Changes in pituitary responses to synthetic ovine corticotrophin releasing factor in fetal sheep

Norman, Laurie J.; Lye, Stephen J.; Wlodek, Mary E.; Challis, John

doi:10.1139/y85-230

Cited by 125 publications

(62 citation statements)

References 21 publications

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“…It has been reported that fetal ACTH plasma levels increase progressively between 110 and 140 d gestation, whereas fetal cortisol levels remain low between 110 -120 d and increase between 125-140 d gestation (32). McMillen et al (33) also found that fetal plasma ACTH concentrations double between 120 and 136 d and 140 and 143 d gestation.…”

Section: Discussionmentioning

confidence: 96%

Chronic Maternal Fluoxetine Infusion in Pregnant Sheep: Effects on the Maternal and Fetal Hypothalamic-Pituitary-Adrenal Axes

Morrison¹,

Riggs

Chien

et al. 2004

Pediatr Res

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Depression during pregnancy is frequently treated with the selective serotonin reuptake inhibitor, fluoxetine (FX). FX increases serotonergic neurotransmission and serotonin plays a role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. We have therefore investigated the effect of chronic administration of FX to the pregnant ewe on the maternal and fetal HPA axes. Nineteen late-gestation sheep were surgically prepared for chronic study of the fetus. FX (n ϭ 7, 98.5 g/kg/d) or sterile water (control, n ϭ 8) was administered to the ewe for 8 d by constant rate i.v. infusion with an initial FX bolus dose of 70 mg. Maternal and fetal plasma ACTH and cortisol concentrations were determined at 0700 h each day. Maternal plasma ACTH concentrations fell on infusion d 2, but no changes were observed in maternal plasma cortisol concentrations. Fetal plasma ACTH concentrations increased on infusion d 7, and fetal plasma cortisol concentrations increased on infusion d 6, 7, and 8 in the FX group. In addition, the regression coefficient for the relationship between fetal ACTH and cortisol levels was significantly greater in the FX group compared with the control group. Thus, maternal FX treatment increased fetal plasma cortisol concentration. These results are of particular interest in the context that exposure of the fetus to excess glucocorticoids at critical windows during development has been shown to increase the risk of poor health outcomes in later life. Clinical depression occurs in 5-15% of pregnant women (1). Treatment of depression during pregnancy is important to fetal outcome by preventing poor maternal self-care and nutrition, disturbed sleep, lack of prenatal care, increased exposure to alcohol and drugs, and a higher risk of suicide by the mother (1). Depression at 28 wk gestation is related to an increase in negative pregnancy outcome, including an increased risk of low-birth-weight newborns, preterm delivery, and small-forgestational-age newborns (2). FX is a SSRI that increases serotonergic neurotransmission and is prescribed clinically for the treatment of depression, obsessive-compulsive disorder, and bulimia (3). It and other SSRIs have become increasingly used for the treatment of depression in pregnancy because of their effectiveness and lower incidence of maternal side effects and wider safety margin compared with tricyclic antidepressants and monoamine oxidase inhibitors (4, 5). However, there have been several reports that use of these drugs during pregnancy can increase the incidence of adverse pregnancy outcomes, including preterm delivery, fetal growth restriction, and poor neonatal adaptation (5-8). There is also evidence for postnatal consequences of prenatal SSRI exposure, including reduced weight gain, slight delays in psychomotor development and motor movement control, and our own findings of reduced facial and heart rate responses to painful stimuli (9 -11). ABSTRACT40

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Section: Discussionmentioning

confidence: 96%

Chronic Maternal Fluoxetine Infusion in Pregnant Sheep: Effects on the Maternal and Fetal Hypothalamic-Pituitary-Adrenal Axes

Morrison¹,

Riggs

Chien

et al. 2004

Pediatr Res

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“…adrenocorticotropic hormone; ovine fetus IN HUMANS AND MANY MAMMALIAN SPECIES, the late-gestation surge in fetal plasma cortisol levels stimulates final stage development of the lung and other organ systems (7,22) and indeed, in sheep, initiates birth (19,32). Parturition occurring before this surge is associated with increased fetal mortality and morbidity, most notably as a consequence of lung immaturity.…”

mentioning

confidence: 99%

Infusion of ACTH stimulates expression of adrenal ACTH receptor and steroidogenic acute regulatory protein mRNA in fetal sheep

Carey¹,

Su²,

Valego³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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-The late-gestation plasma cortisol surge in the sheep fetus is critical for stimulating organ development and parturition. Increased adrenal responsiveness is one of the key reasons for the surge; however, the underlying mechanisms are not fully understood. Our recent studies suggest that ACTH-mediated increased expression of ACTH receptor (ACTH-R) and steroid acute regulatory protein (StAR) may play a role in enhancing responsiveness. Hence, we examined effects of ACTH infusion in fetal sheep on mRNA expression of these two mediators of adrenal responsiveness and assessed the functional consequences of this treatment in vitro. Fetuses of ϳ118 and 138 days of gestational age (dGA) were infused with ACTH-(1-24) for 24 h. Controls received saline infusion. Arterial blood was sampled throughout the infusion. Adrenals were isolated and analyzed for ACTH-R and StAR mRNA, or cells were cultured for 48 h. Cells were stimulated with ACTH, and medium was collected for cortisol measurement. Fetal plasma ACTH and cortisol concentrations increased over the infusion period in both groups. ACTH-R mRNA levels were significantly higher in ACTH-infused fetuses in both the 118 and 138 dGA groups. StAR mRNA increased significantly in both the 118 and 138 dGA groups. Adrenal cells from ACTH-infused fetuses were significantly more responsive to ACTH stimulation in terms of cortisol secretion than those from saline-infused controls. These findings demonstrate that increases in circulating ACTH levels promote increased expression of ACTH-R and StAR mRNA and are coupled to heightened adrenal responsiveness. adrenocorticotropic hormone; ovine fetus IN HUMANS AND MANY MAMMALIAN SPECIES, the late-gestation surge in fetal plasma cortisol levels stimulates final stage development of the lung and other organ systems (7, 22) and indeed, in sheep, initiates birth (19, 32). Parturition occurring before this surge is associated with increased fetal mortality and morbidity, most notably as a consequence of lung immaturity. Whereas the sequence of events leading to cortisol production per se are well understood, the precise mechanisms involved in driving the rise in fetal plasma cortisol in late gestation are yet to be fully explained.It is apparent that important changes take place at each level of the hypothalamic-pituitary adrenal axis, leading to the prepartum increase in fetal plasma cortisol. An intact hypothalamic pituitary connection is essential, as clearly demonstrated by hypothalamic pituitary disconnection (HPD) studies in fetal sheep, in which the major consequences of this disruption are the absence of the cortisol surge (11,34,38,48,53) and delayed parturition (1, 2, 4, 33). Increased adrenal responsiveness also is a critical mediating factor (18,21,41,51). Two important effectors to this end, the adrenocorticotropic hormone receptor (ACTH-R, specifically known as the melanocortin-2 receptor) and steroid acute regulatory protein (StAR), exhibit ontogenic increases in expression that occur in parallel to the cortisol surge (8,17,49)...

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“…Another explanation may be that factors other than ACTH stimulate the adrenal gland a t this stage of gestation. For instance, a-melanocyte-stimulating hormone, growth hormone and proopiomelanocortin-derived peptides have all been shown to have stimulatory actions on the adrenal gland although their precise role in the physiologic control of adrenocortical activity is not understood (20)(21)(22)(23)(24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

Effects of Naloxone on the Preparturient Increase in Adrenocorticotrophin and Cortisol in Foetal Sheep

Challis

1991

J Neuroendocrinology

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Parturition in sheep is preceded by a rapid increase in foetal pituitary-adrenal activity. Administration of exogenous opioids increases foetal plasma adrenocorticotrophin (ACTH) and cortisol concentrations after Day 125 of pregnancy (term = 145 days). In order to test the hypothesis that endogenous opioids regulate the increase in pituitary-adrenal activity prior to parturition in foetal sheep, we measured changes in plasma ACTH and cortisol in response to administration of either naloxone (1.2 mg intravenous bolus followed by a 2.5 mg/h continuous infusion for 2 h; foetal body weight approximately 2.5 kg) or saline to chronically catheterized foetal sheep at 2-day intervals between Day 140 and the onset of parturition. In addition, we utilized a computerized algorithm (Munro) to examine the precise characteristics of ACTH and cortisol secretion in control and naloxone-treated foetuses.The pattern of ACTH and cortisol secretion in saline-infused control foetuses was highly pulsatile but varied considerably between individual foetuses. ACTH pulses occurred on average every 40 min but were not always coincident with pulses of cortisol.There were no significant changes in average ACTH concentrations, pulse frequency or amplitude between foetuses sampled at 3 to 4 and 1 to 2 days before parturition, In contrast, average cortisol concentrations and pulse amplitude were significantly (P<0.05) increased, whereas pulse frequency was reduced, in foetuses at 1 to 2 days before parturition. Naloxone caused a significant (P < 0.05) inhibition of ACTH concentrations when compared with pretreatment values and with saline-treated controls, an effect which persisted for at least 2 h after the end of naloxone infusion. However, there were no significant differences during naloxone treatment in the frequency or amplitude of ACTH or cortisol pulses nor in the mean cortisol concentration. We conclude that ACTH and cortisol are secreted in a pulsatile fashion in the late gestation foetal sheep and that these pulses are not always coincident with each other. Blockade of endogenous opioid activity during the preparturient increase in pituitaryadrenal activity in foetal sheep, results in a reduction in plasma concentrations of ACTH. These results therefore provide evidence for the tonic regulation of foetal pituitary-adrenal activity by endogenous opioids during the final days prior to birth in the sheep.In sheep, a dramatic preparturient increase in the activity of the roetal hypothalamo-pituitary-adrenal axis is pivotal to the onset of birth. However, the neuroendocrine mechanisms which control foetal pituitary-adrenal function in the sheep, are poorly understood (1). Indeed, there is scant information as to the nature of adrenocorticotrophin (ACTH) and cortisol secretion during this important stage of foetal development. In adult animals, ACTH m d cortisol secretion is pulsatile (2) and a complex interaction between a number of neurotransmitter and neuropeptide systems, regulate the activity of this axis (3). However, until...

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Changes in pituitary responses to synthetic ovine corticotrophin releasing factor in fetal sheep

Cited by 125 publications

References 21 publications

Chronic Maternal Fluoxetine Infusion in Pregnant Sheep: Effects on the Maternal and Fetal Hypothalamic-Pituitary-Adrenal Axes

Chronic Maternal Fluoxetine Infusion in Pregnant Sheep: Effects on the Maternal and Fetal Hypothalamic-Pituitary-Adrenal Axes

Infusion of ACTH stimulates expression of adrenal ACTH receptor and steroidogenic acute regulatory protein mRNA in fetal sheep

Effects of Naloxone on the Preparturient Increase in Adrenocorticotrophin and Cortisol in Foetal Sheep

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