Suppression of arousal by progesterone in fetal sheep

1997 ◽  
Vol 9 (8) ◽  
pp. 767 ◽  
Author(s):  
Kelly J. Crossley ◽  
Marcus B. Nicol ◽  
Jonathan J. Hirst ◽  
David W. Walker ◽  
Geoffrey D. Thorburn†
Keyword(s):  
Fetal Brain ◽  
Late Gestation ◽  
High Rate ◽  
Emg Activity ◽  
Fetal Sheep ◽  
Progesterone Production ◽  
Progesterone Synthesis ◽  
Ovine Fetus ◽  
High Concentrations ◽  
Vascular Catheters

The high rate of progesterone synthesis by the placenta in late gestation exposes the ovine fetus to high concentrations of progesterone and its metabolites that may affect activity of the fetal brain. The aim of this study was to determine the effect of inhibiting maternal progesterone synthesis on sleep–wake activity in fetal sheep. Fetal and maternal vascular catheters, a fetal tracheal catheter, and electrodes for recording fetal electrocortical (ECoG), electro-ocular (EOG) and nuchal muscle electromyographic (EMG) activity were implanted. At 128–131 days gestation, progesterone production was inhibited by an injection of trilostane (50 mg), a 3β-hydroxysteroid dehydrogenase inhibitor. Vehicle solution or progesterone (3 mg h -1 ) was then infused into the ewe between 6 and 12 h after the trilostane treatment. Maternal progesterone concentrations were significantly reduced from 1–24 h after trilostane treatment (P < 0·05) when followed by vehicle infusion. Fetal breathing movements (FBM), EOG, nuchal muscle EMG, and behavioural arousal increased 12 h after trilostane treatment (P < 0 · 05). In contrast, there was no change in fetal arousal, EOG, EMG or FBM activities when progesterone was infused after the trilostane treatment. These findings show that progesterone can influence fetal behaviour, and indicates that normal progesterone production tonically suppresses arousal, or wakefulness in the fetus.

Effect of alteration of maternal plasma progesterone concentrations on fetal behavioural state during late gestation

1997 ◽  
Vol 152 (3) ◽  
pp. 379-386 ◽  
Author(s):  
M B Nicol ◽  
J J Hirst ◽  
D Walker ◽  
G D Thorburn
Keyword(s):  
Plasma Concentrations ◽  
Maternal Plasma ◽  
Late Gestation ◽  
Emg Activity ◽  
Fetal Sheep ◽  
Plasma Progesterone ◽  
Fetal Plasma ◽  
Progesterone Synthesis ◽  
Progesterone Metabolites ◽  
Vascular Catheters

Placental progesterone synthesis exposes the fetus to high levels of progesterone and progesterone metabolites during late gestation which may influence fetal behaviour. To determine the role of maternal progesterone synthesis in the control of fetal arousal state and fetal breathing movements (FBM), the effect of raising and lowering maternal progesterone concentrations was examined in chronically catheterised fetal sheep. Fetal and maternal vascular catheters, fetal tracheal and amniotic fluid catheters as well as electrodes for recording fetal electrocortical (ECoG), electro-ocular (EOG) and nuchal muscle electromyographic (EMG) activity were implanted between 118 and 122 days gestational age (GA). Progesterone, 100 mg, administered twice daily i.m. for 3 days (130–133 days GA) resulted in a marked elevation in maternal plasma progesterone concentrations (370 ± 121%, n=5, P<0·05), but had no effect on fetal plasma concentrations. Fetal EOG episodes and the duration of fetal behavioural arousal were significantly suppressed throughout the progesterone treatment period (74·4–81·1% and 58–65% respectively, P<0·05, n=5). Four ewes received Trilostane (25 mg i.v.), a 3β-hydroxysteroid dehydrogenase inhibitor, between 136 and 140 days GA. Maternal and fetal progesterone concentrations were significantly lowered by 60 min after treatment (19·8 ± 8·0% and 39·5 ± 24·3% respectively, P<0·05). The incidence of fetal EOG activity increased from a pretreatment level of 26·8 ± 1·5 min/h to 30·3 ± 2·8 min/h at 1–6 h and to 35·0 ± 1·7 min/h (P<0·05) during the 7–12 h after Trilostane treatment. The duration of FBM episodes was significantly higher at 1–6 h and 7–12 h after Trilostane treatment (19·5 ± 3·0 and 23·6 ± 5·5 min/h respectively, P<0·05) compared with pretreatment levels (11·2 ± 1·2 min/h). We conclude that increasing maternal progesterone levels suppresses fetal EOG activity and behavioural arousal, whereas reducing maternal progesterone synthesis leads to an elevation of EOG activity and FBM. Journal of Endocrinology (1997) 152, 379–386

Urocortin: a mechanism for the sustained activation of the HPA axis in the late-gestation ovine fetus?

2002 ◽  
Vol 283 (1) ◽  
pp. E165-E171 ◽  
Author(s):  
Alison C. Holloway ◽  
David C. Howe ◽  
Gabriel Chan ◽  
Vicki L. Clifton ◽  
Roger Smith ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Late Gestation ◽  
Pituitary Cells ◽  
Fetal Sheep ◽  
Antisense Probe ◽  
Pomc Mrna ◽  
Ovine Fetus ◽  
Ovine Fetal ◽  
Sustained Activation

We hypothesized that urocortin might be produced in the pituitary of the late-gestation ovine fetus in a manner that could contribute to the regulation of ACTH output. We used in situ hybridization and immunohistochemistry to identify urocortin mRNA and protein in late-gestation fetal pituitary tissue. Levels of urocortin mRNA rose during late gestation and were associated temporally with rising concentrations of pituitary proopiomelanocortin (POMC) mRNA. Urocortin was localized both to cells expressing ACTH and to non-ACTH cells by use of dual immunofluorescence histochemistry. Transfection of pituitary cultures with urocortin antisense probe reduced ACTH output, whereas added urocortin stimulated ACTH output from cultured pituitary cells. Cortisol infusion for 96 h in chronically catheterized late-gestation fetal sheep significantly stimulated levels of pituitary urocortin mRNA. We conclude that urocortin is expressed in the ovine fetal pituitary and localizes with, and can stimulate output of, ACTH. Regulation of urocortin by cortisol suggests a mechanism to override negative feedback and sustain feedforward of fetal hypothalamic-pituitary-adrenal function, leading to birth.

Effect of intermittent umbilical cord occlusion on fetal respiratory activity and brain adenosine in late-gestation sheep

2002 ◽  
Vol 14 (1) ◽  
pp. 35 ◽  
Author(s):  
Carole S. Watson ◽  
Rachel Schaefer ◽  
Susan E. White ◽  
Jacobus H. Homan ◽  
Laurence Fraher ◽  
...  
Keyword(s):  
Umbilical Cord ◽  
Fetal Brain ◽  
Extracellular Fluid ◽  
Inhibitory Effect ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Arterial Ph ◽  
Tracheal Pressure ◽  
Ovine Fetal ◽  
Arterial Po2

It was hypothesized that intermittent umbilical cord occlusion (UCO) would inhibit ovine fetal breathing movements (FBM) in association with increased cerebral adenosine levels. To test this hypothesis, on two successive days during late gestation (133–134 days; term = 146 days), microdialysis samples were collected from the brains of 10 chronically instrumented fetal sheep during 2-h periods of complete UCO induced every 30 min (Day 1: 2-min UCOs; Day 2: 4-min UCOs). Control fetuses (n = 10) underwent no UCO. Tracheal pressure was measured throughout. This regimen resulted in a decrease in fetal arterial PO2 (PaO2) during each UCO to 7.3 0.8 mmHg (P<0.01; Day 1) and 8.4 1.1 mmHg (P<0.01; Day 2). Throughout each UCO period, fetal arterial pH (pHa) decreased to 7.28 0.02 (P<0.01; Day 1) and 7.11 0.07 (P<0.01; Day 2). The hourly incidence of FBM decreased significantly only on Day 2, from 38.6 4.1% to 4.1 1.6% (P<0.01). The frequency of deep isolated inspiratory efforts increased from 4.7 2.0 h–1 to 17.6 6.1 h–1 (P<0.05; Day 1) and from 2.2 0.9 h–1 to 33.6 4 h–1 (P<0.01; Day 2). The amplitude of both FBM and deep isolated inspiratory efforts increased during the UCO periods on both days. The concentration of cerebral extracellular fluid (ECF) adenosine during UCO increased by 219 215% (P<0.05; Day 1) and 172 107% (P<0.05; Day 2) over the baseline periods. In conclusion, the severity of the inhibitory effect of repeated UCO on FBM depends, in part, on the length of the occlusions. The inhibition of FBM during intermittent UCO may be mediated by the increase in ECF adenosine in the fetal brain. Furthermore, FBM and deep isolated inspiratory efforts appear to be regulated by different mechanisms.

Divergent changes in plasma ACTH and pituitary POMC mRNA after cortisol administration to late-gestation ovine fetus

1998 ◽  
Vol 274 (3) ◽  
pp. E417-E425 ◽  
Author(s):  
T. M. Jeffray ◽  
S. G. Matthews ◽  
G. L. Hammond ◽  
J. R. G. Challis
Keyword(s):  
Plasma Cortisol ◽  
Late Gestation ◽  
Pars Intermedia ◽  
Mrna Levels ◽  
Plasma Acth ◽  
Negative Feedback Regulation ◽  
Fetal Sheep ◽  
Pomc Mrna ◽  
Free Cortisol ◽  
Ovine Fetus

Plasma concentrations of cortisol and adrenocorticotropic hormone (ACTH) rise in the late-gestation sheep fetus at approximately the same time as there is an increase in the plasma levels of corticosteroid- binding globulin (CBG). We hypothesized that intrafetal cortisol infusion during late pregnancy would stimulate an increase in fetal plasma CBG, which in turn would bind cortisol and diminish glucocorticoid negative-feedback regulation of the fetal pituitary, leading to an increase in plasma ACTH concentrations. Cortisol was infused into chronically catheterized fetal sheep beginning at 126.1 ± 0.5 days of gestation and continued for 96 h. Control fetuses were infused with saline. In cortisol-infused fetuses, the plasma cortisol concentrations rose significantly from control levels (4.4 ± 0.6 ng/ml) to 19.3 ± 3.1 ng/ml within 24 h and remained significantly elevated throughout the infusion period. Plasma immunoreactive (ir) ACTH concentrations were significantly elevated in cortisol-infused fetuses within 24–48 h and remained significantly higher than in controls throughout the 96-h experimental period. Plasma free cortisol concentrations increased 10-fold and remained significantly elevated in cortisol-infused animals, despite a rise in plasma corticosteroid-binding capacity. Levels of pituitary proopiomelanocortin (POMC) mRNA in the fetal pars distalis and pars intermedia were 96 and 38% lower, respectively, after 96 h of cortisol infusion. Therefore physiological elevations of plasma cortisol, in the late-gestation ovine fetus, lead to increases in mean plasma irACTH concentrations, but this is not associated with increases in fetal pituitary POMC mRNA levels.

Genomic analysis of neuroendocrine development of fetal brain-pituitary-adrenal axis in late gestation

2006 ◽  
Vol 24 (3) ◽  
pp. 218-224 ◽  
Author(s):  
Maureen Keller-Wood ◽  
Melanie J. Powers ◽  
Jason A. Gersting ◽  
Nyima Ali ◽  
Charles E. Wood
Keyword(s):  
Brain Stem ◽  
Hpa Axis ◽  
Fetal Brain ◽  
Genomic Analysis ◽  
Brain Regions ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Genomic Expression ◽  
Feedback Sensitivity ◽  
Critical Components

The present study was performed to identify the changes in genomic expression of critical components of the hypothalamus-pituitary-adrenal (HPA) axis in the second half of gestation in fetal sheep. We isolated mRNA from pituitary, hypothalamus, hippocampus, and brain stem in fetal sheep at 80, 100, 120, 130, and 145 days of gestation and 1 and 7 days after delivery ( n = 4–5/group). Using real-time RT-PCR, we measured mRNA expression levels of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), serum- and glucocorticoid-induced kinase-1 (sgk1), proopiomelanocortin (POMC), CRF, and arginine vasopressin (AVP). Both MR and GR were highly expressed in pituitary and hippocampus; in all tissues GR was more highly expressed than MR. AVP was more highly expressed than CRF in hypothalamus. MR, GR, and sgk1 expression were increased postnatally in brain stem, and sgk1 expression was increased postnatally in hypothalamus. GR expression was reduced in pituitary in term fetuses compared with younger ages. Hypothalamic CRF expression was increased at the end of gestation compared with younger ages, and AVP expression was increased in newborn lambs. Pituitary POMC was increased at 100 days of gestation compared with 80 days; hypothalamic POMC was increased at 120 days. Overall, the results demonstrate the expression of both MR and GR in brain regions important for control of the HPA axis. Decreases in expression of GR in pituitary at the end of gestation might contribute to the decreased corticosteroid negative feedback sensitivity at term in this species.

Sympathoadrenal responses during hypoglycemia, hyperinsulinemia, and hypoxemia in the ovine fetus

1991 ◽  
Vol 261 (1) ◽  
pp. E95-E102 ◽  
Author(s):  
W. R. Cohen ◽  
G. J. Piasecki ◽  
H. E. Cohn ◽  
J. B. Susa ◽  
B. T. Jackson
Keyword(s):  
Insulin Infusion ◽  
Plasma Concentrations ◽  
Sympathetic Nerves ◽  
Significant Rise ◽  
Late Gestation ◽  
Plasma Catecholamine ◽  
Fetal Sheep ◽  
Ovine Fetus ◽  
Per Se ◽  
Adrenal Secretion

Interrelations of sympathoadrenal function and changes in glucose and insulin homeostasis were studied in chronically cannulated late gestation fetal sheep. Catecholamine secretory rates (based on direct adrenal sampling) and plasma concentrations were determined in the fetus during 2 h of insulin-induced hypoglycemia, during a period of hypoxemia, and during hyperinsulinemia per se (i.e., without hypoglycemia). Fetal insulin infusion (5–10 mU.kg-1.min-1) resulted in hypoglycemia and a significant rise in secretion of epinephrine but not of norepinephrine. By contrast, fetal hypoxemia caused a prompt and significant increase in adrenal secretion of both norepinephrine and epinephrine. Changes in peripheral plasma catecholamine levels were usually, but not always, qualitatively similar to those in adrenal secretion; the latter was a far more sensitive indicator of adrenal function. Hyperinsulinemia per se caused no change in adrenal secretory rates or plasma concentrations of catecholamines. Nevertheless, insulin infusion caused a fetal tachycardia even in the absence of hypoglycemia and hypoxemia, suggesting either a direct effect on the heart or stimulation of sympathetic nerves.

Long-term hypoxia modulates expression of key genes regulating adrenomedullary function in the late gestation ovine fetus

2007 ◽  
Vol 293 (5) ◽  
pp. R1997-R2005 ◽  
Author(s):  
Charles A. Ducsay ◽  
Kim Hyatt ◽  
Malgorzata Mlynarczyk ◽  
Brandon K. Root ◽  
Kanchan M. Kaushal ◽  
...  
Keyword(s):  
Nicotinic Receptor ◽  
Messenger Rna ◽  
Acute Stress ◽  
Selective Reduction ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Subunit Expression ◽  
Ovine Fetus ◽  
And Control

We previously communicated that long-term hypoxia (LTH) resulted in a selective reduction in plasma epinephrine following acute stress in fetal sheep. The present study tested the hypothesis that LTH selectively reduces adrenomedullary expression of phenylethanolamine-N-methyltransferase (PNMT), the rate-limiting enzyme for epinephrine synthesis. We also examined the effect of LTH on adrenomedullary nicotinic, muscarinic, and glucocorticoid receptor (GR) expression. Ewes were maintained at high altitude (3,820 m) from 30 to 138 days gestation (dGA); adrenomedullary tissue was collected from LTH and age-matched, normoxic control fetuses at 139–141 dGA. Contrary to our hypothesis, in addition to PNMT, adrenomedullary expression (mRNA, protein) of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) were reduced in the LTH fetus. Immunocytochemistry indicated that TH and DBH expression was lower throughout the medulla, while PNMT appeared to reflect a reduction in PNMT-expressing cells. Nicotinic receptor alpha 1, 2, 3, 5, 6, 7, beta 1, 2, and 4 subunits were expressed in the medulla of LTH and control fetuses. Messenger RNA for alpha 1 and 7 and beta 1 and 2 subunits was lower in LTH fetuses. Muscarinic receptors M1, M2, and M3 as well as the GR were also expressed, and no differences were noted between groups. In summary, LTH in fetal sheep has a profound effect on expression of key enzymes mediating adrenomedullary catecholamine synthesis. Further, LTH impacts nicotinic receptor subunit expression potentially altering cholinergic neurotransmission within the medulla. These findings have important implications regarding fetal cardiovascular and metabolic responses to stress in the LTH fetus.

scholarly journals Genomics of estradiol-3-sulfate action in the ovine fetal hypothalamus

2012 ◽  
Vol 44 (13) ◽  
pp. 669-677 ◽  
Author(s):  
Maria Belen Rabaglino ◽  
Elaine Richards ◽  
Nancy Denslow ◽  
Maureen Keller-Wood ◽  
Charles E. Wood
Keyword(s):  
Feeding Behavior ◽  
Transforming Growth Factor ◽  
Fetal Brain ◽  
Ovis Aries ◽  
Late Gestation ◽  
Postnatal Life ◽  
Growth Factor Signaling ◽  
Fetal Sheep ◽  
Ovine Fetal ◽  
Agouti Related Protein

In fetal sheep during late gestation sulfoconjugated estrogens in plasma reach a concentration 40–100 times greater than unconjugated estrogens. The objective of the present study was to determine the genomics of estradiol-3-sulfate (E2S) action in the ovine fetal brain. The hypothesis was that E2S stimulates genes involved in the neuroendocrine pathways that direct or facilitate fetal development at the end of gestation. Four sets of chronically catheterized ovine twin fetuses were studied (gestational age: 120–127 days gestation) with one infused with E2S intracerebroventricularly (1 mg/day) and the other remaining untreated (control). After euthanasia, mRNA samples were extracted from fetal brains. Only hypothalamic samples were employed for this study given the important function of this brain region in the control of the hypothalamus-pituitary-adrenal axis. Microarray analysis was performed following the Agilent protocol for one-color 8 × 15 microarrays, designed for Ovis aries. A total of 363 known genes were significantly upregulated by the E2S treatment ( P < 0.05). Network and enrichment analyses were performed using the Cytoscape/Bingo software, and the results validated by quantitative real-time PCR. The main overrepresented biological processes resulting from this analysis were feeding behavior, hypoxia response, and transforming growth factor signaling. Notably, the genes involved in the feeding behavior (neuropeptide Y and agouti-related protein) were the most strongly induced by the E2S treatment. In conclusion, E2S may be an important component of the mechanism for activating orexigenic, hypoxia responsiveness and neuroprotective pathways in the lamb as it approaches postnatal life.

Blood pressure and heart rate in the ovine fetus: ontogenic changes and effects of fetal adrenalectomy

1999 ◽  
Vol 276 (1) ◽  
pp. H248-H256 ◽  
Author(s):  
Nobuya Unno ◽  
Chi H. Wong ◽  
Susan L. Jenkins ◽  
Richard A. Wentworth ◽  
Xiu-Ying Ding ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Plasma Cortisol ◽  
Time Windows ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Long Term Study ◽  
Arterial Blood ◽  
Ovine Fetus

Ontogenic changes in baseline and 24-h rhythms of fetal arterial blood pressure (FABP) and heart rate (FHR) and their regulation by the fetal adrenal were studied in 18 fetal sheep chronically instrumented at 109–114 days gestation (GA). In the long-term study, FABP and FHR were continuously recorded from 120 days GA to spontaneous term labor (>145 days GA) in five animals. Peak times (PT) and amplitudes (Amp) of cosinor analysis were compared at 120–126, 127–133, and 134–140 days GA. Consistent, significant linear increases in FABP and linear decreases in FHR were observed in all fetuses. Significant 24-h rhythms in FABP and FHR were observed during all the time windows. In the adrenalectomy study, to test the hypothesis that fetal cortisol plays a key role in cardiovascular maturation, fetal adrenals were removed in eight animals (ADX); sham fetal adrenalectomy was performed on five animals (Con). Cortisol (4 μg/min) was infused intravenously in four ADX fetuses from day 7postsurgery for 7 days (ADX+F). No significant changes in PT and Amp in FABP and FHR were observed. Plasma cortisol levels remained low in Con and ADX fetuses (<4.9 ng/ml). Cortisol infusion increased fetal plasma cortisol to 22.3 ± 3.2 ng/ml (mean ± SE) on day 13 in ADX+F fetuses. FABP increased in control and ADX+F but not ADX fetuses; FHR decreased in control and ADX but rose in ADX+F fetuses. These results suggest that, in chronically instrumented fetal sheep at late gestation, 1) increases in FABP and decreases in FHR are maintained consistently from 120 to 140 days GA, with distinct 24-h rhythms, the PT and Amp of which remain unchanged, and 2) the physiological increase in FABP is dependent on the fetal adrenal; bilateral removal of the fetal adrenals does not prevent the ability of cortisol to produce a sustained increase in FABP.

Effect of hyperinsulinemia on amino acid utilization in the ovine fetus

2000 ◽  
Vol 279 (6) ◽  
pp. E1294-E1304 ◽  
Author(s):  
Patti J. Thureen ◽  
Bryan Scheer ◽  
Susan M. Anderson ◽  
Janet A. Tooze ◽  
David A. Young ◽  
...  
Keyword(s):  
Amino Acid ◽  
Nitrogen Utilization ◽  
Late Gestation ◽  
Amino Acid Solution ◽  
Fetal Sheep ◽  
Amino Acid Utilization ◽  
Lysine Concentration ◽  
Ovine Fetus ◽  
Nitrogen Uptake Rate ◽  
Amino Acid Concentrations

We studied the effect of an acute 4-h period of hyperinsulinemia (H) on net utilization rates (AAURnet) of 21 amino acids (AA) in 17 studies performed in 13 late-gestation fetal sheep by use of a novel fetal hyperinsulinemic-euglycemic-euaminoacidemic clamp. During H [84 ± 12 (SE) μU/ml H, 15 ± 2 μU/ml control (C), P < 0.00001], euglycemia was maintained by glucose clamp (19 ± 0.05 μmol/ml H, 1.19 ± 0.04 μmol/ml C), and euaminoacidemia (mean 4.1 ± 3.3% increase for all amino acid concentrations [AA], nonsignificantly different from zero) was maintained with a mixed amino acid solution adjusted to keep lysine concentration constant and other [AA] near C values. H produced a 63.7% increase in AAURnet (3.29 ± 0.66 μmol · min−1 · kg−1 H, 2.01 ± 0.55 μmol · min−1 · kg−1 C, P < 0.001), accounting for a 60.1% increase in fetal nitrogen uptake rate (2,064 ± 108 mg · day−1 · kg−1 H, 1,289 ± 73 mg · day−1 · kg−1 C, P < 0.001). Mean AA clearance rate (AAURnet/[AA]) increased by 64.5 ± 18.9% ( P < 0.001). Thus acute physiological H increases net amino acid and nitrogen utilization rates in the ovine fetus independent of plasma glucose and [AA].

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