Article summary with Developmental origins of the human hypothalamic-pituitary-adrenal axis by Howland a.o. - 2017

What is the developmental origins of disease or fetal programming model?

This model predicts that early exposures to adverse events and signals have life-long consequences for physical and psychological health. Programming refers to the effects of an environmental signal that acts during a sensitive developmental period to influence the construction of specific organ systems.

How can environmental cues experienced during fetal development influence health across the lifespan according to the fetal programming model?

A developing fetus is sensitive and responsive to maternal nutritional, immune, vascular, and endocrine signals. Those signals convey information about the quality of the external environment. In response to those signals, the fetus adjust its developmental trajectory to prepare for life after birth. These developmental alterations are not necessarily bad, if the postnatal environment matches the one predicted by the prenatal environment. But if there is a mismatch, the risk for disease may increase.

How is the hypothalamic-pituitary-adrenal axis related to prenatal experiences and later health outcomes?

The hypothalamic-pituitary-adrenal (HPA) axis is formed during fetal life and susceptible to prenatal influences. A mature HPA axis controls reactions to stress and regulates many body processes, such as digestion, the immune system, mood and emotion, and energy storage. Programming of the HPA axis during fetal life is proposed as a primary mechanism by which early experiences are linked to later health outcomes.

What is corticotropin-releasing hormone?

Corticotropin-releasing hormone (CRH) is a highly conserved peptide hormone comprising 41 amino acid residues. In the anterior pituitary it mediates the release of corticotrophin leading to the release of adrenocortical steroids. CRH is the primary regulator of the HPA axis. It is responsible for the release of many hormone events that mobilize the body´s physiological and psychological resources to cope with stress.

What is the role of cortisol in dysregulation of the HPA axis?

Cortisol binds to two types of receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Stress-induced elevations of cortisol lead to activation and regulation of cardiovascular and immune systems, utilization of energy stores, and inhibition of feeding, reproductive, and growth functions. High levels of cortisol inhibit HPA activity by binding to MRs and GRs. Prolonged or chronic stress may result in the dysregulation of the HPA axis.

How is HPA axis dysregulation related to adverse health outcomes?

The relation between HPA axis functioning and disease is complex and bidirectional. HPA axis functioning serves as a risk factor for as well as a consequence of disease. HPA axis dysregulation has been associated with different pathological conditions, such as metabolic and cardiovascular disease, obesity, hypertension, altered immune function, sleep disturbances, and affective disorders.

What is the role of the placenta in the link between maternal and fetal stress?

During the prenatal period there are big changes in both the maternal and developing fetal stress systems. The placenta is primarily responsible for these changes. The placenta produces its own hormones which bind to maternal hormone receptors and adjust maternal physiology to benefit both the mother and the fetus. One of the hormones produced by the placenta is CRH, which is the primary regulator of the stress response system. It both influences and is influenced by maternal and fetal stress signals. Though the placenta produces the main amount of CRH, the fetal stress system is immature and relies heavily upon maternal and placental inputs. The prenatal stress response system can be seen as an integrated maternal-placental-fetal steroidogenic unit.

How can prenatal psychological and biological stress influence the development of the fetal HPA axis?

Fetal exposure to maternal and placental stress hormones is seen as a primary biological pathway by which prenatal stress can influence the development of the fetal HPA axis. Maternal cortisol and placental CRH are important stress hormones which program the developing fetal HPA axis. The maternal-placental-fetal steroidogenic unit produces a lot of these hormones, which is normal. But extreme stress and rapidly increasing levels of stress hormones influence the development of the fetal HPA axis and may lead to preterm birth.

What does existing scientific research say about postnatal HPA axis functioning and maternal prenatal stress?

One limitation of the scientific research is the broad range of measures of prenatal stress and HPA axis functioning. Though, while variable in their methodologies and results, the studies provide strong support for the notion that prenatal stress programs the developing fetal HPA axis. The results can be organized in categories of neonates, infants, children, adolescents, and adults.

• Neonates exposed to elevated levels of maternal depressive symptoms exhibited higher levels of ACTH and higher levels of urinary cortisol. The studies suggest that prenatal stress predicts heightened HPA axis activity during the neonatal period.
• Stress-exposed infants show higher levels of cortisol responses and infants of mothers with prenatal depressive disorders show higher cortisol levels and greater response to stressors. After the first several months of life there is a developmental shift in HPA axis functioning and a period of hyporesponsiveness to stress. Infants that were exposed to higher levels of prenatal stress show greater HPA axis hypoactivity at this stage of development.
• Studies show a hyperactivity of the HPA axis in children exposed to higher levels of prenatal stress.
• Adolescents exposed to prenatal stress show hypoactivity in cortisol output and a flatter diurnal cortisol decline.
• With regards to adults, prenatal stress-exposed adults exhibited hypoactivity in several domains. They showed increased reactivity to stressors, with greater increases in cortisol in response to the stressor. There were no differences in diurnal cortisol output.

How does synthetic glucocorticoid exposure influence the HPA axis function?

Women at risk of premature delivery are often given synthetic glucocorticoids, because it reduces mortality and promotes lung maturity among infants born preterm. Because it is hard to determine if a woman will deliver preterm, many women receive synthetic glucocorticoids. However, evidence indicates that prenatal synthetic glucocorticoid exposures are related to dysregulated postnatal HPA axis function. This provides support for the programming effects of excess glucocorticoids on long-term HPA axis functioning.

What could we infer from the discrepancies in the results of studies looking at prenatal stress and HPA axis functioning?

It is possible that discrepancies found in the studies actually reflect developmental patterns. There are two possibilities:

• Both diurnal cortisol output and cortisol response to stress vary over the course of development. After the first few months of infancy there appears to be a period of hyporesponsiveness of the stress system, which coincides with the emergence of the diurnal rhythm of the HPA axis.
• Activity of the HPA axis may differ depending on whether stressors are acute or chronic. Exposure to prenatal stress may result in a more reactive HPA axis initially, but prolonged hyperactivity may eventually result in downregulation of the system, with a dampening of diurnal cortisol output and hyporeactivity to stress later in life.

How can the timing of prenatal stress be of importance for fetal HPA axis development?

Studies show that prenatal exposures during different gestational intervals exert differential effects, depending on the fetal developmental processes that are occurring at that time. Since maternal stress responsiveness is downregulated as gestation advances, stressful events that are experienced early in pregnancy may trigger greater maternal stress responses and may exert greater influence on the fetus than stressors that are experienced later in gestation.

How can fetal sex moderate the programming effects of prenatal stress on the fetal HPA axis?

Studies show that there are sex-specific trajectories of fetal development, related to the response of the placenta to stress. Females and males show contrasting growth strategies, whereby in response to stressors, females adjust their growth and males do not. The female placenta may be more sensitive and responsive to changes in cortisol concentrations during gestation as compared to the male placenta.

What should future research focus on with regards to investigating the effect of prenatal maternal stress on HPA axis functioning?

Future research should focus on placental CRH as an indicator of prenatal stress-induced alterations in HPA axis functioning, as placental CRH is a direct and integrative index of fetal exposure to a variety of stressors. Secondly they should further investigate the interactive influence of genes and environmental stressors on HPA axis development, especially looking at methylation in the promoter region of NR3C1, the gene encoding the glucocorticoid receptor. Finally, future research should examine how the pre and postnatal environments act independently or synergistically to shape development of the HPA axis.