Corticosteroid-binding globulin (CBG) production by hepatic and extra-hepatic sites in the ovine fetus; effects of CBG on glucocorticoid negative feedback on pituitary cells in vitro

1995 ◽  
Vol 146 (1) ◽  
pp. 121-130 ◽  
Author(s):  
E T M Berdusco ◽  
K Yang ◽  
G L Hammond ◽  
J R G Challis
Keyword(s):  
Negative Feedback ◽  
Binding Capacity ◽  
Late Gestation ◽  
Pituitary Cells ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Free Cortisol ◽  
Corticosteroid Binding Globulin ◽  
Ovine Fetus ◽  
Acth Release

Abstract Plasma cortisol levels increase in fetal sheep during late gestation and this is associated with an increase in plasma corticosteroid-binding globulin (CBG) concentrations. However, the relative tissue sources of plasma CBG, the ontogeny of its biosynthesis and glycoform composition have not been established in the ovine fetus. Therefore we examined whether changes in plasma corticosteroid binding capacity (CBC) in fetal sheep during late gestation were associated with different patterns of glycosylation and reflected changes in tissue CBG expression. Since free cortisol is considered the bioactive fraction, we measured changes in the percent and absolute free cortisol in fetal plasma during late gestation. In order to examine whether CBG alters cortisol negative feedback at the level of the fetal pituitary, we also examined the effect of exogenous CBG in mediating the glucocorticoid-induced suppression of basal and corticotrophin-releasing hormone (CRH)-stimulated ACTH release from fetal pituitary cells in culture. The mean free cortisol concentration in plasma was not different between days 15 and 20 prior to parturition, and between 5 and 10 days prepartum, although it did rise between these times. Plasma CBC in chronically catheterized fetuses rose from 23·3 ± 4·6 ng/ml at day 115 to 86·5 ± 20·8 ng/ml at term and then decreased rapidly after birth. Between day 125 and day 140 of pregnancy approximately 10% of fetal plasma CBG was retarded by Concanavalin-A chromatography. This proportion increased at birth and attained adult values of >70% by one month of age. By Northern blotting the relative levels of CBG mRNA in the fetal liver did not change between days 100 and 125, then increased significantly at day 140, but declined at term and in newborn lambs. CBG mRNA was undetectable in total RNA from lung, kidney, hypothalamus and placentomes, but was present in the fetal pituitary at days 125 and 140. Reverse transcription-PCR was used to confirm the presence of CBG mRNA in pituitary tissue from term fetuses. In cultures of term fetal pituitary cells, added CBG attenuated the cortisol- but not the dexamethasone-mediated suppression of basal and CRH-stimulated ACTH release. We conclude that in fetal sheep there is an increase in the corticosteroid binding capacity of plasma during late pregnancy which regulates, in part, free cortisol levels in the circulation. The liver is the major site of CBG biosynthesis in the fetus and at least until day 140 of gestation the rise in plasma CBC is associated with an increase in hepatic CBG mRNA levels. The fetal pituitary was also established as a site of CBG production. Output of ACTH by cultured pituitary cells was inhibited by cortisol and this effect was diminished in the presence of added CBG. This study supports a role for systemic CBG in modulating the availability of cortisol to the fetal pituitary and suggests an additional way of modifying feedback effects of cortisol at the pituitary through its own production of CBG. Journal of Endocrinology (1995) 146, 121–130

Effects of incremental cortisol and adrenalectomy on plasma corticosteroid binding capacity in fetal sheep

1995 ◽  
Vol 73 (11) ◽  
pp. 1568-1573 ◽  
Author(s):  
Treena M. Jeffray ◽  
Edward T. M. Berdusco ◽  
John R. G. Challis ◽  
Megan Wallace ◽  
Abigail Fowden
Keyword(s):  
Plasma Cortisol ◽  
Binding Capacity ◽  
Strong Support ◽  
Significant Rise ◽  
Late Gestation ◽  
Total Plasma ◽  
Individual Values ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Corticosteroid Binding Globulin

The effects of incremental cortisol infusion or fetal adrenalectomy on plasma corticosteroid-binding capacity (CBC) were examined in sheep fetuses during late gestation (term ≈ 150 days). Cortisol, infused from day 120 at 1.5 mg/day for the first 3 days, 2.5 mg/day for the next 5 days, and 3.5 mg/day for the final 2 days, stimulated a significant rise in plasma CBC and immunoreactive corticosteroid binding globulin (CBG). There was a significant positive correlation between individual values for total plasma cortisol concentrations and CBC values. In contrast, fetal adrenalectomy at day 115 prevented the rise in plasma CBC found in intact fetuses at term. These experiments show that exogenous cortisol, given in a manner that mimics the prepartum rise in fetal plasma cortisol, stimulates CBG biosynthesis, whereas abolition of the cortisol rise prevents the increase in CBG. The study provides strong support for the proposal that the prepartum increase in CBG biosynthesis in fetal sheep occurs in response to the progressive rise in adrenal cortisol output by the fetus towards term.Key words: corticosteroid binding globulin, cortisol, adrenalectomy, fetus, sheep.

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.

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.

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.

Cortisol feedback regulation of pulsatile ACTH secretion in fetal sheep during late gestation

1994 ◽  
Vol 267 (4) ◽  
pp. E521-E527 ◽  
Author(s):  
E. M. Apostolakis ◽  
L. D. Longo ◽  
S. M. Yellon
Keyword(s):  
Binding Capacity ◽  
Feedback Regulation ◽  
Late Gestation ◽  
Acth Secretion ◽  
Negative Feedback Regulation ◽  
Fetal Sheep ◽  
Secretory Rate ◽  
Ovine Fetus ◽  
Near Term

In fetal sheep, plasma cortisol and adrenocorticotropic hormone (ACTH) concentrations increase during late gestation to surge within 72 h of birth (approximately 146 days gestation). To determine the feedback role of cortisol in control of pulsatile ACTH secretion, six chronically catheterized fetuses were treated with cortisol (1 microgram/h i.v.) for 96 h at 133 days gestation. Before (133 days), during (134 and 137 days), and after (142 days) cortisol treatment (5-min sampling for 2 h), ACTH pulses were evident in each fetus. At 134 days, ACTH pulse peak, nadir, and estimated secretory rate were significantly increased while frequency, amplitude, mean concentrations, and cortisol binding capacity (CBC) were unchanged. At 137 days, most characteristics of pulsatile ACTH secretion remained enhanced compared with pretreatment controls. At 142 days (96 h postinfusion), ACTH secretion parameters returned to pretreatment levels, but cortisol concentrations remained elevated. Cortisol infusion was then reinitiated at 142 days and, 22–24 h later, parameters of ACTH secretion increased except for amplitude, secretory rate, and CBC activity. The data indicate an absence of cortisol negative feedback regulation of pulsatile ACTH secretion. Rather, the ACTH rise that accompanied cortisol infusion suggests that cortisol exerts a positive feedforward influence on ACTH secretion in the ovine fetus near term.

scholarly journals Cortisol infusion in late-gestation hypothalamo-pituitary disconnected sheep fetus restores pituitary cell responsiveness to arginine vasopressin

2009 ◽  
Vol 296 (2) ◽  
pp. E300-E304 ◽  
Author(s):  
Luke C. Carey ◽  
Stephen B. Tatter ◽  
James C. Rose
Keyword(s):  
Signal Transduction ◽  
Arginine Vasopressin ◽  
Plasma Cortisol ◽  
Pituitary Cell ◽  
Late Gestation ◽  
Pituitary Cells ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Inositol 1,4,5 Trisphosphate ◽  
Sheep Fetus

Corticotrophs in the fetal sheep become increasingly responsive to arginine vasopressin (AVP) in late gestation. We previously reported that this may be due in part to corresponding increases in signal transduction (inositol 1,4,5-trisphosphate, IP3). These ontogenic changes are prevented by hypothalamo-pituitary disconnection (HPD), which also prevents fetal plasma cortisol concentrations from increasing in late gestation. This led us to hypothesize that cortisol is involved in mediating the changes in pituitary responsiveness. HPD was performed on fetal sheep at 120 days gestational age (dGA). Half of the HPD fetuses were infused with cortisol for 3 days beginning at 135–137 dGA (HPD+C). The remaining HPD fetuses and a group of sham-operated control fetuses were infused with saline. Pituitary cells were isolated and cultured. After 48 h, a subset of cells was stimulated with 100 nM AVP for 2 h, and the medium was collected for ACTH analysis. Another subset of cells was stimulated with 100 nM AVP for 30 min, and the formation of IP3 was determined. Plasma cortisol concentrations increased rapidly within the first 6 h after infusion (5.2 ± 1.9 to 29.7 ± 4.9 ng/ml) but did not increase thereafter. Cells from HPD+C and sham-operated fetuses secreted significantly more ACTH than those from HPD fetuses (% increase from control: 33.0 ± 8.8%, 47.9 ± 10.6%, and 11.9 ± 2.4%, respectively). IP3 formation was significantly increased in cells from HPD+C and sham-operated compared with HPD fetuses (% increase from control: 17.7 ± 4.4%, 18.9 ± 4.3%, and 4.6 ± 1.5%, respectively). These findings support the idea that cortisol plays a role in mediating the increase in pituitary responsiveness to AVP in the late-gestation fetal sheep.

Prostaglandin E2 enhances AVP-stimulated but not CRF-stimulated ACTH secretion from cultured fetal sheep pituitary cells

1992 ◽  
Vol 132 (1) ◽  
pp. 33-38 ◽  
Author(s):  
A. N. Brooks ◽  
F. Gibson
Keyword(s):  
Direct Action ◽  
Specific Interaction ◽  
Plasma Concentrations ◽  
Concomitant Administration ◽  
Late Gestation ◽  
Prostaglandin E ◽  
Pituitary Cells ◽  
Acth Secretion ◽  
Fetal Sheep ◽  
Fetal Plasma

ABSTRACT This study examined the ability of prostaglandin E2 (PGE2) to regulate ACTH secretion from cultured anterior pituitary cells of fetal sheep between days 130 and 140 of gestation (term = 145 days). Corticotrophin-releasing factor (CRF) and arginine vasopressin (AVP) induced dose-dependent (0·1–1000 nmol/l) increases in ACTH secretion from fetal sheep pituitary cells maintained in culture for 6 days, with AVP being significantly (P<0·01) more potent than CRF. PGE2 (1000 nmol/l) significantly (P<0·05) enhanced the ability of AVP, but not CRF, to stimulate ACTH secretion. However, PGE2 given alone (0·1–1000 nmol/l) had no effect on ACTH secretion. Concomitant administration of CRF and AVP induced a greater release of ACTH than after treatment with either peptide alone, a synergistic interaction which was unaffected by simultaneous administration of PGE2. These results provide evidence for a direct action of PGE2 on ACTH secretion from the fetal sheep pituitary gland via a specific interaction with AVP. This interaction may allow increased fetal plasma concentrations of PGE2, seen during late gestation, to stimulate fetal pituitary–adrenal maturation. Journal of Endocrinology (1992) 132, 33–38

scholarly journals Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia

2015 ◽  
Vol 308 (4) ◽  
pp. E306-E314 ◽  
Author(s):  
Satya S. Houin ◽  
Paul J. Rozance ◽  
Laura D. Brown ◽  
William W. Hay ◽  
Randall B. Wilkening ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Hepatic Glucose Production ◽  
Plasma Concentrations ◽  
Glucose Production ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Hepatic Glucose ◽  
Molar Percent ◽  
Glucose Output

Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 ( P < 0.05). The liver transitioned from net glucose uptake (basal, 5.1 ± 1.5 μmol/min) to output by d4 (2.8 ± 1.4 μmol/min; P < 0.05 vs. basal). The [U-13C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 ± 0.01, vs. d4: 0.89 ± 0.01, P < 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 ( P < 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia ( P < 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia.

Inhibin and follistatin concentrations in fetal tissues and fluids during gestation in sheep: evidence for activin in amniotic fluid

1994 ◽  
Vol 141 (2) ◽  
pp. 219-229 ◽  
Author(s):  
S Wongprasartsuk ◽  
G Jenkin ◽  
J R McFarlane ◽  
M Goodman ◽  
D M de Kretser
Keyword(s):  
Amniotic Fluid ◽  
Adrenal Glands ◽  
Late Gestation ◽  
Pituitary Cells ◽  
Fetal Sheep ◽  
Fetal Testis ◽  
Cells In Culture ◽  
Tissue Extracts ◽  
Significant Difference ◽  
The Individual

Abstract The concentrations of inhibin and follistatin in amniotic fluid and in tissue extracts from the placenta, gonads and adrenals of fetal sheep were measured using radioimmunoassays. These tissue extracts were from whole fetuses from days 16 to 45 and from the individual organs from day 46 to 145 (term) and were assayed at multiple dilutions. The capacity of these extracts to alter FSH production of rat anterior pituitary cells in culture was also assessed at multiple dilutions. Immunoactive inhibin concentrations in amniotic fluid from both sexes increased during gestation and levels were significantly greater in males than females. Peak concentrations of immunoreactive inhibin of 11·2±1·9 ng/ml were found in males at 116–125 days of gestation. Follistatin concentrations did not change throughout gestation and no significant difference was noted between sexes. Mean follistatin levels throughout gestation were 3·0±0·9 ng/ml for males and 3·7±0·9 ng/ml for females. Despite the potential for FSH inhibition by inhibin and follistatin, amniotic fluid from both sexes at all stages of gestation stimulated FSH secretion in the pituitary cell bioassays, suggesting the presence of activin which was confirmed by the measurement of immunoactive activin (13·3±2·5 ng/ml) in a specific radioimmunoassay. Maximum concentrations of immunoactive and bioactive inhibin in placental extracts were observed in late gestation (2·2 ±0·6 and 3·8±1·6 ng/g respectively) and there was no significant difference between sexes. Follistatin concentrations in placental cotyledons ranged from 11·5 to 27·1 ng/g with no significant difference between sexes. In view of the higher follistatin concentrations compared with inhibin, it is likely that the capacity of placental extracts to suppress FSH production by pituitary cells in culture is due predominantly to follistatin. Immunoactive inhibin was observed in high concentrations in the fetal testis throughout gestation; with concentrations increasing to a maximum of 1993·0± 519·7 ng/g at 126–135 days of gestation with a ratio of bioactive: immunoactive inhibin of 1:20. Although bioactive and immunoactive inhibin was also observed in fetal ovaries and adrenals from both male and female fetuses, concentrations were lower than those observed in fetal testes. Follistatin concentrations in the fetal testis were elevated between 70 and 95 days (97·6 ng/g) and then declined. Similar concentrations were found in the adrenal glands of both sexes (males 83·5–103·3 ng/g: females 55·3–95·8 ng/g). In both males and females, immunoactive inhibin concentrations in fetal adrenals increased during gestation peaking at levels of 34·4±16·5 and 27·8± 9·0 ng/g respectively. These data suggest that the capacity of adrenal extracts to suppress FSH production by pituitary cells is due to both inhibin and follistatin. These studies demonstrated that significant concentrations of immunoactive inhibin and follistatin are present in amniotic fluid, and the fetal gonads, adrenal glands and placenta in sheep. The role of these proteins during fetal development requires further study. Journal of Endocrinology (1994) 141, 219–229

Alterations in oxytocin prohormone processing during early development in the fetal sheep

1992 ◽  
Vol 263 (3) ◽  
pp. R738-R740 ◽  
Author(s):  
M. Morris ◽  
M. Castro ◽  
J. C. Rose
Keyword(s):  
Fetal Development ◽  
Plasma Levels ◽  
Umbilical Artery ◽  
Umbilical Vein ◽  
Late Gestation ◽  
Developmental Changes ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Prohormone Processing ◽  
Specific Antisera

Oxytocin (OT) prohormone processing was studied in fetal sheep. Using specific antisera that recognize the amidated and the COOH-terminal extended forms of OT, we measured arterial and venous levels of the OT peptides in fetal sheep plasma at 94 and 138 days of gestation. Plasma levels of the COOH-terminal extended forms, OT-X, were highest early in development, 35.7 +/- 9.8 vs. 14.3 +/- 5.7 pg/ml (94 vs. 138 days). The ratio of the plasma peptides, OT-X to OT, was higher in the young fetus (35 +/- 11.6 vs. 3.1 +/- 1.3, 94 vs. 138 days). There were also developmental changes in the umbilical artery-umbilical vein differences, with positive values noted in late gestation. These results demonstrate that the changes in the processing of the OT precursor that occur during fetal development are reflected by alterations in the relative amounts of prohormone and amidated hormone found in fetal plasma.

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