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J R Challis

Publications and source records attributed to J R Challis.

At least 145 records · Page 8Linked to original sources
PubMed1990

Changes in glucocorticoid receptor number in the hypothalamus and pituitary of the sheep fetus with gestational age and after adrenocorticotropin treatment.

The concentrations of ACTH and cortisol both rise in the plasma of fetal lambs during late pregnancy, reflecting maturation of the fetal hypothalamic-pituitary-adrenal axis and providing the stimulus for parturition. The failure of rising cortisol to suppress plasma ACTH may be due to altered sensitivity of glucocorticoid negative feedback. To examine the possibility that this effect might be mediated through changes in the number of glucocorticoid receptors (GR) in the fetal hypothalamus and pituitary, we measured changes in GR number in these tissues from fetuses at discrete times of pregnancy between day 60 and term (day 145) and from newborn lambs and adult sheep. We also determined the effect of intrafetal ACTH administration in amounts known to produce premature parturition on GR number in fetuses at days 125-130 of gestation. Binding of [1,2,4-N-3H]triamcinolone acetonide to dispersed cell preparations of fetal pituitary and hypothalamus was saturable, temperature dependent, glucocorticoid specific, and of high affinity (2-3 X 10(-9) M). The number of GR in the pituitary always exceeded that in the hypothalamus. In both tissues GR number rose between days 60-70 to highest values on days 100-110, then decreased until day 125. GR number in the pituitary rose again at term, paradoxically at a time of rising endogenous glucocorticoid levels. However, after ACTH administration, there was a significant decrease in GR number in both hypothalamus and pituitary. These results indicate that altered efficacy of glucocorticoid negative feedback in term fetuses is not due to a decrease in pituitary or hypothalamic GR number. The rise in GR number at term and the fall after intrafetal ACTH treatment raises the possibility that mechanisms exist in the fetus allowing normal autoregulation of GR to be overridden at term.

Adrenocorticotropic Hormone↗
PubMed1990

Failure to maintain interspecific pregnancy after transfer of Dall's sheep embryos to domestic ewes.

Over a 3-year period, 32 Dall's sheep (Ovis dalli dalli) embryos were transferred into 24 domestic sheep (O. aries) recipients and 4 were transferred into 2 Dall's sheep recipients. In the first year, none of the 10 O. aries recipients was diagnosed pregnant. In the following 2 years, 9 (37%) of the domestic sheep recipients were pregnant on Day 18, 8 (33%) on Day 40, 6 (25%) on Day 90 and 4 (16%) on Day 120; 1 aborted at Day 125 and another at Day 145. Pregnancies were established only in ewes that had previously been recipients of Dall's sheep embryos. The 2 remaining pregnant sheep were treated with progesterone from Day 125 until the fetuses were determined to be dead at Day 145. Both of the Dall's sheep recipients (Year 2) established pregnancies; 1 live Dall's sheep lamb was born 174 days after mating. No differences in serum progesterone, oestrone, prostaglandin F-2 alpha metabolites or cortisol concentrations could be detected during pregnancy between recipients carrying Dall's sheep embryos, recipients receiving progesterone treatment or domestic ewes carrying domestic sheep pregnancies. Six fetuses were necropsied (1 at Day 125 and 5 at Day 145-146): all fetuses were premature and had various degrees of hydranencephaly. No significant differences were found when cotyledon numbers were compared among domestic ewes carrying Dall's sheep lambs. Dall's sheep ewes lambing naturally and domestic ewes lambing naturally. These results demonstrate that the transfer of Dall's sheep embryos to domestic ewes results in the establishment but subsequent loss of pregnancy and that these losses occur throughout gestation.

Animals↗
PubMed1990

Steroid, corticotrophin-releasing hormone, ACTH and prostaglandin interactions in the amnion and placenta of early pregnancy in man.

Corticotrophin-releasing hormone (CRH) is produced by both the placenta and fetal membranes at term in man, and CRH mRNA has been detected in human placental tissue. The synthesis of CRH and its control during early pregnancy, however, have not been established, and the role of CRH produced in the placenta and fetal membranes is not known. We examined whether amnion and placental tissue obtained between 12 and 15 weeks of gestation produced CRH in vitro, whether steroid modulation of output occurred and whether CRH affected prostaglandin (PG) output by the placenta and amnion. Immunoreactive (ir) CRH output by amnion (2.8 +/- 0.31 (S.E.M.) nmol/10(5) cells) was significantly (P less than 0.01) greater than that from placenta (1.76 +/- 0.21 nmol/10(5) cells). Output of ir-CRH decreased in the presence of progesterone, but increased in the presence of cortisol and dexamethasone. There was no significant effect of progesterone or ir-CRH output by placental cells; however, ir-CRH output was increased in the presence of dexamethasone and cortisol. There was no significant effect of corticosterone on ir-CRH output by either amnion or placental cells. Both ACTH and CRH stimulated the output of PGE2 and PGF2 alpha by amnion cells. In contrast, there was no significant effect of PGE2 output by placental cells maintained in the presence of either human CRH or ACTH. Output of PGF2 alpha by placental cells was increased in the presence of both CRH and ACTH. We conclude that both amnion and placental tissue produce CRH in early gestation, and that this output is modulated by steroids.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1990

Cortisol inhibits ACTH but not the AVP response to hypoxaemia in fetal lambs at days 123-128 of gestation.

During acute hypoxemia in fetal sheep the elevation in ACTH concentration in the fetal circulation at days 125-129 is greater than that at term, but similar rises in AVP occur at both times. To examine whether the diminished ACTH response is due to elevated endogenous cortisol, and if there is differential control of ACTH and AVP release in hypoxemia, we infused either vehicle or cortisol (5 micrograms/min) into fetal sheep at days 123-128 for 5 h before and then during a 2-h period of acute hypoxemia (mean PaO2 decrease 8.2 mmHg) without acidemia. During cortisol infusion, plasma cortisol rose to 40-50 ng/ml, similar to values in term fetuses. In vehicle-infused fetuses, cortisol rose from 2.1 to 7.0 ng/ml at +1 to +2 h of hypoxemia. ACTH rose significantly during hypoxemia in the vehicle-infused fetuses, and this response was attenuated by cortisol infusion. In contrast, fetal AVP rose significantly during hypoxemia both in the presence and absence of cortisol infusion. Fetal breathing movements, and electroocular activity decreased during hypoxemia, and these responses were not altered by cortisol. We conclude that cortisol exerts differential negative feedback on ACTH but not on AVP release during hypoxemia. The maintained AVP response may facilitate cardiovascular adjustments of the fetus to hypoxemia even when endogenous cortisol is elevated, such as near term.

Adrenocorticotropic Hormone↗
PubMed1989

Fetal and adult sheep adrenal cortical cells contain glucocorticoid receptors.

Specific receptors for glucocorticoids were identified in the fetal and adult sheep adrenal cortex by a whole-cell binding assay using [3H]triamcinolone acetonide ([3H]TA) as the radiolabelled ligand. [3H]TA binding sites were saturable and of high affinity, with dissociation constant (Kd) of 2-3nM. Scatchard analysis revealed a single class of binding sites with a binding capacity (Bmax) of 207 and 5 fmol/10(6) cells for d100 fetuses and adults, respectively. By single point analyses at saturating [3H]TA concentration, we found that glucocorticoid receptors (GR) were present in the fetal adrenal cortex as early as d60. Highest concentrations were found at d100-110. GR decreased to d125, then increased to term (approx. d145) before declining again in newborn and adult animals. This demonstration of glucocorticoid receptors in ovine fetal adrenal cortical cells provides a mechanistic basis for the concept that glucocorticoids may act, perhaps in a paracrine or autocrine fashion, to influence adrenocorticotropin (ACTH)-induced activation of fetal adrenal function and the events leading to parturition.

Adrenal Cortex↗
PubMed1989

Local stimulation of prostaglandin production by corticotropin-releasing hormone in human fetal membranes and placenta.

Corticotropin-releasing hormone is produced by the human placenta and fetal membranes, but its physiological significance is not established. We examined the possibility that CRH might affect prostaglandin output by these intra-uterine tissues. Primary cultures of amnion, chorion, decidua and placenta were established from tissue obtained from women at term elective cesarean section were maintained in the presence of increasing concentrations of synthetic hCRH. PG output at 48h was measured by radioimmunoassay. hCRH stimulated PGE2 output by amnion, chorion and placenta, but not by decidual tissue. PGF2 alpha output was stimulated in amnion, decidua and placenta but not chorion, whereas output of 13, 14-dihydro-15-keto PGF2 alpha was stimulated in all four tissues. We conclude that hCRH stimulates prostaglandin output by human placenta, decidua and the fetal membranes, raising the possibility of paracrine or autocrine interactions between CRH and prostaglandins in vivo.

Amnion↗
PubMed1989

Fetal and maternal endocrine responses to prolonged reductions in uterine blood flow in pregnant sheep.

To examine the effects of sustained (48-hour) hypoxemia on fetal and maternal adrenocorticotropic hormone concentrations and on maternal progesterone, uterine blood flow was reduced in eight sheep at day 128 of pregnancy by means of an adjustable Teflon clamp placed around the maternal common internal iliac artery. Control measurements were made in four animals in which the vascular clamp was not adjusted. Fetal PaO2 fell from 20.6 +/- 1.1 mm Hg (mean +/- SEM) to 16.6 +/- 0.6 mm Hg within 1 hour after application of the clamp and remained suppressed during 48 hours. There was a transient acidemia at 1 to 2 hours that had corrected by 8 hours. Fetal adrenocorticotropic hormone levels rose from 24 +/- 6 to 1320 +/- 205 pg/ml at 2 hours but decreased by 16 hours. Measured by high-pressure liquid chromatography, more than 95% of immunoreactivity corresponded to adrenocorticotropic hormone1-39. Fetal cortisol levels rose by 6 hours and remained elevated through 48 hours. Maternal adrenocorticotropic hormone, cortisol, and progesterone levels were unchanged during the study period. We conclude that fetal hypoxemia-acidemia after restriction of uterine blood flow provokes fetal adrenocorticotropic hormone release, but the elevation in adrenocorticotropic hormone is not sustained. However, the level of fetal cortisol rises progressively, consistent with fetal adrenal activation.

Adrenal Glands↗
PubMed1989

Adrenocorticotropic hormone, cortisol, and progesterone changes in the lamb during the perinatal period.

Although the changes in circulating concentrations of adrenocorticotropic hormone, cortisol, and progesterone are well established for the fetal and neonatal lamb, there is little information on these hormones in the immediate perinatal period. We have examined the relationship between these hormones and systemic blood gas tensions and substrate concentrations in the perinatal period. Measurements were made in arterial blood of seven unanesthetized fetal sheep at 138 to 141 days' gestation during low- and high-voltage electrocortical activity. After cesarean delivery each newborn lamb was studied again at 2, 5, and 10 minutes and at 2 and 24 hours while awake. There was no correlation between fetal or maternal adrenocorticotropic hormone, cortisol, or progesterone and fetal electrocortical activity. Within 2 to 5 minutes of delivery there was a dramatic increase in neonatal immunoreactive adrenocorticotropic hormone concentrations associated with an increase in plasma cortisol. Neonatal Pao2 rose progressively, but a mixed respiratory and metabolic acidosis was evident during the first 10 minutes after delivery. This was partially corrected by 2 hours of neonatal life and was fully corrected by 24 hours of life. We conclude that rapid responsiveness of the fetal pituitary-adrenal axis occurs in response to birth in the absence of active labor, and we suggest that this may have survival value for the preterm fetus.

Adrenocorticotropic Hormone↗
PubMed1989

Prostaglandin E2 metabolism in the human fetal membranes.

Prostaglandins play a pivotal role in the initiation and maintenance of labor, but the sources that contribute to the production of primary prostaglandins (prostaglandin E2 and prostaglandin F2 alpha) remain controversial. In decidua, prostaglandin F2 alpha may be formed de novo or from prostaglandin E2 through 9-ketoreductase activity, although it has been suggested that metabolism to 13,14-dihydro-15-ketoprostaglandin E2 through 15-hydroxyprostaglandin dehydrogenase is dominant. To examine this possibility, and to determine changes with labor, we examined interconversions of prostaglandin E2 to prostaglandin F2 alpha, 13,14-dihydro-15-ketoprostaglandin E2 and 13,14-dihydro-15-ketoprostaglandin F2 alpha by dispersed cells of decidua, chorion, and amnion obtained from patients at term elective cesarean section or after spontaneous labor. Incubations were performed with increasing concentrations (1 to 100 ng/ml) of prostaglandin E2 for 2 and 4 hours, and products were measured by radioimmunoassay. The 13,14-dihydro-15-ketoprostaglandin E2 was measured as 11-deoxy-13,14-dihydro-15-keto-11 beta, 16 psi-cycloprostaglandin E2. Basal output of prostaglandin E2 increased between cesarean section and spontaneous labor from 190.6 +/- 109 pg/10(5) cells (+/- SE) to 605.2 +/- 346.8 in amnion, nondetectable to 24.5 +/- 11.2 in chorion, and 18 +/- 16 to 69 +/- 25.8 in decidua. For both cesarean section and spontaneous labor patients there was very little conversion of prostaglandin E2 by the amnion, substantial conversion to 13,14-dihydro-15-ketoprostaglandin E2 by the chorion, and some conversion to 13,14-dihydro-15-ketoprostaglandin E2 by the decidua. Percentage conversions did not change with labor. Prostaglandin F2 alpha was formed by all tissues but only in trace amounts. All tissues from one cesarean section patient showed substantial conversion of prostaglandin E2 to prostaglandin F2 alpha, but very little 13,14-dihydro-15-ketoprostaglandin E2 or 13,14-dihydro-15-ketoprostaglandin F2 alpha formation, indicating either a decrease or deficiency in the 15-hydroxyprostaglandin dehydrogenase activity. We conclude that conversion of exogenous prostaglandin E2 to prostaglandin F2 alpha can occur in intrauterine tissues, but this does not normally contribute significantly to the prostaglandin F2 alpha output by the human decidua and fetal membranes.

Amnion↗
PubMed1989

Vitamin D3 metabolites stimulate prostaglandin production by human fetal membranes and placenta in vitro.

In the present study we examined whether the vitamin D3 metabolites, 25-hydroxyvitamin D and 1-25-dihydroxycholecalciferol affected the production of the prostaglandins PGE2 and PGF2 alpha in human fetal membranes and placenta in vitro. Human amnion, chorion, decidual, and placental cells were maintained in primary monolayer culture. Treatment with the vitamin D3 metabolites resulted in an increase in PGE2 and PGF2 alpha production by amnion, decidua, and placental cells; however, these effects varied with time and were different between tissues. Although there was no significant increase in the production of PGE2 and PGF2 alpha by chorion cells in vitro, there was a significant increase in the production of prostaglandin F metabolites after treatment with the vitamin D3 metabolites. The data suggest that the vitamin D3 metabolites may increase free calcium availability and the conversion of arachidonic acid to the prostaglandins. The data do not, however, exclude the possibility that the vitamin D3 metabolites act at other points of arachidonic acid metabolism. These findings raise the possibility of a paracrine role for the vitamin D3 metabolites in the modulation of prostaglandin production within the human fetal membranes and placenta.

Calcitriol↗
PubMed1989

Ontogeny of the insulin response to glucose in fetal and adult sheep.

The purpose of the present experiments was to examine in sheep whether the fetal insulin response to glucose was present by day 110 (d110) of pregnancy and whether the magnitude of the fetal insulin response changed between d110 and d145 (term). We also compared the responses observed in fetuses to those of adult nonpregnant sheep. Basal concentrations of glucose measured in plasma collected from the fetal femoral artery rose progressively between d110 and d145 of gestation, but did not attain the plasma glucose concentrations measured in adult sheep. Peak glucose concentrations in fetuses were achieved 10 min following the bolus injection of glucose (0.8 g/kg estimated fetal body weight) into the fetal femoral vein, and peak values increased with gestational age. Significantly higher peak glucose concentrations were achieved in adult sheep. The concentration of insulin rose rapidly in fetuses at d110, and a similar time course of insulin release in plasma was seen at all gestational ages. The peak plasma insulin concentrations were achieved at 20 min and were significantly greater in older (d140-145) than younger (d125-130) fetuses (p less than 0.05). Peak insulin values in fetuses were much less than in adult sheep. In adult sheep glucose and insulin concentrations remained elevated at 120 min following the injection of glucose, whereas in the fetus the concentration of insulin had returned to preinjection values by 60 min. The insulin/glucose ratio did not change in fetal lambs over the last one third of gestation and was not different from the adult sheep.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Maturation and activation of hypothalamic-pituitary adrenal function in fetal sheep.

The progressive rise in the concentration of cortisol in the plasma of fetal sheep during late pregnancy arises from the sequential maturation of the fetal HPA axis. In addition, cortisol itself occupies a central role in accelerating this process through a series of feed-forward mechanisms. Before days 100-110 of pregnancy AVP appears to predominate over CRH as the major corticotropin-releasing factor in the fetus. Pituitary responsiveness to CRH increases progressively after day 100, and precedes maturation of fetal adrenal responsiveness to endogenous or exogenous ACTH. Cortisol accelerates the increase in the ratio of adult-fetal corticotropes in the fetal pituitary. In addition, cortisol modulates the mechanism by which ACTH activates fetal adrenal function, possibly through an action at the level of the ACTH receptor. Cortisol appears also to mediate the rise in fetal plasma CBG concentrations during late pregnancy, and may thereby alter the efficacy of the negative feedback process. In women, cortisol acts on the placenta to promote rather than to inhibit CRH output. CRH from the placenta may reach significant concentrations in the fetal circulation and augment the drive to fetal ACTH release. It may also act in a paracrine fashion to promote placental POMC gene expression. The importance of placental CRF and ACTH in the sheep is not yet apparent. These feed-forward loops establish a series of positive cascades that ensure concurrent rises in plasma ACTH and cortisol in the fetal circulation during late pregnancy. We suggest that this sequence leads to, and is broken by, the process of birth.

Adrenal Glands↗
PubMed1989

Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta.

The levels of immunoreactive CRH are elevated in both maternal and fetal plasma in late gestation and labor, but fall precipitously after parturition. The major source of this peptide is thought to be the placenta. We determined if the placenta and also the amnion, chorion, and decidua produce CRH, whether this material has biological activity, and whether CRH output is modulated by glucocorticoids and progesterone. In an in vitro monolayer culture system CRH was produced by the fetal membranes and decidua. Media immunoreactive CRH concentrations averaged 625 +/- 45 (SE) pg/10(5) cells in amnion, 701 +/- 56 pg/10(5) cells in chorion, and 580 +/- 60 pg/10(5) cells in decidual tissue obtained at cesarean section. This output was similar to that by the placenta (906 +/- 121 pg/10(5) cells). These values increased in tissue obtained after spontaneous labor. A single peak of CRH immunoreactivity eluting at the same position as synthetic human CRH, and possessing biological activity, was found in all tissues. There was a dose-dependent increase in CRH output by all tissue types when cells were maintained in the presence of increasing concentrations of cortisol and dexamethasone. In contrast, increasing concentrations of progesterone decreased CRH output by all tissue types. We conclude that immuno- and biologically active CRH is produced not only in the human placenta, but also in the fetal membranes. CRH output by the placenta/fetal membranes is moderated by steroids, and changes with labor. These findings raise the possibility of a regulatory system similar to that of the hypothalamic pituitary axis, but residing within the placenta and fetal membranes.

Adrenocorticotropic Hormone↗
PubMed1989

Controls of corticotrophin-releasing factor output by hypothalamic tissue from fetal sheep in vitro.

Corticotrophin-releasing factor (CRF) is thought to be an important physiological regulator of the pituitary-adrenal axis in fetal sheep and, as such, plays a fundamental role in the initiation of parturition in this species. However, little is known of the controls of CRF secretion from the fetal hypothalamus. We looked for the presence of CRF in fetal hypothalami, and examined whether the hypothalamic CRF concentration or molecular species changed in relation to gestational age. We established an in-vitro perifusion system to examine the release of CRF from perifused hypothalami taken from fetuses at day 100 and day 140 of pregnancy, under basal conditions and in response to potassium depolarization and/or dexamethasone administration. Immunoreactive CRF was present in fetal hypothalami as early as day 100 (2.42 +/- 0.99 (S.E.M.) micrograms/g protein, n = 9) and in similar concentrations at day 140 (2.31 +/- 0.69 micrograms/g protein, n = 9). There was a significant (P less than 0.05) increase in hypothalamic CRF content to 14.79 +/- 4.09 micrograms/g protein (n = 16) between day 122 and day 135 of gestation. Using Sephadex G-75 chromatography, hypothalamic extracts at day 100, days 122-135 and day 140 eluted with a single peak of immunoreactivity which corresponded to synthetic ovine CRF(1-41). The basal release of CRF from perifused hypothalami at day 140 (76.6 +/- 10.4 pg/fraction, n = 8) was significantly (P less than 0.05) greater than at day 100 (50.1 +/- 10.2 pg/fraction, n = 11). Dexamethasone significantly inhibited basal CRF release at day 140 of gestation but not at day 100.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The effects of hypoxemia with progressive acidemia on fetal renal function in sheep.

In order to determine the effects of fetal hypoxemia on renal blood flow, glomerular filtration rate (GFR) and urethral and urachal urine output, we examined the effects of 3 h maternally-induced (9% O2, 3% CO2, 88% N2) fetal hypoxaemia on 10 chronically-instrumented fetal sheep between 127-135 days of gestation. Fetal arterial pH fell significantly during the second and third hours of hypoxia and this coincided with a significant increase in fetal arterial blood pressure (P less than 0.05). During the second hour of hypoxia, with mild acidaemia, fetal GFR decreased significantly and then, during the third hour, fetal GFR, urethral and total urine output were significantly elevated. During the 2-h recovery period urachal and total, but not urethral urine output, were significantly elevated (P less than 0.05). The data suggested that the increase in GFR and urine output measured during the third hour of hypoxia and the recovery period may reflect a pressure diuresis.

Animals↗
PubMed1988

Discordant accelerated pulmonary maturation after adrenocorticotropic hormone-induced labor in twin sheep fetuses.

To examine the role of parturition on lung maturation in sheep, we studied parameters of lung development in singleton fetuses treated with pulsatile adrenocorticotropic hormone or saline solution from day 127 or twin pregnancies in which one fetus only received pulsatile adrenocorticotropic hormone from day 127 until labor occurred. These parameters were compared with those of term fetuses (145 days). Pulsatile adrenocorticotropic hormone provoked labor in a mean (+/- SEM) of 102.6 +/- 6.6 and 181.0 +/- 18.0 hours in single and twin pregnancies, respectively. Adrenal/body weight ratios increased similarly in adrenocorticotropic hormone-treated single and twin fetuses at delivery, and basal cortisol levels were two- to threefold higher prepartum in adrenocorticotropic hormone-treated fetuses. Little change in plasma cortisol levels occurred in singletons treated with saline solution or in twins not infused with adrenocorticotropic hormone. The lung weight/body weight was not altered in any group. Lung distensibility and stability were doubled to term values in fetuses treated with pulsatile adrenocorticotropic hormone compared with controls and untreated twins. Mean lavage phosphatidylcholine levels rose from 0.07 to 0.11 mg/gm in saline solution-treated or untreated fetuses to 0.20 to 0.23 mg/gm in pulsatile adrenocorticotropic hormone-treated singletons or twins, compared with 0.63 mg/gm at term. Phosphatidylcholine production increased from 0.51 dpm/gm/hr in saline solution-treated fetuses to 0.73 and 0.89 dpm/gm/hr in the single and twin pulsatile adrenocorticotropic hormone-infused fetuses, respectively; phosphatidylcholine production was 0.62 dpm/gm/hr in the noninfused twin. Lungs of twins treated with pulsatile adrenocorticotropic hormone were morphologically more mature than those of untreated twins. We conclude that fetal endocrine responses to exogenous adrenocorticotropic hormone, rather than the stimuli associated with labor per se, are responsible for lung maturation in the fetal sheep.

Adrenocorticotropic Hormone↗