Prenatal CRH: An integrating signal of fetal distress.

Curt A Sandman

doi:10.1017/s0954579418000664

Abstract

Corticotropin-releasing hormone (CRH) is distributed throughout the brain and in peripheral sites but primarily is localized in the paraventricular nucleus of the hypothalamus. It is a "master" stress hormone that is responsible for the synthesis of proopiomelanocortin (POMC) in the anterior pituitary gland. Behaviorally active peptide hormones, including adrenocorticotropin hormone (ACTH) and B-endorphin, are liberated from POMC by enzymes to activate critical processes during stress. CRH is not detectable in the circulation even during extreme stress. However, during human pregnancy, the human placenta expresses the gene for CRH (pCRH) resulting in detectable levels in maternal plasma that increases 20- to 40-fold over the course of gestation. Placental CRH is identical to CRH of hypothalamic origin in size, structure, immunoreactivity, and bioactivity. However, unlike the negative feedback between adrenal cortisol and hypothalamic CRH, cortisol stimulates the synthesis and release of pCRH. The bidirectional release of pCRH into maternal and fetal compartments is associated with regulating the timing of delivery, remodeling the fetal nervous system, and influencing developmental trajectories. Fetal exposure to pCRH during early and late gestation is associated with unique patterns of cortical thinning in school-age children. Placental CRH is elevated in response to physical and behavioral stress and may be an integrative marker of early adversity.

Highlights

The desert-dwelling Western Spadefoot toad lays her eggs in pools of rainwater during the Spring
Harris proposed that the hypothalamus synthesized hormones that were released into the portal system stimulating the pituitary to syntheize and release hormones into the circulation
We have no evidence for the former possibility, but we have reported that human fetal exposure to elevated cortisol at 15 weeks gestation is associated with increased amygdala volume in 7-year-old children (Buss et al, 2012)

Summary

Placental CRH and fetal behavior

In a series of prospective studies to examine the influence of the intrauterine environment on the fetus, we have focused on the neurodevelopmental consequences of fetal exposure to patterns of psychobiological signals. We found that fetal exposure to the lowest concentrations of pCRH (i.e., bottom quartile) early in gestation ( 15 weeks gestation) was associated with heightened fetal startle reflecting enhanced fetal maturity and accelerated neurological development This partially confirmed the findings of an earlier and smaller study that assessed the effects of fetal exposure to pCRH on fetal memory and attention by presenting a series of repeated VAS, interrupted by a novel VAS. Fetal exposure to the lowest level of pCRH at 15 weeks gestation was associated with the most efficient FHR dishabituation index (Sandman, 2015) These findings suggested that exposure to CRH early in pregnancy influenced (programmed) fetal maturation as measured by startle and habituation: high concentrations “retard” maturation and low levels accelerate it. As we will see below, the association between the timing of fetal exposure to pCRH and the structure of the nervous system may be much more complex

Placental CRH and physical growth and development

Findings

Conclusion