Corticotropin-Releasing Hormone (CRH) Programs the Fetal and Maternal Brain.

Corticotropin-releasing hormone (CRH) is a 41-amino acid neuropeptide that is synthesized primarily in the paraventricular nucleus of the hypothalamus and has a major role in regulating pituitary-adrenal function and the physiological response to stress [1,2]. The hypothalamic-pituitary-adrenal (HPA) axis participates in a remarkable surveillance and response system which has evolved and is conserved, so that many species from the desert dwelling Western Spadefoot tadpole to the human fetus can detect threats to survival and adjust their developmental trajectory [3,4]. For instance, rapidly evaporating pools of desert water result in elevation of CRH in the pathway between the brain and the pituitary gland (median eminence) of the tadpole, initiating metamorphic climax to escape imminent peril [5,6]. If the CRH response is blocked during environmental desiccation, then the rate of development is arrested and the tadpole's survival is compromised. There are long-term consequences for the tadpole that survives this stressful challenge because its growth is stunted and it is at a disadvantage in competing with a normally developing toad foraging for food or reproducing. Normally, as described for the tadpole, stress activates the expression of hypothalamic CRH which stimulates the cascade of events preparing the organism for “fight or flight”. The maternal HPA system is altered dramatically during human pregnancy because the placenta expresses the genes for CRH. Placental CRH (pCRH) increases several hundred-fold as pregnancy advances and reaches levels in the maternal circulation at term observed only in the hypothalamic portal system during physiological stress [7]. In contrast to the inhibitory influence of maternal stress signals (e.g. cortisol) on expression of the CRH gene in the hypothalamus, maternal cortisol activates the promoter region in the placenta and stimulates its synthesis [8,9]. This positive feedback system contains both a signal to the fetus (elevated cortisol) that the host environment (the mother) is threatened [10], and a measurable response from the fetus (increased pCRH production). The rapid increase in pCRH that is stimulated by stress signals from the mother begins a cascade of events resulting in myometrial activation and in extreme cases, premature birth [11]. Human infants born early suffer a similar fate as the tadpole including a panoply of motor, sensory and neurological impairments that persist for a lifetime [12,13]. There are well-established neurological consequences associated with preterm birth, however it is the intrauterine conditions that determine the birth phenotype and alter the developmental trajectory. The fetus whether born early or at term, participates in its own development by incorporating messages about the nature of the maternal and intrauterine milieu and adapting its developmental program to prepare for postnatal survival. In addition to the growing acceptance that a significant proportion of variation in infant and adult health outcomes and disease risk is attributable to developmental processes during fetal life in response to a variety of environmental, social, psychological, physiological and genetic influences, there is newer information that the host, the mother, also is programmed by the processes specific and unique to pregnancy.