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Fetal and Neonatal HPA Axis

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ABSTRACT

Stress is an integral part of life. Activation of the hypothalamus‐pituitary‐adrenal (HPA) axis in the adult can be viewed as mostly adaptive to restore homeostasis in the short term. When stress occurs during development, and specifically during periods of vulnerability in maturing systems, it can significantly reprogram function, leading to pathologies in the adult. Thus, it is critical to understand how the HPA axis is regulated during developmental periods and what are the factors contributing to shape its activity and reactivity to environmental stressors. The HPA axis is not a passive system. It can actively participate in critical physiological regulation, inducing parturition in the sheep for instance or being a center stage actor in the preparation of the fetus to aerobic life (lung maturation). It is also a major player in orchestrating mental function, metabolic, and cardiovascular function often reprogrammed by stressors even prior to conception through epigenetic modifications of gametes. In this review, we review the ontogeny of the HPA axis with an emphasis on two species that have been widely studied—sheep and rodents—because they each share many similar regulatory mechanism applicable to our understanding of the human HPA axis. The studies discussed in this review should ultimately inform us about windows of susceptibility in the developing brain and the crucial importance of early preconception, prenatal, and postnatal interventions designed to improve parental competence and offspring outcome. Only through informed studies will our public health system be able to curb the expansion of many stress‐related or stress‐induced pathologies and forge a better future for upcoming generations. © 2016 American Physiological Society. Compr Physiol 6:33‐62, 2016.

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Figure 1. Figure 1. The HPA axis with specific reference to developmental aspects discussed in this review. Adapted, with permission, from Paul et al. ().
Figure 2. Figure 2. Comparative timeline of the onset of function in the HPA axis between human, sheep and rat. Values are given as a % of total pregnancy time taking 42 weeks, 140 days, and 21 days as representative of full‐term pregnancy for human, sheep, and rat, respectively. Note that in all three species, the onset of pituitary ACTH production appears to precede that of hypothalamic neuropeptides such as CRH, AVP, and OT. Detailed ages for each species are given in the text and their equivalent in percentage gestation is provided on the figure.
Figure 3. Figure 3. The feto‐placental unit in the human and nonhuman primate for the production of estrogens. The fetal zone of the adrenal gland cannot process DHEAS further into estrogens because it lacks the enzyme HSD3B (hydroxysteroidogenase 3B). Instead, DHEAS is converted to estrogens in the placenta, which lacks the ability to produce DHEAS from cholesterol because of the absence of CYP17 enzyme converting 17OH‐Pregnenolone into DHEA.
Figure 4. Figure 4. Changes in plasma levels of DHAS and adrenal weight as a function of gestation in the fetal rhesus monkey. A large parallel increase in fetal adrenal weight and DHEAS production marks the last trimester of fetal life and prepares for delivery. Reused from Serón‐Ferré M et al. (), with permission from the Endocrine Press.
Figure 5. Figure 5. Hormonal integration of the fetal HPA axis and the placenta in human pregnancy. The fetal pituitary secretes ACTH, which stimulates the synthesis and release of cortisol from the definitive zone of the adrenal cortex and DHEAS from the fetal zone of the adrenal cortex. Cortisol exerts negative feedback inhibition on the hypothalamo‐pituitary unit (left). DHEAS is converted to estrogens by the placenta (right). Estrogen and CRH, secreted by the placenta, may facilitate fetal ACTH secretion (right).
Figure 6. Figure 6. Hormonal integration of the fetal HPA axis and the placenta in sheep pregnancy. The fetal pituitary secretes ACTH, which stimulates the synthesis and secretion of cortisol from the adrenal cortex. In addition to its negative feedback action (left), preparturient increases in plasma cortisol concentration induce CYP17 in the placenta, allowing for increased secretion of estrogen which, in turn, augments myometrial activity and may further facilitate fetal ACTH secretion.
Figure 7. Figure 7. Increased activity in the HPA axis of the fetal sheep toward the end of gestation as evidenced by large increases in plasma cortisol (top) and ACTH (bottom). Reused with permission from Rose JC et al. ().
Figure 8. Figure 8. Left panel: The fetal cerebral cortex and other brain regions contain high concentrations of PGE2, and express the enzymes required for local biosynthesis of PGE2 (). Shown are tissue concentrations of PGE2 (top), PGHS2 mRNA (middle), and PGHS2 protein (bottom), plotted as a function of fetal gestational age. Reproduced with permission. Right panel: Inhibition of brain PTGS2 (PGHS2) by intracerebroventricular infusion of nimesulide prolongs gestation. Frequency of fetuses remaining in utero is plotted as a function of fetal gestational age (). Reproduced with permission by the Endocrine Society.
Figure 9. Figure 9. Ontogeny of the HPA axis in the rat showing age‐related increase in hypothalamic CRH content (top left) and low plasma ACTH responses to ether stress during the first 7 days of life, although the pituitary remain responsive to exogenous CRH during this period (top, right). In contrast, plasma beta‐endorphin response to ether stress is highest on PND7 and declines thereafter (bottom, left). Plasma corticosterone levels after ether stress remain very low until PND13, after which time, the adrenal gland emerges from the stress hyporesponsive period (bottom, right). Reused with permission from De Kloet ER et al. ().
Figure 10. Figure 10. Age‐dependent stimulation of the pituitary by oCRH (10 μg/kbg BW) demonstrates that while the pituitary is already well responsive byPND10 (top), adrenal corticosterone output is low during the first 14 days of life (bottom). Reused from Walker CD et al. (), with permission from the Endocrine Press.
Figure 11. Figure 11. Schematic overview of the key points in control of the neonatal HPA axis activity during the stress hyporesponsive period (SHRP) in the rodent. Adrenal corticosterone secretion is low under basal conditions and is hyporesponsive to mild stressors. In contrast, CRH neurons can respond to these mild stressors but the signal is poorly transduced from brain to pituitary, in part because of potent GR‐mediated negative feedback. Although the stress‐induced rises of corticosterone during the SHRP are small, the bioavailability of the hormone is high. ACTH, adrenocorticotropic hormone; GR: glucocorticoid receptor, MR, mineralocorticoid receptor. Reused with permission from Champagne DL et al. ().
Figure 12. Figure 12. Models of GR‐mediated CRH downregulation. (A) A DNA binding‐dependent mechanism. A GR holoreceptor monomer binds to the nGRE and recruits DnMT3b. DnMT3b methylates the promoter and subsequently leads to the recruitment of MeCP2. GR and/or MeCP2 recruit HDAC1. The assembled then represses CRH expression. (B) A DNA binding‐independent mechanism. A GR holoreceptor bound or not bound to MeCP2 associates with DnMT3b. A GR‐MeCP2‐HDAC1, assembles at the promoter. The order of recruitment and assembly are not known. Me, methyl; MeCP2, Methyl CpG binding protein 2. Reused from Sharma D et al. (), with permission from the Endocrine Press.
Figure 13. Figure 13. Epigenetic programming of AVP. Experience‐dependent activation of neurons in the PVN during early life leads to phosphorylation of MeCP2 inhibiting its DNA binding to and repression of AVP. In the absence of MeCP2‐binding DNA, hypomethylation gradually evolves in early life stressed mice underpinning reduced MeCP2 occupancy at the AVP enhancer and maintaining epigenetic control of AVP expression into later life. Reused with permission from Murgatroyd C et al. ().
Figure 14. Figure 14. Handling provides for multisensoral stimulation of pups, leading to changes in pup physiology and changes in maternal behavior that appear to mediate the handling effect on hippocampal glucocorticoid receptor gene expression. In response to the handling manipulation, circulating levels of triiodothyronine increase and these stimulate hippocampal 5‐HT activity at the level of the hippocampus. In vitro studies with cultured hippocampal neurons reveal that 5‐HT can directly modulate glucocorticoid receptor expression in hippocampal neurons and that this effect is mediated by a 5‐HT7‐like receptor, which is positively coupled to cAMP. Thus, hippocampal cAMP formation, PKA activity, and mRNA levels for AP‐2 and NGFI‐A are increased together with their binding to their respective consensus sequences, such as those found on a promoter for the human glucocorticoid receptor gene. This leads to both demethylation of the promoter and histone acetylation which increases GR expression. Glucocorticoid feedback on HPA axis is thus enhanced by the higher expression of hippocampal GR. Modified, with permission, from Meaney MJ et al. ().


Figure 1. The HPA axis with specific reference to developmental aspects discussed in this review. Adapted, with permission, from Paul et al. ().


Figure 2. Comparative timeline of the onset of function in the HPA axis between human, sheep and rat. Values are given as a % of total pregnancy time taking 42 weeks, 140 days, and 21 days as representative of full‐term pregnancy for human, sheep, and rat, respectively. Note that in all three species, the onset of pituitary ACTH production appears to precede that of hypothalamic neuropeptides such as CRH, AVP, and OT. Detailed ages for each species are given in the text and their equivalent in percentage gestation is provided on the figure.


Figure 3. The feto‐placental unit in the human and nonhuman primate for the production of estrogens. The fetal zone of the adrenal gland cannot process DHEAS further into estrogens because it lacks the enzyme HSD3B (hydroxysteroidogenase 3B). Instead, DHEAS is converted to estrogens in the placenta, which lacks the ability to produce DHEAS from cholesterol because of the absence of CYP17 enzyme converting 17OH‐Pregnenolone into DHEA.


Figure 4. Changes in plasma levels of DHAS and adrenal weight as a function of gestation in the fetal rhesus monkey. A large parallel increase in fetal adrenal weight and DHEAS production marks the last trimester of fetal life and prepares for delivery. Reused from Serón‐Ferré M et al. (), with permission from the Endocrine Press.


Figure 5. Hormonal integration of the fetal HPA axis and the placenta in human pregnancy. The fetal pituitary secretes ACTH, which stimulates the synthesis and release of cortisol from the definitive zone of the adrenal cortex and DHEAS from the fetal zone of the adrenal cortex. Cortisol exerts negative feedback inhibition on the hypothalamo‐pituitary unit (left). DHEAS is converted to estrogens by the placenta (right). Estrogen and CRH, secreted by the placenta, may facilitate fetal ACTH secretion (right).


Figure 6. Hormonal integration of the fetal HPA axis and the placenta in sheep pregnancy. The fetal pituitary secretes ACTH, which stimulates the synthesis and secretion of cortisol from the adrenal cortex. In addition to its negative feedback action (left), preparturient increases in plasma cortisol concentration induce CYP17 in the placenta, allowing for increased secretion of estrogen which, in turn, augments myometrial activity and may further facilitate fetal ACTH secretion.


Figure 7. Increased activity in the HPA axis of the fetal sheep toward the end of gestation as evidenced by large increases in plasma cortisol (top) and ACTH (bottom). Reused with permission from Rose JC et al. ().


Figure 8. Left panel: The fetal cerebral cortex and other brain regions contain high concentrations of PGE2, and express the enzymes required for local biosynthesis of PGE2 (). Shown are tissue concentrations of PGE2 (top), PGHS2 mRNA (middle), and PGHS2 protein (bottom), plotted as a function of fetal gestational age. Reproduced with permission. Right panel: Inhibition of brain PTGS2 (PGHS2) by intracerebroventricular infusion of nimesulide prolongs gestation. Frequency of fetuses remaining in utero is plotted as a function of fetal gestational age (). Reproduced with permission by the Endocrine Society.


Figure 9. Ontogeny of the HPA axis in the rat showing age‐related increase in hypothalamic CRH content (top left) and low plasma ACTH responses to ether stress during the first 7 days of life, although the pituitary remain responsive to exogenous CRH during this period (top, right). In contrast, plasma beta‐endorphin response to ether stress is highest on PND7 and declines thereafter (bottom, left). Plasma corticosterone levels after ether stress remain very low until PND13, after which time, the adrenal gland emerges from the stress hyporesponsive period (bottom, right). Reused with permission from De Kloet ER et al. ().


Figure 10. Age‐dependent stimulation of the pituitary by oCRH (10 μg/kbg BW) demonstrates that while the pituitary is already well responsive byPND10 (top), adrenal corticosterone output is low during the first 14 days of life (bottom). Reused from Walker CD et al. (), with permission from the Endocrine Press.


Figure 11. Schematic overview of the key points in control of the neonatal HPA axis activity during the stress hyporesponsive period (SHRP) in the rodent. Adrenal corticosterone secretion is low under basal conditions and is hyporesponsive to mild stressors. In contrast, CRH neurons can respond to these mild stressors but the signal is poorly transduced from brain to pituitary, in part because of potent GR‐mediated negative feedback. Although the stress‐induced rises of corticosterone during the SHRP are small, the bioavailability of the hormone is high. ACTH, adrenocorticotropic hormone; GR: glucocorticoid receptor, MR, mineralocorticoid receptor. Reused with permission from Champagne DL et al. ().


Figure 12. Models of GR‐mediated CRH downregulation. (A) A DNA binding‐dependent mechanism. A GR holoreceptor monomer binds to the nGRE and recruits DnMT3b. DnMT3b methylates the promoter and subsequently leads to the recruitment of MeCP2. GR and/or MeCP2 recruit HDAC1. The assembled then represses CRH expression. (B) A DNA binding‐independent mechanism. A GR holoreceptor bound or not bound to MeCP2 associates with DnMT3b. A GR‐MeCP2‐HDAC1, assembles at the promoter. The order of recruitment and assembly are not known. Me, methyl; MeCP2, Methyl CpG binding protein 2. Reused from Sharma D et al. (), with permission from the Endocrine Press.


Figure 13. Epigenetic programming of AVP. Experience‐dependent activation of neurons in the PVN during early life leads to phosphorylation of MeCP2 inhibiting its DNA binding to and repression of AVP. In the absence of MeCP2‐binding DNA, hypomethylation gradually evolves in early life stressed mice underpinning reduced MeCP2 occupancy at the AVP enhancer and maintaining epigenetic control of AVP expression into later life. Reused with permission from Murgatroyd C et al. ().


Figure 14. Handling provides for multisensoral stimulation of pups, leading to changes in pup physiology and changes in maternal behavior that appear to mediate the handling effect on hippocampal glucocorticoid receptor gene expression. In response to the handling manipulation, circulating levels of triiodothyronine increase and these stimulate hippocampal 5‐HT activity at the level of the hippocampus. In vitro studies with cultured hippocampal neurons reveal that 5‐HT can directly modulate glucocorticoid receptor expression in hippocampal neurons and that this effect is mediated by a 5‐HT7‐like receptor, which is positively coupled to cAMP. Thus, hippocampal cAMP formation, PKA activity, and mRNA levels for AP‐2 and NGFI‐A are increased together with their binding to their respective consensus sequences, such as those found on a promoter for the human glucocorticoid receptor gene. This leads to both demethylation of the promoter and histone acetylation which increases GR expression. Glucocorticoid feedback on HPA axis is thus enhanced by the higher expression of hippocampal GR. Modified, with permission, from Meaney MJ et al. ().
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Charles E. Wood, Claire‐Dominique Walker. Fetal and Neonatal HPA Axis. Compr Physiol 2015, 6: 33-62. doi: 10.1002/cphy.c150005