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

Abstract

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 ...

Glucocorticoids as regulatory signals during intrauterine development

“…However, if the endocrine changes persist after restoration of normal conditions, they may become more detrimental to intrauterine development and compromise the ability of the fetus to respond to subsequent environmental challenges. For example, fetal HPA responses to stressful stimuli, such as hypoxia, are known to be altered by prior exposure to glucocorticoids (Fletcher et al 2003;Jellyman et al 2004). Likewise, early activation of the switch in the somatotrophic axis from local GH-independent IGF-I synthesis to GH-dependent hepatic production of endocrine IGF-I is likely to affect growth of many fetal tissues long after normal fetal glucocorticoid levels are restored.…”

“…; Jellyman et al . ). Likewise, early activation of the switch in the somatotrophic axis from local GH‐independent IGF‐I synthesis to GH‐dependent hepatic production of endocrine IGF‐I is likely to affect growth of many fetal tissues long after normal fetal glucocorticoid levels are restored.…”

Glucocorticoids and Preterm Hypoxic-Ischemic Brain Injury: The Good and the Bad

“…However, in near-term fetal sheep maternal dexamethasone (2 maternal injections 24 h apart) before moderate isocapnic hypoxia, which does not cause overt neural injury, was associated with impaired cardiovascular responses, with significant bradycardia and increased acidosis during hypoxia 8 hours after the second injection, whereas there was no effect 3 days after the second injection [113, 114]. Despite suppression of hypothalamic-pituitary axis function [115], low doses of dexamethasone augmented the glycemic response to hypoxia in near-term sheep fetuses [116]. …”

Hormones as epigenetic signals in developmental programming

“…In addition to altering the normal pattern of tissue development, early exposure to glucocorticoids changes fetal responses to adverse conditions in utero both during the period of exposure and thereafter. In sheep, the metabolic, endocrine and cardiovascular responses to hypoxaemia are altered by administration of dexamethasone to either the mother or the fetus (Fletcher et al 2003; Jellyman et al 2004 a , b ). Glucocorticoids prolong the bradycardic response, increase the femoral vasoconstrictor response and enhance the increments in plasma neuropeptide Y, glucose and lactate to hypoxaemia during the period of steroid exposure (Fletcher et al 2000 b , 2003; Jellyman et al 2005).…”

“…For instance, the catecholamine and AVP responses to hypoxaemia are suppressed during dexamethasone treatment but are enhanced after treatment relative to the responses in saline‐treated control animals (Fletcher et al 2000 b , 2004). Similarly, the fetal pituitary–adrenocortical response to hypoxaemia is abolished during dexamethasone treatment but is two‐ to threefold greater than control values 48 h after treatment ceases, in association with down‐regulation of glucocorticoid receptors (GR) in the fetal pituitary (Fletcher et al 2004; Jellyman et al 2004 b ). In addition, pretreatment of the sheep fetus with cortisol increases pulmonary growth and liquid accumulation in response to subsequent obstruction of the fetal trachea (Boland et al 1997).…”