Review
Early programming of the hypothalamo–pituitary–adrenal axis

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Abstract

The ability of the early environment to program the hypothalamo–pituitary–adrenal (HPA) axis has been documented in several species. There is considerable evidence that a similar process can also occur in humans. Studies of animals indicate that the phenotype of HPA function following early manipulation depends on the timing and intensity of the manipulation, in addition to the gender of the fetus or neonate. There is considerable interplay between the HPA and the hypothalamo–pituitary–gonadal axes, and emerging evidence indicates that this interaction is modified by early environmental manipulation. Studies are rapidly unraveling the mechanisms that underlie developmental programming of the HPA axis. Understanding these mechanisms could hold the key to the development of therapeutic interventions aimed at reversing the impact of an adverse intrauterine or neonatal environment.

Section snippets

Prenatal stress and HPA function in adult life

Prenatal stress (PS) during pregnancy permanently programs neuroendocrine and behavioral responses in offspring (for review see [2]). Most studies have been undertaken in the rat, with fewer studies in the primate, guinea pig and cow. The PS paradigm typically involves induction of maternal stress from one to three times a day, either throughout or at selected time points during pregnancy.

In rat offspring, PS is generally associated with increased responsiveness of the HPA axis to stress;

Transduction of stress signals from mother to fetus

The route by which PS programs HPA activity and behavior in offspring is not entirely clear. Stress will lead to many cardiovascular and endocrine changes in the mother, including increases in the secretion of ACTH, β-endorphin, glucocorticoids (GCs) and catecholamines. The placenta forms a structural and biochemical barrier to many of these maternal factors, although several will enter the fetus. Alternatively, there might be indirect effects on the fetus via modification of placental

Prenatal synthetic glucocorticoid exposure and HPA function

Unlike the situation for endogenous GCs, 11β-HSD2 has a low affinity for sGC (e.g. dexamethasone and betamethasone), and so they pass rapidly from mother to fetus. Maternal treatment with sGC has provided a useful tool with which to investigate the impact of GC on the development and subsequent function of the HPA axis. This is also an important line of clinical investigation, because sGC is used routinely to treat women (∼10% of pregnancies) who are at risk of delivering prematurely [48]. sGC

Relevance of HPA programming to human disease

Alterations in HPA activity throughout life will impact on adult health because of altered tissue exposure to endogenous GC. Elevated plasma cortisol has been associated with atherosclerosis, immunosuppression, depression and cognitive impairment, in addition to raised cholesterol levels and increased incidence of T2DM 68., 69.. In the central nervous system, it is possible that compromise in the developing hippocampus (i.e. reduction of pyramidal neurons or alterations in axonal/dendritic

Summary

The perinatal environment programs HPA function and associated behavior throughout life, and there is considerable evidence that this can also occur in humans. The phenotype of HPA function following perinatal manipulation depends clearly on the timing, duration and intensity of the manipulation, in addition to gender. Studies are rapidly unraveling the mechanisms that underlie developmental programming of the HPA axis. Understanding these mechanisms could facilitate the development of

Acknowledgements

My studies cited herein were supported by the Canadian Institutes of Health Research (MOP-49511, MT-14691) and the Natural Sciences and Engineering Council of Canada.

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