No evidence for HPA reset in adult sheep with high blood pressure due to short prenatal exposure to dexamethasone

Dodic, Miodrag; Peers, Arianne; Moritz, Karen M.; Hantzis, Vicky; Wintour, E. M.

doi:10.1152/ajpregu.00222.2001

Cited by 22 publications

(11 citation statements)

References 39 publications

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“…In dexamethasone animals in the present study, basal and stimulated plasma ACTH and cortisol concentrations were similar to saline controls after the dexamethasone had cleared from the maternal and the fetal circulations, consistent with previous studies in lambs (37), adult sheep (38), and human neonates (39 -41). Conversely, Fletcher et al (9) reported not only restored but also enhanced ACTH responses to acute hypoxemia 2 d after cessation of direct fetal treatment with low doses of dexamethasone.…”

Section: Dexamethasone and The Materno-fetal Hpa Axissupporting

confidence: 92%

Pituitary-Adrenal Responses to Acute Hypoxemia During and After Maternal Dexamethasone Treatment in Sheep

et al. 2004

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The effects of maternal dexamethasone treatment on hypothalamic-pituitary-adrenal axis function were determined during basal and hypoxemic conditions in maternal and fetal sheep. Under halothane, ewes and their fetuses were catheterized at 117 d gestation (term ϭ 145 d). Starting at 124 d, the ewes received i.m. injections of two doses of either dexamethasone (12 mg) or saline at 24-h intervals. All animals experienced one episode of hypoxemia when the dexamethasone was present in the maternal and fetal circulations [125 Ϯ 1 d (H1)] and a second episode of hypoxemia when the steroid was no longer detectable in either the maternal or fetal circulations [128 Ϯ 1 d (H2)]. The fall in partial pressure of oxygen in arterial blood in response to hypoxia was similar in the two episodes in both the fetal and the maternal blood. Maternal dexamethasone treatment diminished maternal and fetal basal plasma cortisol but not ACTH during the normoxic period of H1 but not H2. In control animals, hypoxemia induced increases in fetal but not maternal ACTH and cortisol concentrations. In dexamethasone-treated animals, maternal ACTH and cortisol concentrations also remained unchanged from baseline in both H1 and H2. In contrast, fetal plasma ACTH and cortisol responses to hypoxemia were significantly suppressed during H1 but not H2. Correlation of fetal plasma ACTH and cortisol concentrations suggested diminished cortisol output without a change in adrenocortical responsiveness in dexamethasone-treated fetuses during H1 but not H2. Since the pioneering discovery of Liggins (1) that glucocorticoids are essential for the maturation of fetal systems in preparation for extrauterine life, synthetic glucocorticoids, such as dexamethasone, have been used routinely in human clinical practice to treat pregnant women who are at risk of preterm delivery (2-4). Such prophylactic treatment mimics the normal prepartum increase in endogenous cortisol output by the fetal adrenal that switches tissue accretion to differentiation (5). Antenatal glucocorticoid treatment has resulted in significant decreases in the incidence of respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, and neonatal mortality associated with preterm birth (3,6).Despite the clear benefits of antenatal glucocorticoid therapy, concerns have been expressed about the safety of the current dosing regimen, in particular with regards to maternal and fetal adrenal suppression resulting from negative feedback by the synthetic steroid (4). In addition, the effects of synthetic glucocorticoids on the fetal defense responses to hypoxemic insults have been identified by the National Institutes of Health in the United States as an area of research needed to guide intrapartum clinical care (4). This is important for two reasons. First, the ovine hypothalamic-pituitary-adrenal (HPA) axis is activated in response to acute hypoxemia in the mother and the fetus and plays an integral role in the fetal defense response to acute hypoxemia (7). Second, episodes of ...

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Section: Dexamethasone and The Materno-fetal Hpa Axissupporting

confidence: 92%

Pituitary-Adrenal Responses to Acute Hypoxemia During and After Maternal Dexamethasone Treatment in Sheep

et al. 2004

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“…While maternal undernutrition in early pregnancy in the sheep results in changes within the fetal and postnatal HPA axis, administration of dexamethasone to ewes for 2 days at 27 days gestation did not alter plasma ACTH or cortisol responses to hemorrhage of GR and MR expression in the hippocampus or hypothalamus (108). Similarly, while administration of cortisol during the same gestational age window results in a transient increase in GR and MR expression within the hippocampus some 100 days later during late gestation, this was not sustained into the postnatal period (105).…”

Section: Glucocorticoid Exposure During Pregnancy and The Programmmentioning

confidence: 81%

Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming

McMillen

Robinson²

2005

Physiological Reviews

1,682

1,366

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The "fetal" or "early" origins of adult disease hypothesis was originally put forward by David Barker and colleagues and stated that environmental factors, particularly nutrition, act in early life to program the risks for adverse health outcomes in adult life. This hypothesis has been supported by a worldwide series of epidemiological studies that have provided evidence for the association between the perturbation of the early nutritional environment and the major risk factors (hypertension, insulin resistance, and obesity) for cardiovascular disease, diabetes, and the metabolic syndrome in adult life. It is also clear from experimental studies that a range of molecular, cellular, metabolic, neuroendocrine, and physiological adaptations to changes in the early nutritional environment result in a permanent alteration of the developmental pattern of cellular proliferation and differentiation in key tissue and organ systems that result in pathological consequences in adult life. This review focuses on those experimental studies that have investigated the critical windows during which perturbations of the intrauterine environment have major effects, the nature of the epigenetic, structural, and functional adaptive responses which result in a permanent programming of cardiovascular and metabolic function, and the role of the interaction between the pre- and postnatal environment in determining final health outcomes.

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“…Prenatal glucocorticoid exposure permanently increases basal plasma corticosterone levels in adult rats (20,49); however, control and dex-treated rats showed similar elevations in corticosterone levels following a restraint stress (20). There is no evidence of altered activation of the HPA axis in sheep following dex treatment in early pregnancy (10).…”

Section: Discussionmentioning

confidence: 93%

Maternal dexamethasone treatment at midgestation reduces nephron number and alters renal gene expression in the fetal spiny mouse

Dickinson¹,

Walker²,

Wintour³

2007

American Journal of Physiology-Regulatory, Integrative and Comp

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103

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Dickinson H, Walker DW, Wintour EM, Moritz K. Maternal dexamethasone treatment at midgestation reduces nephron number and alters renal gene expression in the fetal spiny mouse. Am J Physiol Regul Integr Comp Physiol 292: R453-R461, 2007. First published August 31, 2006; doi:10.1152/ajpregu.00481.2006.-We investigated the effects of maternal glucocorticoid exposure in the spiny mouse, a precocial species with a relatively long gestation, few offspring, and in which nephrogenesis is complete before birth. We hypothesized that exposure of the fetus to glucocorticoids before the formation of glomeruli would result in adult hypertensive offspring with fewer nephrons. Furthermore, we hypothesized that this nephron deficit would result from changes in expression of genes involved in branching morphogenesis. Osmotic pumps implanted in pregnant spiny mice at midgestation (day 20) delivered dexamethasone (dex; 125 g/kg) or saline for 60 h. Females were killed at day 23 of gestation and kidneys were frozen for real-time PCR analysis or allowed to deliver their offspring. At 20 wk of age, blood pressure was measured in the offspring for 1 wk before nephron number was determined using unbiased stereology. Males and females exposed to dex had significantly fewer nephrons (male: saline: 7,870 Ϯ 27, dex: 6,878 Ϯ 173; female: saline: 7,526 Ϯ 62, dex: 5,886 Ϯ 382; P Ͻ 0.001) compared with controls. Dex had no effect on basal blood pressure. Fetal kidneys collected at day 23 of gestation from dex-exposed mothers showed increased mRNA expression of BMP4 (P Ͻ 0.05), TGF-␤1 (P Ͻ 0.05), genes known to inhibit branching morphogenesis and gremlin (P Ͻ 0.01), an antagonist of BMP4, compared with saline controls. This study shows for the first time an upregulation of branching morphogenic genes in the fetal kidney in a model of excess maternal glucocorticoids that leads to a nephron deficit in the adult. This study also provides evidence that a reduced nephron number does not necessarily lead to development of hypertension.BMP4; TGF-␤1; gremlin; stereology; Acomys cahirinus; fetal programming IT IS NOW WELL ESTABLISHED that early-life environmental factors, such as maternal undernutrition or stress, during critical periods of development can lead to permanent changes in structure and function of organs and tissues. These changes have been shown to significantly increase the risk of developing diseases in adult life such as cardiovascular disease, diabetes, and metabolic syndrome (see reviews in Refs. 12,25,46). What has emerged from many of these studies is that there are key windows of development that are more susceptible to particular insults.Numerous models are currently being used to investigate the mechanisms of the developmental origins of adult disease including maternal undernutrition, both global (14,15,47,52,54) and nutrient specific such as low protein (19,45,53,55), uterine artery ligation to induce fetal growth restriction (39), and maternal glucocorticoid exposure (7-9, 34, 35, 51). It has been proposed that the effects of...

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No evidence for HPA reset in adult sheep with high blood pressure due to short prenatal exposure to dexamethasone

Cited by 22 publications

References 39 publications

Pituitary-Adrenal Responses to Acute Hypoxemia During and After Maternal Dexamethasone Treatment in Sheep

Pituitary-Adrenal Responses to Acute Hypoxemia During and After Maternal Dexamethasone Treatment in Sheep

Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming

Maternal dexamethasone treatment at midgestation reduces nephron number and alters renal gene expression in the fetal spiny mouse

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