The critical importance of the fetal hypothalamus-pituitary-adrenal axis

Abstract

The fetal hypothalamus-pituitary-adrenal (HPA) axis is at the center of mechanisms controlling fetal readiness for birth, survival after birth and, in several species, determination of the timing of birth. Stereotypical increases in fetal HPA axis activity at the end of gestation are critical for preparing the fetus for successful transition to postnatal life. The fundamental importance in fetal development of the endogenous activation of this endocrine axis at the end of gestation has led to the use of glucocorticoids for reducing neonatal morbidity in premature infants. However, the choice of dose and repetition of treatments has been controversial, raising the possibility that excess glucocorticoid might program an increased incidence of adult disease (e.g., coronary artery disease and diabetes). We make the argument that because of the critical importance of the fetal HPA axis and its interaction with the maternal HPA axis, dysregulation of cortisol plasma concentrations or inappropriate manipulation pharmacologically can have negative consequences at the beginning of extrauterine life and for decades thereafter.

Maternal hormonal milieu influence on fetal brain development

“…As the predominant reaction is the placental inactivation of active glucocorticoids (cortisol) to their inactive 11‐keto forms (cortisone) by 11β‐HSD2, fetuses are usually protected from the relatively high maternal glucocorticoid levels during pregnancy (Liggins, ). Nevertheless, some of the cortisone synthesized during transplacental exchange is converted back to cortisol in target tissues, including brain (Wood & Keller‐Wood, ). During late gestation, 11β‐HSD2 placental expression decreases, exposing the fetus to increasing levels of glucocorticoids and facilitating fetal maturation (Cottrell, Seckl, Holmes, & Wyrwoll, ); (Figure ).…”

“…Thus, in early gestation, cortisol of maternal origin represents the primary source of cortisol and correlates strongly with fetal compartment levels, with cortisol increasing over the three trimesters (Harris & Seckl, 2011); (Figure 1). Residing in an area of known moderate to severe iodine insufficiency the coordination of fetal readiness for extrauterine life and the timing of parturition (Liggins et al, 1967;McDonald & Nathanielsz, 1991;Wood & Keller-Wood, 2016). Human placenta produces CRH and ACTH that are delivered into fetal and maternal circulation (Goland et al, 1993).…”

Persistent Zika virus infection in porcine conceptuses is associated with elevated in utero cortisol levels

“…In utero glucocorticoid (cortisol in pigs and humans) levels are important for fetal brain development and offspring health [1,2]. It is well known that several pathogens (hepatitis B virus, cytomegalovirus, and HIV) may affect cortisol balance [3][4][5].…”

The Hypothalamic-Pituitary-Adrenal Axis and the Fetus

“…Maternal morbidity is common. Prematurity and intrauterine fetal deaths are frequent [53, 54]. Reversible hypertrophic obstructive cardiomyopathy in the fetus has been reported [55].…”