On the function of placental corticotropin‐releasing hormone: a role in maternal‐fetal conflicts over blood glucose concentrations

Abstract

Throughout the second and third trimesters, the human placenta (and the placenta in other anthropoid primates) produces substantial quantities of corticotropin-releasing hormone (placental CRH), most of which is secreted into the maternal bloodstream. During pregnancy, CRH concentrations rise over 1000-fold. The advantages that led selection to favour placental CRH production and secretion are not yet fully understood. Placental CRH stimulates the production of maternal adrenocorticotropin hormone (ACTH) and cortisol, leading to substantial increases in maternal serum cortisol levels during the third trimester. These effects are puzzling in light of widespread theory that cortisol has harmful effects on the fetus. The maternal hypothalamic-pituitary-adrenal (HPA) axis becomes less sensitive to cortisol during pregnancy, purportedly to protect the fetus from cortisol exposure. Researchers, then, have often looked for beneficial effects of placental CRH that involve receptors outside the HPA system, such as the uterine myometrium (e.g. the placental clock hypothesis). An alternative view is proposed here: the beneficial effect of placental CRH to the fetus lies in the fact that it does stimulate the production of cortisol, which, in turn, leads to greater concentrations of glucose in the maternal bloodstream available for fetal consumption. In this view, maternal HPA insensitivity to placental CRH likely reflects counter-adaptation, as the optimal rate of cortisol production for the fetus exceeds that for the mother. Evidence pertaining to this proposal is reviewed.

Second-trimester amniotic fluid corticotropin-releasing hormone and urocortin in relation to maternal stress and fetal growth in human pregnancy

“…However, the blood samples were obtained at later stages (i.e., at 31 weeks' gestation or directly after preterm birth) than our amniotic fluid samples were. Increased CRH levels do not seem to cause fetal growth restriction, yet conversely, growth restriction appears to reflect hostile intrauterine conditions to which the placenta responds to with greater CRH secretion in order to speed up fetal growth and secure survival (Gangestad et al, 2012). Remarkable examples of such responses have been observed in animal species.…”

“…For example, maternal CRH concentrations during the early second trimester predict pre-, post-, and at term deliveries (McLean et al, 1995). However, it recently has been postulated that rather than causing growth restriction or preterm birth, elevated CRH concentrations reflect a placental response to adverse intrauterine conditions to enhance the flow of nutrients to the fetus and accelerate growth (Gangestad, Caldwell Hooper, & Eaton, 2012). If these heightened metabolic demands cannot be met anymore, birth onset is triggered.…”

Middle Childhood: An Evolutionary-Developmental Synthesis

“…While intervening to change early life conditions may be desirable in view of their long-term effects, this approach is not always possible or realistic. In addition, prenatal factors such as fetal nutrition and gestational stress may be especially difficult to target, as they do not simply mirror the mother's conditions but reflect a complex-and partially conflictual-interplay between fetal and maternal factors (e.g., Del Giudice 2012; Gangestad et al 2012;Haig 1993). However, the logic of developmental switches (Fig.…”

The Human Placental Methylome

“…These include, for example, up-regulation of System A transporters, which are responsible for transporting amino acids to the fetus (Coan et al 2010;Burton and Fowden 2012), iron transport proteins (Bradley et al 2004), which absorb iron from maternal blood, and placental corticotropin releasing hormone (CRH), which may stimulate maternal glucose production needed to support the growing brain (Gangestad et al 2012). CRH gene promoter DNA methylation has been correlated with its expression in the placenta (Jiang et al 2012); increased gestational age was associated with decreased DNA methylation at CpG sites associated with the CRH gene as well as other cortisol signaling and steroidogenic genes in the placenta (Hogg et al 2013a).…”