

Neuroscience

American Journal of Obstetrics and Gynecology

Molecular Brain Research

Developmental Brain Research

Developmental Brain Research

Critical exposure time for androgenization of the developing hypothalamus in the female rat

Endocrinology

Testing the fetal origins hypothesis in twins: the Birmingham twin study

Diabetologia

Fetal and Infant Origins of Adult Disease

Mothers, Babies and Disease in Later Life

Fetal and placental size and risk of hypertension in adult life

British Medical Journal

Type 2 (non-insulin dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth

Diabetologia

Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease

British Medical Journal

The metabolic clearance rate, blood production, interconversion and transplacental passage of cortisol and cortisone in pregnancy near term

Pediatric Research.

Fetal osteocalcin levels are related to placental 11β-hydroxysteroid dehydrogenase activity

Clinical Endocrinology

Placental 11β-hydroxysteroid dehydrogenase type 2 is the placental barrier to maternal glucocorticoids: ex vivo studies

Clinical Endocrinology

Preterm newborn lamb renal and cardiovascular responses after fetal or maternal antenatal betamethasone

American Journal of Physiology-Regulatory Integrative and Comparative Physiology

Promotional role for glucocorticoids in the development of intracellular signalling: enhanced cardiac and renal adenylate cyclase reactivity to β-adrenergic and non-adrenergic stimuli after low-dose fetal dexamethasone exposure

Journal of Developmental Physiology

Fetal dexamethasone exposure interferes with establishment of cardiac noradrenergic innervation and sympathetic activity

Teratology

The ontogeny of 11β-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor gene expression reveal intricate control of glucocorticoid action in development

Endocrinology

Isolation and cloning of human placental 11β-hydroxysteroid dehydrogenase-2 cDNA

Biochemical Journal

Prenatal dexamethasone causes oligonephronia, sodium retention, and higher blood pressure in the offspring

Pediatric Research

Inhibition of renal growth by prenatal dexamethasone and the programming of blood pressure in the offspring

Journal of the American Society of Nephrology

Size at birth and adrenocortical function in childhood

Clinical Endocrinology

Birth-weight and adult hypertension and obesity in women

Circulation

Birth weight and adult hypertension, diabetes mellitus, and obesity in US men

Circulation

Extensive personal experience-Examination of genotype and phenotype relationships in 14 patients with apparent mineralocorticoid excess

Journal of Clinical Endocrinology and Metabolism

Ontogeny of mRNAs encoding glucocorticoid and mineralocorticoid receptors and 11β-hydroxysteroid dehydrogenases in prenatal rat brain development reveal complex control of glucocorticoid action

Journal of Neuroscience

Postnatal handling induces changes in the hippocampal expression of cyclic nucleotide-dependent response element binding proteins in the rat

Society of Neuroscience Abstracts

An early prenatal exposure to excess glucocorticoid leads to hypertensive offspring in sheep