HORSE SPECIES SYMPOSIUM: Glucocorticoid programming of hypothalamic-pituitary-adrenal axis and metabolic function: Animal studies from mouse to horse1,2

Abstract

Adrenal glucocorticoids, such as cortisol, are essential for normal fetal development and for maintaining homeostasis in adults. Developmental studies in humans and other animals have shown that exposure to excess glucocorticoids during critical windows of perinatal development can program permanent changes in hypothalamic-pituitary-adrenal (HPA) axis function and metabolic function, with adverse implications for the long-term health of the exposed offspring. The current review compares the programming of postnatal HPA axis function and glucose homeostasis among different species overexposed perinatally to glucocorticoids, with emphasis on the horse. The potential role of epigenetic modification of genes involved in the regulation of HPA axis and metabolic function at cellular and molecular levels is also discussed.

Glucocorticoids as regulatory signals during intrauterine development

“…Synthetic glucocorticoids are up to 20 times more potent than their natural counterparts and are poorly inactivated by 11β-HSD2 (Chapman et al 2013). They also bind predominantly to GRs, whereas natural glucocorticoids bind to both GRs and MRs. Clinical and experimental treatment with synthetic glucocorticoids, therefore, also alters fetal growth and development, but the specific effects, mechanisms of action and long-term outcomes of this treatment often differ from those seen in response to natural glucocorticoids (Jellyman et al 2015).…”

“…There are also changes in adult behaviour, memory and appetite regulation after prenatal glucocorticoid exposure in rodents (Huang, 2011;Bouret et al 2015). These adult phenotypic changes tend to be more pronounced with prenatal overexposure to synthetic than natural glucocorticoids and become more obvious with advancing age, possibly due to the reduced functional reserve capacity of adult tissues prematurely switched from accretion to differentiation in utero by glucocorticoid overexposure (Somm et al 2012;Jellyman et al 2015).…”

“…Placental effects. Administration of glucocorticoids to the mother during late gestation reduces placental weight Data are from Fowden & Forhead (2004, 2009, 2014, Fowden et al (2015) and Jellyman et al (2015). Abbreviations: ACTH, adrenocorticotrophic hormone; AT 1 , angiotensin type 1; CRH, corticotrophin-releasing hormone; HPA, hypothalamic-pituitary-adrenal; 11β-HSD, 11β-hydroxysteroid dehydrogenase; IGF, insulin-like growth factor; PG, prostaglandin; PGDH, 15-hydroxy prostaglandin dehydrogenase; PGHS, prostaglandin H 2 sythase; POMC, pro-opiomelanocorticotrophin; T 3 , triiodothyronine; and T 4 , thyroxine.…”

“…In addition, they can affect components of the intracellular signalling pathways for hormones and growth factors; hence, they have local tissue effects independent of the circulating concentrations. For example, glucocorticoids affect the abundance of several proteins in the insulin signalling pathway in fetal skeletal muscle near term, although not expression of the insulin receptor itself (Jellyman et al 2012;Blanco et al 2014). Maturationally, these effects of the glucocorticoids enable the sensitivity of the endocrine axes to be set appropriately for extrauterine life and, in some species, also ensure that fetal maturation is co-ordinated with the onset of parturition.…”

“…For instance, prenatal glucocorticoid exposure alters adult HPA function at every level of the axis from the brain to tissue glucocorticoid bioavailability (Jellyman et al . ). In turn, these programmed changes in HPA function may contribute to the adult cardiometabolic dysfunction associated with prenatal glucocorticoid overexposure.…”