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. 2017 Sep;12(5):321-339.
doi: 10.1080/17446651.2017.1356222. Epub 2017 Aug 2.

Developmental origins of the human hypothalamic-pituitary-adrenal axis

Mariann A Howland  1 , Curt A Sandman  1 , Laura M Glynn  1   2
Affiliations

Developmental origins of the human hypothalamic-pituitary-adrenal axis

Mariann A Howland et al. Expert Rev Endocrinol Metab. 2017 Sep.

Abstract

The developmental origins of disease or fetal programming model predicts that intrauterine exposures have life long consequences for physical and psychological health. Prenatal programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis is proposed as a primary mechanism by which early experiences are linked to later disease risk. Areas covered: This review describes the development of the fetal HPA axis, which is determined by an intricately timed cascade of endocrine events during gestation and is regulated by an integrated maternal-placental-fetal steroidogenic unit. Mechanisms by which stress-induced elevations in hormones of maternal, fetal, or placental origin influence the structure and function of the emerging fetal HPA axis are discussed. Recent prospective studies documenting persisting associations between prenatal stress exposures and altered postnatal HPA axis function are summarized, with effects observed beginning in infancy into adulthood. Expert commentary: The results of these studies are synthesized, and potential moderating factors are discussed. Promising areas of further research highlighted include epigenetic mechanisms and interactions between pre and postnatal influences.

Keywords: CRH; HPA axis; Placenta; cortisol; development; fetal programming; pregnancy; prenatal stress.

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Conflict of interest statement

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

Figure 1.
Figure 1.
Schematic representation of the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, corticotropin-releasing hormone (CRH) is synthesized in the paraventricular nucleus (PVN) of the hypothalamus and released into the hypophyseal portal blood. CRH binds to its receptors on pituitary corticotropes, stimulating the release of adrenocorticotrophic hormone (ACTH). Circulating ACTH binds to its receptors in the adrenal cortex and stimulates the release of cortisol, which mobilizes body systems to respond to the stressor. Elevated circulating cortisol inhibits further HPA axis activity (blue squares) by binding to its two receptor types, glucocorticoid receptors (GRs) and mineralocorticoid receptors (GRs), at the level of the hypothalamus, pituitary, and hippocampus. CRH-producing neurons in the PVN of the hypothalamus are innervated by afferent projections from multiple brain regions (blue and green circles), including the amygdala, which provides excitatory input, and the prefrontal cortex and hippocampus, which provide inhibitory input. ACTH: Adrenocorticotropic hormone; CRH: Corticotropin-releasing hormone; GR: glucocorticoid receptor; MR: mineralocorticoid receptor; PVN: paraventricular nucleus
Figure 2.
Figure 2.
Increases in hypothalamic-pituitary-adrenal and placental hormones in maternal circulation over gestation. Points represent mean levels of these hormones at each gestational interval. ACTH: Adrenocorticotropic hormone; CRH: Corticotropin-releasing hormone; GA: Gestational age
Figure 3.
Figure 3.
Schematic representation of the maternal-placental-fetal steroidogenic unit. Placental corticotropin-releasing hormone (CRH) influences both maternal and fetal stress hormone production. In the maternal compartment, increases in placental CRH promote increased synthesis and release of ACTH and cortisol. Maternal cortisol in turn stimulates placental CRH production, generating a positive feedback loop (green lines). The placental enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD-2) oxidizes maternal cortisol into cortisone, but it is only a partial barrier, with some maternal cortisol entering fetal circulation. The developing fetal hypothalamic-pituitary-adrenal axis is regulated in part by maternal cortisol and placental CRH. Maternal cortisol may inhibit fetal pituitary ACTH release. Placental CRH likely stimulates production of fetal cortisol, both by increasing fetal adrenal responsiveness to ACTH and by direct stimulation of the adrenal. Increased fetal cortisol would in turn stimulate placental CRH production, constituting a second positive feedback loop (green lines). The massive amounts of hormones produced by the maternal-placental-fetal unit benefit both mother and fetus and influence the timing of parturition. ACTH: Adrenocorticotropic hormone; CRH: Corticotropin-releasing hormone; 11β-HSD-2: 11β-hydroxysteroid dehydrogenase 2
Figure 4.
Figure 4.
Time table summarizing fetal hypothalamic-pituitary adrenal (HPA) axis development. ACTH: Adrenocorticotropic hormone; CRH: Corticotropin-releasing hormone; 11β-HSD-2: 11β-hydroxysteroid dehydrogenase 2
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