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Glucocorticoid programming of pituitary-adrenal function: mechanisms and physiological consequences
D O'Regan1, L L Welberg, M C Holmes
1Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
Insights
Adverse fetal events, like low birth weight, can permanently alter adult offspring health through fetal programming. Antenatal glucocorticoids in animal models show lasting effects on cardiovascular, metabolic, and neuroendocrine systems.
Area of Science:
- Developmental biology
- Endocrinology
- Epidemiology
Background:
- Epidemiological studies link adverse fetal events to permanent physiological changes in offspring, termed 'fetal programming'.
- Low birth weight in humans correlates with increased risks of adult cardiovascular, metabolic, and neuroendocrine disorders.
- Glucocorticoids administered during pregnancy reduce birth weight and affect organ maturation, impacting fetal development.
Purpose of the Study:
- To review evidence on how antenatal glucocorticoid exposure affects offspring's long-term health.
- To explore the mechanisms of fetal programming related to glucocorticoids and the hypothalamic-pituitary-adrenal (HPA) axis.
Main Methods:
- Review of existing data from rodent and other animal models.
- Analysis of studies investigating the effects of endogenous and exogenous glucocorticoids during pregnancy.
- Examination of changes in offspring's birth weight, physiology, and behavior.
Main Results:
- Antenatal glucocorticoid exposure in animal models reduced offspring birth weight.
- Offspring exhibited permanent hypertension, hyperglycemia, hyperinsulinemia, altered behavior, and neuroendocrine responses.
- Key processes involved setting the hypothalamic-pituitary-adrenal (HPA) axis 'set point' and glucocorticoid receptor (GR) expression.
Conclusions:
- Antenatal glucocorticoid exposure is a significant factor in fetal programming, leading to long-term health issues in offspring.
- Altered HPA axis function and GR expression are critical mechanisms underlying these programming effects.
- HPA axis hyperreactivity in low birth weight humans may indicate early signs of fetal programming.
Abstract:
Increasing epidemiological evidence supports the notion that adverse events in fetal life permanently alter the structure and physiology of the adult offspring, a phenomenon dubbed 'fetal programming'. In particular, low weight or thinness at birth in humans is associated with an increased risk of cardiovascular and metabolic disorders as well as neuroendocrine dysfunction in adult life. Glucocorticoid administration during pregnancy is well-documented to both reduce offspring birth weight and alter the maturation of organs (hence their use to accelerate fetal lung maturation in premature labour). Here data are reviewed which show, in rodents and other models, that antenatal exposure to endogenous or exogenous glucocorticoids reduces offspring birth weight and produces permanent hypertension, hyperglycaemia, hyperinsulinaemia, altered behaviour and neuroendocrine responses throughout the lifespan. Processes underlying fetal programming include determination of the 'set point' of the hypothalamic-pituitary-adrenal (HPA) axis and of tissue glucocorticoid receptor (GR) expression. Similar HPA axis hyperreactivity occurs in lower birth weight humans and may be an early manifestation of the 'low birth weight' phenotype.