The HPA axis

GCs (cortisol in humans), the end product of the HPA axis, are steroid hormones that are physiologically important for maintaining homeostasis. GCs exert a wide array of key metabolic, endocrine, and immune effects on most cells, perhaps more than any other biological ligand. Furthermore, GCs pass through the blood-brain barrier and with consequences for brain structure and function.

GCs serve as a major mediator of the stress response and promote survival in the face of threat. The cascade of events that produce changes in cortisol release by the adrenals begins with the release of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) by cells in the paraventricular nuclei of the hypothalamus. CRH and AVP are released through capillary vessels to the anterior pituitary in which they stimulate the release of adenocorticotropin (ACTH) hormone into circulation. ACTH stimulates the biosynthesis and release of cortisol from the adrenal cortex.

Because of the damaging effects of chronic exposure to elevated levels of cortisol, the HPA axis is protected by a negative feedback loop whereby cortisol binds to receptors in the pituitary and hypothalamus as well as the hippocampus and prefrontal cortex inhibiting or turning off the HPA axis response. In contrast to the inhibitory role of cortisol on hypothalamic CRH production, cortisol increases the production of CRH in brain regions including the central nucleus of the amygdala, the activation of which plays a role not only in stimulating the HPA axis but also in stimulating increases in central norepinephrine and peripheral activation of the sympathetic nervous system. The activation of the HPA axis, including the release of GCs, involves a complex interaction of multiple central and peripheral stress response systems. The interaction between the HPA axis and the sympathetic nervous system has been critically reviewed by Kvetnansky et al. This review will focus on the primary consequences of GC treatment for the functioning of the HPA axis.

Changes in the maternal HPA axis during pregnancy

In the course of pregnancy, dramatic changes in the functioning of the maternal HPA axis are observed because the placenta expresses the genes for CRH (hCRHmRNA) and the precursor for ACTH and beta-endorphin (proopiomelanocortin). Placental CRH production increases dramatically over gestation and placental CRH plays a central role in the regulation of fetal maturation and the timing of parturition. In contrast to the negative feedback regulation of hypothalamic CRH, cortisol stimulates the expression of hCRHmRNA in the placenta, establishing a positive feedback loop that allows for the simultaneous increase of placental CRH, ACTH, and cortisol over the course of gestation. For example maternal cortisol increases 2- to 4-fold during pregnancy. This physiologic increase exerts broad influences on the developing fetus including maturation of the fetal lungs, the central nervous system (CNS), and other organ systems.

GCs influence fetal brain development by changing neuronal migration, synaptic plasticity, and neurotransmitter activity. Because of the positive feedback between GCs and placental CRH, the effects of excess endogenous or synthetic GCs may be amplified with potentially negative consequences for the developing fetus. The consequences of prenatal treatment with synthetic GCs such as betamethasone and dexamethasone may be more profound as they cross the placenta more easily because they are not readily metabolized by the placental enzyme, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), that protects the fetus from maternal cortisol ( Figure ).

Neuroendocrine interactions among the maternal, placental, and fetal compartments

The top panel depicts the activation (+) and negative feedback inhibition (−) pathways of the HPA system. During pregnancy, CRH is released from the placenta into both the maternal and fetal compartments. In contrast to the negative feedback regulation of hypothalamic CRH, cortisol increases the production of CRH from the placenta. Because of this positive feedback between cortisol and placental CRH, the effects of GCs on the fetus may be amplified. In addition to its effects on placental CRH, maternal cortisol passes through the placenta. However, the effects of maternal cortisol on the fetus are modulated by the presence of a placental enzyme 11βHSD2, which oxidizes it into an inactive form, cortisone. Synthetic GCs used for fetal lung maturation (betamethasone and dexamethasone) cross the placenta more easily because they are not readily metabolized by 11βHSD2. Structures of the HPA axis begin their development early in gestation and become increasingly functional with the progression toward term. See text for description.

CRH, corticotropin-releasing hormone; GC, glucocorticoids; HPA , hypothalamic-pituitary-adrenocortical.

Waffarn. Antenatal corticosteroids and HPA axis function. Am J Obstet Gynecol 2012.

Changes in the maternal HPA axis during pregnancy

In the course of pregnancy, dramatic changes in the functioning of the maternal HPA axis are observed because the placenta expresses the genes for CRH (hCRHmRNA) and the precursor for ACTH and beta-endorphin (proopiomelanocortin). Placental CRH production increases dramatically over gestation and placental CRH plays a central role in the regulation of fetal maturation and the timing of parturition. In contrast to the negative feedback regulation of hypothalamic CRH, cortisol stimulates the expression of hCRHmRNA in the placenta, establishing a positive feedback loop that allows for the simultaneous increase of placental CRH, ACTH, and cortisol over the course of gestation. For example maternal cortisol increases 2- to 4-fold during pregnancy. This physiologic increase exerts broad influences on the developing fetus including maturation of the fetal lungs, the central nervous system (CNS), and other organ systems.

GCs influence fetal brain development by changing neuronal migration, synaptic plasticity, and neurotransmitter activity. Because of the positive feedback between GCs and placental CRH, the effects of excess endogenous or synthetic GCs may be amplified with potentially negative consequences for the developing fetus. The consequences of prenatal treatment with synthetic GCs such as betamethasone and dexamethasone may be more profound as they cross the placenta more easily because they are not readily metabolized by the placental enzyme, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), that protects the fetus from maternal cortisol ( Figure ).

Neuroendocrine interactions among the maternal, placental, and fetal compartments

The top panel depicts the activation (+) and negative feedback inhibition (−) pathways of the HPA system. During pregnancy, CRH is released from the placenta into both the maternal and fetal compartments. In contrast to the negative feedback regulation of hypothalamic CRH, cortisol increases the production of CRH from the placenta. Because of this positive feedback between cortisol and placental CRH, the effects of GCs on the fetus may be amplified. In addition to its effects on placental CRH, maternal cortisol passes through the placenta. However, the effects of maternal cortisol on the fetus are modulated by the presence of a placental enzyme 11βHSD2, which oxidizes it into an inactive form, cortisone. Synthetic GCs used for fetal lung maturation (betamethasone and dexamethasone) cross the placenta more easily because they are not readily metabolized by 11βHSD2. Structures of the HPA axis begin their development early in gestation and become increasingly functional with the progression toward term. See text for description.

CRH, corticotropin-releasing hormone; GC, glucocorticoids; HPA , hypothalamic-pituitary-adrenocortical.

Waffarn. Antenatal corticosteroids and HPA axis function. Am J Obstet Gynecol 2012.

Development of the fetal HPA axis

Liggins observed that the fetal HPA axis played a major role in the onset of labor, and its ablation resulted in the underdevelopment of the fetal lungs. Since then, a number of studies have shown that the fetal HPA axis is highly sensitive to excess levels of GC that could alter the regulation of HPA function. The fetal adrenal gland makes unique contributions to both the regulation of fetal development and the timing of parturition.

Morphologically, the fetal adrenal gland is comprised of 3 zones: the outer, definitive zone; a large, inner fetal zone; and an intermediate transitional zone. The fetal adrenals undergo rapid growth throughout gestation, and at term gestation, the fetal adrenals are significantly larger, relative to body weight, than the adult adrenals. The adrenal gland has steroidogenic enzymes as early as the seventh gestational week, and there is evidence for a functional stress response involving an increased production of cortisol in response to pain during the latter half of gestation.

Animal and human data strongly suggest that GCs program the fetal HPA axis with consequences for postnatal functioning. This programming may occur in part through the alterations of brain regions that are both integral to the regulation of stress responses and vulnerable to exposure to stress hormones. Vulnerable regions such as the hippocampus and amygdala undergo rapid development during fetal life. Both are identifiable between 6 and 8 gestational weeks, and by term the basic neuroanatomical architecture of these regions is present.

Cortisol has affinity to 2 receptors, mineralocorticoid receptors and glucocorticoid receptors (GRs). Limited information exists regarding the time course of prenatal development of cortisol receptors in humans. However, data indicate that both receptors types are present in the human hippocampus by 24 gestational weeks.

Animal data

Antenatal GC treatment has a broad range of effects on the fetus including regulation of growth, organ maturation, immune functioning, and the sympathetic nervous system. Alterations to the functioning of the HPA axis is a primary consequence of prenatal GC treatment that is observed in the offspring of a variety of species including rats, sheep, guinea pigs, and nonhuman primates. Data indicate that these changes in the functioning of the HPA axis are associated with alterations of GC receptor number in regions including the prefrontal cortex, hippocampus, amygdala, and pituitary that are important for activation and negative feedback regulation of the HPA axis.

The nature and the magnitude of these effects are determined by the type of steroid used (eg, betamethasone or dexamethasone), the number of doses, and the timing of exposure. Specifically, the binding affinity differs for betamethasone and dexamethasone (eg, dexamethasone has a greater affinity for GR receptors), and there is evidence that these steroids have differential consequences for offspring. In terms of dose, data indicate that exposure to multiple doses is associated with more profound consequences. Finally, organ systems may be most vulnerable to the consequences of GC treatment during times of rapid development. Thus, the timing of treatment will likely determine the nature and the magnitude of the effects.

In addition, the type of synthetic GC and dose also has differential effects on lung maturation and surfactant synthesis. Carefully conducted studies with sheep have further documented that the phenotypic changes to the HPA axis are additionally determined by the developmental stage at the time of assessment. For example, although increased HPA axis activity is observed in the young animal, suppression of HPA axis activity is observed as the animal matures.

Exciting and important new work raises the possibility that prenatal exposure to synthetic GCs may alter reproductive functioning among female offspring and exert intergenerational effects on HPA axis functioning. Dunn et al have recently demonstrated that females exposed to betamethasone in utero require a greater number of ovulatory cycles for successful reproduction as compared with their unexposed counterparts. These data raise the possibility that intrauterine exposure to synthetic GCs may have consequences for fertility among female offspring. Intergenerational consequences of early life experiences for the functioning of the HPA axis have been observed. Potential mechanisms for these effects include altered functioning of endocrine and cardiovascular systems among prenatally exposed females as well as epigenetic changes.

Human data

Less is known about the consequences of antenatal GC exposure in humans. Assessments of cord blood and amniotic fluid indicate acute suppression of endogenous fetal cortisol production and an acute increase in GC bioactivity in response to synthetic GCs. The suppression of endogenous fetal/neonatal cortisol production appears to persist into the immediate postnatal period. Several studies have shown that among preterm infants exposed to antenatal GCs, unstimulated (baseline) cortisol levels are suppressed for several days after treatment during the first postnatal week and then return to normal levels. The assessment of cortisol levels at a single time point during the day provides limited information regarding the functioning of the HPA axis. To better understand the influence of prenatal GC treatment on HPA axis functioning, it is necessary to use serial assessments to evaluate both responses to stressors and the circadian regulation.

Few studies have evaluated the consequences of intrauterine exposure to synthetic GCs on the ability of the HPA axis to respond to a challenge. As reviewed in the Table , the limited existing data, including studies from our own laboratory, suggest that prenatal GC treatment may have persisting effects on the HPA axis and regulation of stress responses. These studies indicate that although suppression of unstimulated/ baseline levels of cortisol is present only during the first several days after treatment, the effects on HPA axis regulation persist.

We have observed that prenatal treatment with a single course of betamethasone is associated with a suppression of the cortisol response to the painful stress of a heel-stick blood draw among preterm infants and that this effect persists for at least 4-6 weeks after birth. Similarly, in a study including a combined sample of term and preterm neonates, Schaffer et al documented a suppressed cortisol response to heel stick. These studies suggest that prenatal GC treatment has implications for HPA axis regulation that persist for at least 8 weeks after treatment, with some evidence for greater consequences associated with exposure to multiple courses.

One of the limitations of existing research is the focus on preterm infants who experience a range of acute medical complications and are exposed to multiple sources of stress as part of their care in neonatal intensive care units. Factors such as preterm birth, acute respiratory illness, and exposure to painful medical procedures have been shown to affect the development of the HPA axis and thus may interfere with the ability to accurately identify and isolate the consequences of GC therapy.

To address this issue, we evaluated the cortisol response to the painful stress of a heel-stick blood draw among full-term infants treated with a single course of the GC betamethasone and a matched comparison group of infants born at term gestation. We found that prenatal treatment with the synthetic GC, betamethasone, was associated with a more pronounced cortisol response to the painful stress of the heel-stick procedure among healthy infants born at term gestation, despite no difference in baseline levels. Interestingly, this heightened cortisol response to the heel-stick procedure is similar to the one observed among term infants exposed to elevated levels of endogenous maternal cortisol during the third trimester. These data suggest a lasting influence of prenatal exposure to excess GCs that has persisting consequences for the functioning of the newborn HPA axis.

There is limited evidence regarding the long-term consequences of prenatal GC treatment for the functioning of the HPA axis. The 2 studies that evaluate the consequences of GC exposure for HPA axis functioning later in infancy yield conflicting results. This may be due to the inclusion of heterogeneous samples of preterm infants who were exposed to different types and doses of steroids at varying times during pregnancy and postpartum.

To our knowledge, only 1 study has evaluated the consequences of antenatal GC treatment for adult HPA axis functioning. At 30 years of age, morning cortisol levels were 7% higher among individuals exposed to antenatal steroids as compared with the control group. This increase was not significant after consideration of factors including sex, birthweight, gestational age at birth, trial type, body mass index, and the use of oral contraceptives. The fact that a tendency for an effect on the HPA axis was observed in the presence of multiple confounding variables and with a limited evaluation of the HPA axis leaves open the possibility that prenatal GC treatment may exert long-term consequences on the functioning of the HPA axis in humans.

Based on the experimental animal data and human observations, it is evident that the HPA axis is particularly vulnerable to exposure to elevated levels of endogenous and exogenous GCs. Dysregulation of HPA axis functioning during infancy may put children at risk for physiological and behavioral problems throughout the life span. A parallel set of observations in a model of prenatal stress having programming effects and adverse outcomes on the fetal HPA axis and the hypothalamus-adrenal-gonadal axis is with the fetal alcohol spectrum disorder, which further confirms that the fetal HPA axis is susceptible to changes secondary to prenatal stress with long-term consequences.

The focus of this review is on the programming consequences of antenatal GC treatment. It is, however, noteworthy that other common antenatal therapies such as administration of beta 2 adrenergic agonists additionally exert developmental influences and may interact with the effects of GC treatment.