Dexamethasone inhibits ovine corticotrophin-releasing factor (oCRF), arginine vasopressin (AVP), and oCRF + AVP stimulated release of ACTH during the last third of pregnancy in the sheep fetus

Norman, Laurie J.; Challis, John

doi:10.1139/y87-187

Cited by 24 publications

(10 citation statements)

References 24 publications

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“…Hypoxemia-induced increases in fetal plasma concentrations of ACTH and cortisol, appropriate for the degree of hypoxemia and the gestational age of the fetus (10,30 -33), were prevented by maternal dexamethasone, consistent with previous studies in fetal sheep (10,34,35). Both direct fetal i.v.…”

Section: Dexamethasone and The Materno-fetal Hpa Axissupporting

confidence: 88%

“…infusion with dexamethasone (10) and dexamethasone implants near the paraventricular nucleus (36) abolished the ACTH and cortisol responses to acute hypoxemia in the ovine fetus during late gestation. Likewise, dexamethasone significantly suppressed systemic corticotrophin-releasing factor and AVP stimulated ACTH and cortisol responses in fetal sheep (35).…”

Section: Dexamethasone and The Materno-fetal Hpa Axismentioning

confidence: 89%

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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: 88%

Section: Dexamethasone and The Materno-fetal Hpa Axismentioning

confidence: 89%

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

et al. 2004

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“…However, at 113-116 days of gestation, exogenous glucocorticoid does not in hibit basal ACTH release in vivo [ 15], whereas a decrease in endogenous fetal cortisol concentrations (produced as a result of decreased maternal cortisol concentrations) will stimulate an increase in fetal plasma ACTH at this time of gestation [16]. In the present study, no significant change in fetal plasma ir-ACTH concentration was de tected when fetal plasma cortisol levels were raised during the infusion of cortisol.…”

Section: Discussioncontrasting

confidence: 52%

“…There is no doubt that glucocorticoids can inhibit the release of ACTH from the fetal pituitary both in vitro [14] and in vivo [15] in late gestation. However, at 113-116 days of gestation, exogenous glucocorticoid does not in hibit basal ACTH release in vivo [ 15], whereas a decrease in endogenous fetal cortisol concentrations (produced as a result of decreased maternal cortisol concentrations) will stimulate an increase in fetal plasma ACTH at this time of gestation [16].…”

Section: Discussionmentioning

confidence: 99%

Effect of Cortisol Infusion on the Pituitary-Adrenal Axis of the Hypothalamo-Pituitary-Disconnected Fetal Sheep

et al. 1992

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In order to determine whether cortisol acts directly at the level of the fetal pituitary to promote pars distalis corticotroph maturation, we have infused cortisol into the hypothalamo-pituitary-disconnected (HPD) fetal sheep from 111 to 117 days of gestation. In this study we have measured fetal plasma cortisol and immunoreactive adrenocorticotrophic hormone (ir-ACTH) concentrations between 105 and 116 days of gestation, and we have determined the proportions of adult- and fetal-type corticotrophs in the pars distalis of catheter control fetuses and in HPD fetuses infused with either saline (HPD + SAL) or cortisol (2 mg/day; HPD + F). The fetal plasma cortisol concentrations did not change significantly following HPD. The mean fetal plasma cortisol concentration between 113 and 116 days was threefold higher in the HPD + F fetuses than that measured in HPD fetuses. Following HPD, fetal plasma ir-ACTH concentrations were significantly higher than in catheter control fetuses. Despite the significant elevation in plasma cortisol concentrations in HPD + F fetuses between 113 and 116 days, plasma ir-ACTH concentrations were not different in these fetuses from HPD fetuses infused with saline. At 117 days of gestation in HPD + F fetuses, the proportion of fetal-type corticotrophs in the pars distalis was significantly less than in the HPD + SAL fetuses; however, there was no significant change in the proportion of adult-type corticotrophs in the pars distalis following cortisol infusion. We have shown that cortisol has a direct trophic effect on the maturation of the pars distalis corticotrophs; however, the full maturation of these cells requires an intact hypothalamo-pituitary axis. These findings demonstrate the importance of the fetal hypothalamus in anterior pituitary corticotroph maturation during the last third of gestation.

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“…The mechanism behind this concomitant surge is not understood, but it is generally thought it must mean either a loss of the negative feedback by cortisol, or the onset of a stimulatory system that is not under inhibitory feedback, or may be even under positive feedback [31]. Glucocorticoids have been shown to inhibit CRH- and AVP-stimulated release of ACTH [32, 33]. Our results show that dexamethasone treatment significantly attenuated the ACTH response to both NMDA and dynorphin A 1–13 indicating rapid inhibitory feedback to both secretagogues.…”

Section: Discussionmentioning

confidence: 99%

The Role of N-Methyl-D-Aspartate Receptors in the Release of Adrenocorticotropin by Dynorphin A<sub>1–13</sub>

Szeto¹,

Soong²,

Wu³

1999

Neuroendocrinology

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We previously reported that dynorphin A_1–13 evokes a significant increase in plasma adrenocorticotropin (ACTH) after intravenous administration in the ovine fetus. This response was not sensitive to naloxone and was regulated differently from the response to U50,488H, a selective ĸ-opioid agonist. NMDA appears to play a role in many of the nonopioid actions of dynorphin. We therefore hypothesized that dynorphin A_1–13 may release ACTH via N-methyl-D-aspartate (NMDA) receptors. To test this hypothesis, we have compared the ACTH response to dynorphin A_1–13 and NMDA in the chronically-instrumented ovine fetus. Our data show that both dynorphin A_1–13 (0.5 mg/kg) and NMDA (4 mg/kg) induced a significant release of immunoreactive ACTH in the late-term ovine fetus. The ACTH response to NMDA was of a smaller magnitude, but of longer duration, when compared to dynorphin A_1–13. The response to both dynorphin A_1–13 and NMDA was significantly attenuated by pretreatment with the noncompetitive NMDA antagonist, MK-801, but was not affected by antagonists of corticotropin-releasing hormone and arginine vasopressin. Finally, the ACTH response to both dynorphin A_1–13 and NMDA were inhibited by dexamethasone. The results of this study indicate a role for NMDA receptors in the action of dynorphin A_1–13, and suggest that NMDA may act directly at the level of the pituitary to release ACTH without the involvement of hypothalamic secretagogues.

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Dexamethasone inhibits ovine corticotrophin-releasing factor (oCRF), arginine vasopressin (AVP), and oCRF + AVP stimulated release of ACTH during the last third of pregnancy in the sheep fetus

Cited by 24 publications

References 24 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

Effect of Cortisol Infusion on the Pituitary-Adrenal Axis of the Hypothalamo-Pituitary-Disconnected Fetal Sheep

The Role of N-Methyl-D-Aspartate Receptors in the Release of Adrenocorticotropin by Dynorphin A<sub>1–13</sub>

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