Repeated Antenatal Glucocorticoid Treatment Decreases Hypothalamic Corticotropin Releasing Hormone mRNA but not Corticosteroid Receptor mRNA Expression in the Fetal Guinea‐Pig Brain

Abstract

Approximately 10% of pregnant women are treated with synthetic glucocorticoids in late gestation, to promote fetal lung maturation. The effectiveness of this treatment has led to the use of repeated dose regimens, with little knowledge of the impact on neuroendocrine development. Animal studies have recently shown that repeated fetal glucocorticoid exposure can lead to permanent changes in hypothalamic-pituitary-adrenal (HPA) function in offspring. In this study, we hypothesized that such treatment modifies corticotropin releasing hormone (CRH), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) systems in the developing limbic system and hypothalamus. Pregnant guinea-pigs were treated with dexamethasone, betamethasone or vehicle on days 40,41,50,51,60 and 61 of gestation (birth = 68 days). On day 62, guinea-pigs were killed and the fetuses rapidly removed. Glucocorticoid treatment resulted in a dose-dependent reduction in plasma cortisol concentrations in both male and female fetuses. There was also a significant reduction in CRH mRNA expression in the hypothalamic paraventricular nucleus. In contrast, exposure to glucocorticoid increased MR mRNA expression in the hippocampus (CA1/2 and CA3) and dentate gyrus of female fetuses. There was a small but significant increase in GR mRNA expression in limbic structures in male fetuses following treatment with 1 mg/kg dexamethasone. However, there was no significant effect of glucocorticoid exposure on hippocampal GR mRNA expression in female fetuses, or hypothalamic GR mRNA in either males or females. In conclusion, repeated maternal glucocorticoid treatment inhibits fetal HPA function. The fact that CRH mRNA levels were reduced indicates that synthetic glucocorticoids enter the fetal brain. By contrast, fetal glucocorticoid exposure does not downregulate GR mRNA, and increases MR mRNA expression. The latter likely reflects removal of circulating endogenous ligand (cortisol). These alterations may form the basis for permanently modified HPA activity in later life.

Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11β-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: ontogeny and effects of prenatal glucocorticoid exposure

“…This is possible since autologous regulation of MR gene expression has been demonstrated previously in the hippocampus of rats (Holmes et al 1995, Kalman & Spencer 2002. Our observations are most consistent with those reported in the guinea pig (Dean et al 2001, McCabe et al 2001 Mean relative mRNA levels of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), 11b-hydroxysteroid dehydrogenase (11bHSD)1, and 11bHSD2 in adult sheep (Cohort 2) grouped according to sex. Data are presented as meanGS.E.M.…”

RETRACTED: Maternal adversity, glucocorticoids and programming of neuroendocrine function and behaviour

“…The maintained increase in fetal plasma ACTH concentrations in the presence of high circulating glucocorticoid near term is paradoxical, as glucocorticoid-negative feedback is known to be operational in the fetus [59][60][61]. Molecular studies of the fetal HPA axis indicate that there is increased central drive at the level of the PVN (CRH and AVP), which in turn leads to increased synthesis and secretion of ACTH from corticotrophs in the anterior pituitary [60,62,63].…”

Antenatal Treatment with Glucocorticoids and the Hypotalamic-Pituitary-Adrenal Axis

“…Neurons in the parvocellular division of the hypothalamic paraventricular nuclei (PVN) synthesize both CRH and AVP, or only CRH, and their axons project to the median eminence where the produced neuropeptides are released. Repeated fetal glucocorticoid exposure to synthetic glucocorticoids, dexamethasone or betamethasone, inhibits fetal HPA function, as significantly decreased levels of CRH mRNA in the hypothalamic PVN in both male and female fetuses were established (32). Delay of CRH release in the external zone of the median eminence, shown by immunocytochemistry, might further confirm the decreased synthetic activity of CRH neurons in the fetus and neonatal offspring after fetal Dx exposure (37).…”

“…Single maternal Dx exposure results in significant increases in MR and GR mRNA in the CA1-2 region of the hippocampus, and MR mRNA in the dentate gyrus in female fetuses, while changes are absent in male guinea pig fetuses (31). After multiple maternal treatment with Dx, marked increases in MR mRNA level in the hippocampus of female fetuses were recorded, while in males enhancement of GR mRNA was shown in limbic structures indicating changed hippocampal feedback sensitivity to glucocorticoids, natural or synthetic (32). Quantitative in situ hybridization demonstrated that the MR mRNA level is transiently decreased after a single Dx injection in the mouse fetus (33).…”