Search Results
You are looking at 1 - 10 of 43 items for
- Author: J. R. G. Challis x
- Refine by access: All content x
Search for other papers by J. R. G. CHALLIS in
Google Scholar
PubMed
A major factor in determining the metabolic clearance rate (MCRB) (Tait & Burstein, 1964) of many steroids is the extent to which these may be metabolized by the liver, and those steroids which are present in plasma largely as the unbound or albumin-bound moiety have been shown to have a high splanchnic extraction (Baird, Horton, Longcope & Tait, 1969). In conscious sheep MCRB values for oestradiol-17β and oestrone (Challis, Harrison & Heap, 1973 and in preparation) are similar to or greater than hepatic blood flow (Katz & Bergman, 1969; Paterson & Harrison, 1972), and it seemed probable that in plasma these steroids were largely associated with albumin rather than bound by high affinity proteins. The binding of oestrogens to ovine serum albumin (OSA) and ovine plasma has therefore been studied using an equilibrium dialysis technique (Paterson & Hills, 1967).
Tritiated oestrogens (oestradiol-17β, E2β; oestrone, E1
Search for other papers by S G Matthews in
Google Scholar
PubMed
Search for other papers by J R G Challis in
Google Scholar
PubMed
Abstract
It is well established that corticotrophin-releasing hormone and vasopressin can induce both synthesis and release of ACTH from the ovine pituitary gland, and that glucocorticoids can inhibit these responses. Changes in the abundance, localization and distribution of proopiomelanocortin (POMC) mRNA and prolactin (PRL) mRNA in the ovine fetal pituitary were examined by in situ hybridization following hypoxaemia applied in the presence or absence of concomitant cortisol in late gestation (day 135). Fetuses were distributed amongst four groups; saline-infused/normoxaemic, cortisol-infused/normoxaemic (0·3 mg/h), saline-infused/hypoxaemic and cortisol-infused/hypoxaemic. Hypoxaemia (6 h) was induced by reducing the maternal PaO2, resulting in a 6–8 mmHg decrease in fetal arterial PO2. Fetal infusions were commenced 5 h prior to and maintained throughout the treatment period. Hypoxaemia, which elevated fetal plasma ACTH and cortisol, caused a significant (P<0·05) increase in POMC mRNA in the pars distalis (PD), but was without effect on POMC mRNA in the pars intermedia (PI). Cortisol infusion attenuated the hypoxaemiainduced increase in POMC mRNA in the PD, but was without effect on non-stimulated steady-state POMC mRNA levels in either the PD or PI. PRL mRNA was only present in the PD and significantly (P<0·05) increased after cortisol infusion and hypoxaemia. In conclusion (i) POMC and PRL mRNA in the PD are increased following moderate hypoxaemia, (ii) cortisol attenuates changes in POMC mRNA but not PRL mRNA in the PD following hypoxaemia and (iii) cortisol increases PRL mRNA levels in the PD. Synthesis of POMC and PRL in the fetal PD is highly sensitive to homeostatic perturbations and glucocorticoids in late gestation.
Journal of Endocrinology (1995) 147, 139–146
Search for other papers by J. R. G. CHALLIS in
Google Scholar
PubMed
Search for other papers by J. L. LINZELL in
Google Scholar
PubMed
SUMMARY
Since blood oestrogen levels are much higher during pregnancy in the goat than in the sheep a continuous isotope infusion technique was used to study oestrone metabolism in five experiments on two goats during late pregnancy and early lactation. The metabolic clearance rate was similar to that in the sheep in all experiments (mean value ± s.e.m., 4·02 ± 0·25 1/min); therefore the high blood oestrone concentrations in late pregnancy (851–2043 pg/ml) were due to high oestrone production rates (4·22–7·54 μg/min). There was some conversion of oestrone to oestradiol-17β by the mammary glands and other tissues (mean conversion ratio 17·1%) and a little (< 10%) binding of oestrone to erythrocytes. The uptake of oestrone by the mammary gland corresponded to < 3% of the total production rate. These results are compared with those obtained for other steroid hormones (progesterone, cortisol) in the goat and sheep.
Search for other papers by S. A. Jones in
Google Scholar
PubMed
Search for other papers by J. R. G. Challis in
Google Scholar
PubMed
ABSTRACT
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/105 cells) was significantly (P<0·01) greater than that from placenta (1·76 ± 0·21 nmol/105 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 PGF2α 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 PGF2α 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. CRH and ACTH stimulate PG output by amnion and placenta in early pregnancy, raising the possibility of local (autocrine and paracrine) interrelations in vivo.
Journal of Endocrinology (1990) 125, 153–159
Search for other papers by A. N. Brooks in
Google Scholar
PubMed
Search for other papers by J. R. G. Challis in
Google Scholar
PubMed
ABSTRACT
To test the hypothesis that endogenous opioids participate in the regulation of the ontogenic development of the hypothalamic-pituitary-adrenal axis in fetal sheep, we measured changes in immunoreactive (ir) ACTH and cortisol concentrations in response to bolus injections of either the [Met]-enkephalin analogue, [d-Ala2,N-Phe4,Met(0)ol5]-enkephalin (FK 33-824; 25 μg), the opioid antagonist naloxone (1 mg), a combination of both, or saline vehicle, administered to chronically catheterized fetal sheep through late gestation.
There were no effects of either FK 33-824, naloxone or saline on the release of ir-ACTH and cortisol at the earliest stage of gestation studied (days 110–115). By days 125–130, FK 33-824 caused a rapid but short-lived (30 min) increase in plasma ir-ACTH (P <0·05) which was accompanied by a smaller but nonsignificant increase in cortisol. Naloxone given concurrently with FK 33-824 abolished this response, thus providing evidence for a specific effect through opioid receptors. Naloxone given alone was without effect. At days 135–140, FK 33-824 caused a significant increase in ir-ACTH which was of similar duration and magnitude to that which occurred at days 125–130. There was a larger basal variation in plasma concentrations of cortisol than at days, 125–130, and a greater increase in cortisol after FK 33-824, although this did not reach statistical significance. Naloxone again reversed the effects of FK 33-824 but was without effect when given alone.
We conclude that opioid receptors capable of mediating the effects of exogenously administered opioid peptides on the pituitary-adrenal axis are present in fetal sheep by days 123–130. However, we have been unable to demonstrate tonic control of this axis by endogenous opioids, since naloxone is ineffective when given alone.
J. Endocr. (1988) 119, 389–395
Search for other papers by J. R. G. CHALLIS in
Google Scholar
PubMed
Search for other papers by J. V. WORKEWYCH in
Google Scholar
PubMed
Search for other papers by J. E. PATRICK in
Google Scholar
PubMed
The concentration of progesterone has been measured in ten women at 34–35 weeks of gestation in blood samples taken at 30 or 60 min intervals during a 24 h study period. Plasma progesterone concentrations showed a distinct diurnal rhythm. Most values determined between 04.00 and 11.00 h were significantly lower than the peak concentrations measured between 13.00 and 01.00 h. The relation of these changes in plasma progesterone to those in plasma cortisol and oestrogens is discussed.
Search for other papers by J. R. G. CHALLIS in
Google Scholar
PubMed
Search for other papers by I. J. DAVIES in
Google Scholar
PubMed
Search for other papers by K. J. RYAN in
Google Scholar
PubMed
SUMMARY
Pregnant rabbits were treated with indomethacin (8–10 mg/kg/day) or dexamethasone (1·2–1·8 mg/kg/day) during late gestation. The effects of these treatments on the concentrations of progesterone and prostaglandin F (PGF) in the peripheral plasma, and the outcome of gestation were studied. Treatment with indomethacin significantly prolonged the length of gestation (P < 0·01) compared with control, untreated animals. In these treated animals, the plasma progesterone levels declined at a similar time to that in control rabbits but the increase in systemic PGF normally seen during late pregnancy was reduced. Dexamethasone treatment reliably induced premature delivery within 3–6 days. The plasma progesterone concentration fell rapidly during the first 24 h of dexamethasone administration, but in no animal was this associated with a significant increase in the plasma levels of PGF.
These results are consistent with the suggestion that prostaglandins are involved in the normal initiation of parturition in the rabbit. They do not support the hypothesis that the effect of dexamethasone on the length of gestation is mediated through an increase in the production of prostaglandin F.
Search for other papers by J. A. GLICKMAN in
Google Scholar
PubMed
Search for other papers by J. E. PATRICK in
Google Scholar
PubMed
Search for other papers by J. R. G. CHALLIS in
Google Scholar
PubMed
Adrenal cells were prepared from non-pregnant (anoestrous) sheep, from ewes at days 50, 100 and 130 of pregnancy and at term, and from animals at 1–5 days post partum. The ability of the cells to respond to adrenocorticotrophin (ACTH1–24), α-melanocyte-stimulating hormone (α-MSH), or combinations of these peptides has been examined in vitro. There was a progressive rise in the basal output of cortisol during pregnancy and in the absence of adrenocorticotrophin the cortisol output from adrenal cells of late pregnant and post-partum sheep was significantly greater than that from the non-pregnant animals. Adrenocorticotrophin increased cortisol output by adrenal cells at all times tested. In anoestrous sheep the amount of ACTH required to produce half the maximum output of steroid (ED50) was 8 pg/ml. The ED50 increased in early pregnancy to 112 pg/ml and then fell to < 5 pg/ml between day 100 and term. At term both the stimulation ratio and the absolute increment in cortisol output elicited by a maximal concentration of ACTH were greater than at any other time tested in pregnant or non-pregnant sheep. Cortisol output during pregnancy was not increased by α-MSH, although at term the stimulatory effect of ACTH1–24 was partially antagonized by α-MSH.
These results suggest that there may be an increase in the responsiveness of the maternal adrenal during pregnancy, although the factor(s) responsible remains unknown.
Search for other papers by S G Matthews in
Google Scholar
PubMed
Search for other papers by K Yang in
Google Scholar
PubMed
Search for other papers by J R G Challis in
Google Scholar
PubMed
Abstract
Developmental changes in pituitary glucocorticoid receptor (GR) mRNA were examined during gestation and early neonatal life using in situ hybridization. Pituitaries were harvested from sheep fetuses at days 60–80, 100–120, 130–135, 140–142 and term, and from lambs of days 0–7 and 30–60, and adults. GR mRNA was present in the pars distalis by day 60, levels increased through gestation, and there was a redistribution of GR mRNA, resulting in a relatively greater abundance at the base of the pars distalis. At term, there was a significant (P<0·05 compared with the day 140–142 fetuses) elevation of GR mRNA, which was maintained in the newborn lamb, reaching highest levels at days 30–60 of neonatal life. GR mRNA was undetectable in the pars intermedia until day 120, but subsequently increased to high levels at term. Interestingly, the expression of GR mRNA in the pars intermedia dropped precipitously in the newborn (P<0·05 compared with term), though levels recovered in the older lambs and adults. The regional and cellular distribution of GR mRNA correlated closely with the presence of immuno-reactive GR (irGR) in the pituitary; the majority of irGR was present in the nuclei. Intrafetal infusion of cortisol (12 h; 5 μg/min) in late gestation (day 135) had no effect on GR mRNA expression in either the pars distalis or pars intermedia. These results indicated that, in the fetal pituitary, (1) the GR gene is expressed in both the pars distalis and pars intermedia, (2) levels of GR mRNA in the fetal pituitary correlated with the distribution of nuclear irGR, (3) GR mRNA is present at higher levels in the inferior aspect of the pars distalis, its abundance increases immediately prior to parturition and is maintained in the newborn, and (4) cortisol infusion for 12 h does not affect GR mRNA in either region of the pituitary, suggesting that, in the short term, glucocorticoids do not directly regulate GR synthesis.
Journal of Endocrinology (1995) 144, 483–490
Search for other papers by I. S. FRASER in
Google Scholar
PubMed
Search for other papers by J. R. G. CHALLIS in
Google Scholar
PubMed
Search for other papers by G. D. THORBURN in
Google Scholar
PubMed
SUMMARY
A continuous isotope infusion technique was used to measure the metabolic clearance rate (MCRB) and production rate (PRB) of oestradiol-17β in a group of six non-pregnant conscious Chinchilla rabbits. The mean MCRB of oestradiol was 162 ml/min (0·079 1/ min/weight0·75), and at equilibrium a significant proportion of the radioactivity in the circulation was present as oestrone (conversion ratio oestradiol to oestrone, 27·6%). The mean PRB of oestradiol was 4·3 ng/min, which is equivalent to about 5 μg/day. Some day-to-day variation was seen in the endogenous concentrations of oestradiol, oestrone and progesterone although in general the levels of the two oestrogens were less than 30–40 pg/ml, and progesterone levels were below 300 pg/ml apart from short peaks up to 600 pg/ml. These values were compared with previous measurements of the ovarian secretion rate of oestradiol measured directly in anaesthetized animals.
