Biomedical subjects

A L Fowden

Publications and source records attributed to A L Fowden.

At least 37 records · Page 2Linked to original sources

PubMed2004

Postnatal insulin secretion and sensitivity after manipulation of fetal growth by embryo transfer in the horse.

This study examined the effects of intrauterine growth on insulin secretion and resistance in newborn foals. Embryo transfer between small pony and large Thoroughbred mares was used to produce four groups of foals with different birth weights (pony in pony n=7; pony in Thoroughbred n=7; Thoroughbred in Thoroughbred n=8; Thoroughbred in pony n=8). On day 2 after birth, glucose (0.5 g/kg) was administered intravenously to the foal and blood samples were taken for 2 h to determine plasma glucose and insulin concentrations. On day 3, insulin sensitivity was assessed by giving insulin (0.75 U/kg i.v.) and measuring the decrement in plasma glucose in the foals. There were no significant differences in insulin secretion, insulin sensitivity or glucose tolerance between the control and growth-retarded Thoroughbred foals. Overgrown pony foals delivered by Thoroughbred mares had higher basal insulin levels and greater beta cell responses to glucose than the other groups of foals. The relationship between plasma glucose and insulin was also significantly steeper in overgrown pony foals than in the other groups. Variations in intrauterine growth rate, therefore, affect postnatal insulin secretion in the horse. More specifically, it is overgrowth, not growth retardation in utero that alters equine beta cell function in the immediate neonatal period.

Animals↗

PubMed2004

Development of insulin and proinsulin secretion in newborn pony foals.

At birth, the endocrine pancreas must assume a glucoregulatory role if the neonate is to survive the transition from parenteral to enteral nutrition. In species like the horse, neonatal hypoglycaemia is common, which suggests that the glucoregulatory mechanisms are not always fully competent at birth. Hence, this study examined pancreatic beta cell function in newborn foals during nutritional adaptation over the first 10 days post partum. Over a 48 h period at three time intervals after birth (days 1-2, 5-6 and 9-10 post partum), the beta cell responses to suckling and to intravenous administration of glucose, arginine and saline were measured in seven normal pony foals. Basal plasma concentrations of proinsulin, but not insulin or glucose, increased significantly between days 1 and 10. Suckling caused a gradual increase in plasma glucose, which was accompanied by a significant increase in plasma insulin concentrations 15 min after the onset of suckling on days 5 and 9, but not day 1. There was no significant change in plasma proinsulin concentrations in response to suckling at any age. At all ages studied, glucose and arginine administration stimulated an increase in the plasma concentrations of insulin and proinsulin; these beta cell responses did not change significantly with postnatal age. The insulin responses to glucose were significantly greater than those of arginine at each time period. Glucose clearance was significantly slower on day 1 than subsequently. Proinsulin and glucose, but not insulin, concentrations decreased significantly after saline administration at all three ages. At each time period, there was a significant positive relationship between the plasma insulin and proinsulin concentrations, the slope of which was significantly shallower on days 1-2 than subsequently. These results show that equine beta cells are responsive to glucose and arginine and release both insulin and proinsulin during the immediate postnatal period. They also suggest that newborn foals may be insulin resistant on the first day after birth.

Animal Nutritional Physiological Phenomena↗

PubMed2004

Effects of manipulating intrauterine growth on post natal adrenocortical development and other parameters of maturity in neonatal foals.

REASONS FOR PERFORMING STUDY: Intrauterine growth retardation (IUGR) impairs post natal adaptive responses and is associated with increased adrenocortical activity in many species. OBJECTIVES: To determine whether a restricted or enhanced intrauterine environment affects neonatal adaptation and adrenocortical function in horses. METHODS: Embryos from large (577 kg) Thoroughbred (TB) mares were transferred to smaller (343 kg) pony (P) mares and vice versa, to create a restricted (TB-in-P, n = 11) or enhanced (P-in-TB, n = 8) intrauterine environment. Control groups (TB-in-TB, n = 8; P-in-P, n = 7) were also included. RESULTS: Thirty foals were born live at full term (range 314-348 days) and 4 (3 TB-in-P, 1 P-in-TB) were stillborn between 275 and 335 days. TB-in-P foals were significantly (P<0.05) lighter than TB-in-TB, but heavier than P-in-P foals. TB-in-P foals took longer to first stand and suck and some had fetlock hyperextension and low (<4 g/l) plasma immunoglobulin G concentrations. Other foal groups showed normal behavioural responses. Haematological parameters were normal in all 4 groups of foals. Plasma ACTH levels were high at birth and plasma cortisol concentrations increased after delivery and returned to baseline within 6 h post partum in all but the TB-in-P foals, which had elevated levels until 48 h post partum. Plasma cortisol concentrations increased in all groups following exogenous ACTH administered on Days 1 and 5 postpartum. CONCLUSIONS: The TB-in-P foals showed IUGR and impaired post natal adaptive responses with basal hypercortisolaemia. POTENTIAL RELEVANCE: Foals born following IUGR may require clinical assistance in the early post natal period, but appear mature with respect to adrenocortical function.

Adrenal Cortex↗

PubMed2003

Ovine feto-placental metabolism.

Fetal growth depends on the transplacental nutrient supply, which, in turn, is determined partially by the consumption and production of nutrients by the uteroplacental tissues. In fetal sheep, the rates of growth and umbilical glucose uptake decline coincidently towards term in parallel with the normal prepartum rise in plasma cortisol. While cortisol is known to reduce growth in fetal sheep, its effects on the uteroplacental handling and delivery of nutrients remain unknown. Hence, this study, quantified the rates of umbilical uptake and uteroplacental consumption of nutrients in preterm fetuses infused with cortisol for 5 days to mimic the prepartum cortisol surge. Umbilical uptakes of glucose and lactate, but not oxygen, were significantly lower in cortisol- than saline-infused fetuses, irrespective of whether values were expressed as absolute or weight-specific rates. The rate of uteroplacental consumption of glucose, but not oxygen, was significantly higher in cortisol- than saline-infused animals. Absolute rates of uteroplacental lactate production were lower in cortisol-infused animals. When all data were combined, fetal plasma cortisol levels were positively correlated to uteroplacental glucose consumption and inversely related to umbilical glucose uptake. Cortisol treatment had no apparent effect on placental mRNA expression for the glucose transporters, GLUT-1 and GLUT-3. The results demonstrate that cortisol is physiological regulator of uteroplacental metabolism and nutrient delivery to the sheep fetus. These observations have important implications for fetal growth both in late gestation and during adverse intrauterine conditions, which raise fetal cortisol levels earlier in gestation.

Animals↗

PubMed2003

Ontogeny of uteroplacental progestagen production in pregnant mares during the second half of gestation.

In pregnant mares during late gestation, little, if any, progesterone (P4) is found in the maternal circulation. Hence, quiescence of the equine uterus is believed to be maintained by metabolites of pregnenolone and P4 known as progestagens, which are produced by the uteroplacental tissues. However, little is known about the ontogeny, distribution, or actual rates of uteroplacental progestagen production in pregnant mares and their fetuses during the second half of pregnancy. Therefore, the present study measured the rates of uteroplacental uptake and output of eight specific progestagens in chronically catheterized, pregnant pony mares from 180 days to term. No significant uteroplacental uptake of any of the eight individual progestagens was observed from the uterine circulation. In contrast, significant uteroplacental uptake was observed for five of the eight individual progestagens from the umbilical circulation, and the uptakes increased toward term. The major uteroplacental progestagen outputs were 5 alpha-pregnane-3,20-dione (5 alphaDHP) and 20 alpha-hydroxy-5 alpha-pregnan-3-one (20 alpha 5P). These were released into both the umbilical and uterine circulations at rates that increased toward term. The majority of the total uteroplacental 20 alpha 5P output was distributed into the uterine circulation at all gestational ages studied. In contrast, distribution of the total uteroplacental 5 alphaDHP output switched from preferential delivery into the uterine circulation before 220 days of gestation to release predominantly into the umbilical circulation after 260 days. These findings demonstrate that uteroplacental progestagen production changes during the second half of gestation, which may have important implications for the maintenance of pregnancy and the onset of labor in the mare.

Animals↗

PubMed2003

Hindlimb glucose and lactate metabolism during umbilical cord compression and acute hypoxemia in the late-gestation ovine fetus.

The metabolic adaptation of the hindlimb in the fetus to a reversible period of adverse intrauterine conditions and, subsequently, to a further episode of acute hypoxemia has been examined. Sixteen sheep fetuses were chronically instrumented with vascular catheters and transit-time flow probes. In nine of these fetuses, umbilical blood flow was reversibly reduced by 30% from baseline for 3 days (umbilical cord compression), while the remaining fetuses acted as sham-operated, age-matched controls. Acute hypoxemia was subsequently induced in all fetuses by reducing maternal fractional inspired oxygen concentration for 1 h. Paired hindlimb arteriovenous blood samples were taken at appropriate intervals during cord compression and acute hypoxemia, and by using femoral blood flow and the Fick principle, substrate delivery, uptake, and output were calculated. Umbilical cord compression reduced blood oxygen content and delivery to the hindlimb and increased hindlimb oxygen extraction and blood glucose and lactate concentration in the fetus. However, hindlimb glucose and oxygen consumption were unaltered during umbilical cord compression. In contrast, hindlimb oxygen delivery and uptake were significantly reduced in all fetuses during subsequent acute hypoxemia, but glucose extraction, oxygen extraction, and hindlimb lactate output significantly increased in sham-operated control fetuses only. Preexposure of the fetus to a temporary period of adverse intrauterine conditions alters the metabolic response of the fetal hindlimb to subsequent acute stress. Additional data suggest that circulating blood lactate may be derived from sources other than the fetal hindlimb under these circumstances. The lack of hindlimb lactate output during acute hypoxemia in umbilical cord-compressed fetuses, despite a significant fall in oxygen delivery to and uptake by the hindlimb, suggests that the fetal hindlimb may not respire anaerobically after exposure to adverse intrauterine conditions. hypoxia

Acid-Base Equilibrium↗

PubMed2003

Influence of cortisol on adipose tissue development in the fetal sheep during late gestation.

The present study examined the extent to which the late gestation rise in fetal plasma cortisol influenced adipose tIssue development in the fetus. The effect of cortisol on the abundance of adipose tIssue mitochondrial proteins on both the inner (i.e. uncoupling protein (UCP)1) and outer (i.e. voltage-dependent anion channel (VDAC)) mitochondrial membrane, together with the long and short forms of the prolactin receptor (PRLR) protein and leptin mRNA was determined. Perirenal adipose tIssue was sampled from ovine fetuses to which (i) cortisol (2-3 mg/day for 5 days) or saline was infused up to 127-130 days of gestation, and (ii) adrenalectomised and intact controls at between 142 and 145 days of gestation (term=148 days). UCP1 protein abundance was significantly lower in adrenalectomised fetuses compared with age-matched controls, and UCP1 was increased by cortisol infusion and with gestational age. Adrenalectomy reduced the concentration of the long form of PRLR, although this effect was only significant for the highest molecular weight isoform. In contrast, neither the short form of PRLR, VDAC protein abundance or leptin mRNA expression was significantly affected by gestational age or cortisol status. Fetal plasma triiodothyronine concentrations were increased by cortisol and with gestational age, an affect abolished by adrenalectomy. When all treatment groups were combined, both plasma cortisol and triiodothyronine concentrations were positively correlated with UCP1 protein abundance. In conclusion, an intact adrenal is necessary for the late gestation rise in UCP1 protein abundance but cortisol does not appear to have a major stimulatory role in promoting leptin expression in fetal adipose tIssue. It remains to be established whether effects on UCP1 protein are directly regulated by cortisol alone or mediated by other anabolic fetal hormones such as triiodothyronine.

Adipose Tissue, Brown↗

PubMed2002

The effect of birth weight on hypothalamo-pituitary-adrenal axis function in juvenile and adult pigs.

Programming of the hypothalamo-pituitary-adrenal (HPA) axis during prenatal and early postnatal life may explain, in part, the association between low birth weight (BW) and the increased incidence of cardiovascular and metabolic disease in later life. This study examined the effect of natural variations in BW on HPA axis function in juvenile and adult pigs. Low (< 1.47 kg) and high (> 1.53 kg) BW pure-bred Large White piglets from 15 litters were studied at 3 (n = 47) and 12 (n = 17) months of age. At each age, HPA axis function was tested by hypoglycaemic challenge (I.V. insulin; 0.5 IU (kg body weight)(-1)) and ACTH challenge (I.V. Synacthen, 2 microg (kg body weight)(-1)). At 3 months of age, adrenal size, the ratio of adrenal cortical to medullary area and stimulated cortisol concentrations were elevated in pigs that were of low BW and that remained small after birth. At 12 months of age, thinness at birth was associated with elevated adrenal responsiveness to insulin-induced hypoglycaemia. These results are consistent with the hypothesis that impaired fetal and early postnatal growth are associated with altered HPA axis function in later life.

Adrenal Glands↗

PubMed2002

The effect of birth weight on glucose tolerance in pigs at 3 and 12 months of age.

AIMS/HYPOTHESIS: The aim of this study was to examine the effect of birth weight on glucose tolerance in juvenile and adult pigs. METHODS: Low (<1.47 kg) and high (>1.53 kg) birth weight piglets from 15 litters were studied at 3 ( n=47) and 12 ( n=17) months of age. At each age, selected pigs were tranquilised and catheters were inserted into the dorsal aorta and caudal vena cava under general anaesthesia. After recovery, glucose (0.5 g/kg; i.v.) was administered and regular arterial blood samples were taken for 2 h for plasma glucose and insulin measurements. Hepatic gluconeogenic enzyme activities were measured at post mortem. RESULTS: At 12, but not at 3 months of age, the area under the glucose and insulin curves after glucose administration were greater ( p<0.05) in low rather than in high birth weight pigs. The glucose area at 12 months was negatively correlated with body weight and BMI at birth. Disproportionate shape at birth was associated with reduced hepatic gluconeogenic enzyme concentrations and low birth weight pigs had reduced basal glucose concentrations at 12 months of age. CONCLUSION/INTERPRETATION: This study has shown an association between low birth weight and thinness at birth and glucose intolerance at 12 months of postnatal age, but not at 3 months. This effect was not due to insulin deficiency or increased hepatic gluconeogenic enzyme activity.

Aging↗

PubMed2002

Control of growth hormone receptor and insulin-like growth factor-I expression by cortisol in ovine fetal skeletal muscle.

Insulin-like growth factor (IGF)-I has an important role in myogenesis but its developmental regulation in skeletal muscle before birth remains unknown. In other tissues, cortisol modulates IGF gene expression and is responsible for many of the prepartum maturational changes essential for neonatal survival. Hence, using RNase protection assays and ovine riboprobes, expression of the IGF-I and growth hormone receptor (GHR) genes was examined in ovine skeletal muscle during late gestation and after experimental manipulation of fetal plasma cortisol levels by fetal adrenalectomy and exogenous cortisol infusion. Muscle IGF-I, but not GHR, mRNA abundance decreased with increasing gestational age in parallel with the prepartum rise in plasma cortisol. Abolition of this cortisol surge by fetal adrenalectomy prevented the prepartum fall in muscle IGF-I mRNA abundance. Conversely, raising cortisol levels by exogenous infusion earlier in gestation prematurely lowered muscle IGF-I mRNA abundance but had no effect on GHR mRNA. When all data were combined, plasma cortisol and muscle IGF-I mRNA abundance were inversely correlated in individual fetuses. Cortisol is, therefore, a developmental regulator of IGF-I gene expression and is responsible for suppressing expression of this gene in ovine skeletal muscle near term. These observations have important implications for muscle development both before and after birth, particularly during conditions which alter intrauterine cortisol exposure.

Adrenalectomy↗

PubMed2002

Effects of prevailing hypoxaemia, acidaemia or hypoglycaemia upon the cardiovascular, endocrine and metabolic responses to acute hypoxaemia in the ovine fetus.

Although it is established that the fetus can successfully withstand a single, acute hypoxaemic challenge during gestation, little is known about what effects prevailing adverse intrauterine conditions might have on the fetal response to acute hypoxaemia. The aims of this study were therefore: (1) to characterise the effects of prevailing and sustained hypoxaemia, acidaemia or hypoglycaemia on the fetal cardiovascular responses to an episode of acute hypoxaemia; and (2) to determine the effects of these adverse intrauterine conditions on mechanisms mediating these cardiovascular responses. Thirty-three Welsh Mountain sheep fetuses were chronically instrumented (1-2 % halothane) between 117 and 125 days of gestation (term is ca 145 days) with amniotic and vascular catheters and with a transit-time flow probe around a femoral artery. The animals were divided retrospectively into four groups based upon post-surgical, sustained, basal blood oxygen (chronically hypoxaemic; P(a,O2), 17.3 +/- 0.5 mmHg; n = 8), glucose (chronically hypoglycaemic; blood glucose, 0.49 +/- 0.03 mmol l(-1); n = 6) and acid-base (chronically acidaemic; pH(a), 7.25 +/- 0.01; n = 5) status. Values for compromised fetuses were -2 S.D. from a group of control (n = 14) fetuses. At 130 +/- 4 days, a 1 h episode of acute, isocapnic hypoxaemia (9 % O(2) in N(2), to reduce carotid P(a,O2) to 12 +/- 1 mmHg) was induced in all fetuses by reducing the maternal inspired O(2) fraction (F(I,O2)). Fetal cardiovascular variables were recorded at 1 s intervals throughout the experimental protocol and arterial blood samples taken at appropriate intervals for biophysical (blood gases, glucose, lactate) and endocrine (catecholamines, vasopressin, cortisol, ACTH) measures. During acute hypoxaemia all fetuses elicited hypertension, bradycardia and femoral vasoconstriction. However, prevailing fetal compromise altered the cardiovascular and endocrine responses to a further episode of acute hypoxaemia, including: (1) enhanced pressor and femoral vasoconstriction; (2) greater increments in plasma noradrenaline and vasopressin during hypoxaemia; and (3) basal upward resetting of hypothalamic-pituitary-adrenal axis function. Only chronically hypoxaemic fetuses had significantly elevated basal concentrations of noradrenaline and enhanced chemoreflex function during acute hypoxaemia. These data show that prevailing adverse intrauterine conditions alter the capacity of the fetus to respond to a subsequent episode of acute hypoxaemia; however, the partial contributions of hypoxaemia, acidaemia or hypoglycaemia to mediating these responses can vary.

Acid-Base Equilibrium↗

PubMed2002

The effects of birth weight on basal cardiovascular function in pigs at 3 months of age.

In man, epidemiological studies have shown that low birth weight (BW) is associated with an increased risk of cardiovascular disease in later life. In this study, the long-term consequences of variations in natural BW on basal cardiovascular function were investigated in pigs at 3 months of postnatal age. Low (< 1.41 kg; n = 20) and high (> 1.52 kg; n = 20) BW Large White piglets were selected from a total of 12 litters for study at 3 months of age. Basal mean arterial pressure (MAP) and heart rate (HR) were recorded for approximately 30 min using standard recording equipment and basal arterial blood samples were taken for hormone analyses. Concentrations of angiotensin-converting enzyme (ACE) were also measured in kidney, lung and plasma. Basal MAP, but not HR, in 3-month-old pigs was significantly inversely related to BW and positively related to the ratio of head length to BW. Postnatal growth rate of low BW pigs was slower than that of high BW pigs such that low BW piglets remained significantly smaller at 3 months of age. There were no differences in basal plasma adrenaline or cortisol concentrations between low and high BW pigs. However, basal plasma noradrenaline concentrations were significantly elevated in low BW compared to high BW pigs. Renal and pulmonary ACE levels were significantly reduced in low BW compared to high BW pigs. These data show that basal MAP in 3-month-old pigs is negatively associated with BW and positively correlated to disproportionate size at birth. This effect was associated with an increase in basal plasma noradrenaline concentrations.

Aging↗

PubMed2002

The effect of a reversible period of adverse intrauterine conditions during late gestation on fetal and placental weight and placentome distribution in sheep.

Adverse intrauterine conditions occurring during early to mid-gestation or throughout the whole of gestation influence placental weight and the distribution of placentome types in sheep. However, no study to date has investigated the effect of a reversible period of adverse intrauterine conditions during late gestation upon fetal and placental weight and placentome distribution in sheep. Twenty-two sheep fetuses were chronically instrumented with an inflatable cord occluder, amniotic and vascular catheters and with a Transonic flow probe around an umbilical artery. At 125 days (term isca.145 days) the occluder was inflated to reduce umbilical blood flow by ca.30 per cent for 3d in 12 fetuses (umbilical cord compressed, UCC). The occluder was then deflated and umbilical blood flow allowed to return to baseline. The remaining 10 fetuses acted as sham-operated controls in which the occluder remained deflated at all times. At 135-137dGA ewes were humanely killed and tissues collected, weighed and placentomes classified. A reduction in umbilical blood flow by approximately 30 per cent from baseline for 3 days in UCC fetuses led to mild fetal asphyxia throughout the period of cord-compression. After deflation of the occluder cuff, umbilical blood flow returned to a level that was significantly greater than that measured during baseline. Umbilical cord compression had no effect on fetal body weight but significantly increased fetal adrenal weight relative to body weight. While the total number of placentomes was not altered by cord-compression, total placentome weight and the total weight of C/D-type placentomes were both reduced in UCC relative to control placentae. In addition, the mean weight of placentomes, and of C/D-type placentomes specifically, was significantly lower in UCC relative to control placentae. When expressed as a percentage of the total number of placentomes in the placenta, there was a significantly lower percentage of C/D-type placentomes in UCC relative to control placentae. In addition, there was a significant relationship between the total number of placentomes and the percentage C/D-type placentomes in control, but not UCC, placentae. The data suggest that a temporary, reversible period of adverse intrauterine conditions occurring late in gestation in sheep has persisting effects upon the placenta, mean placentome weight and placentome distribution.

Adrenal Glands↗

PubMed2002

The effects of cortisol on the binucleate cell population in the ovine placenta during late gestation.

Large granulated binucleate cells (BNCs) producing placental lactogen (PL) and pregnancy-associated glycoproteins (PAG) are present in all ruminant placentae throughout pregnancy. These BNC account for 15-20% of the cells in ovine trophectoderm for most of gestation but decrease in number close to term at the same time that fetal cortisol levels rise. The present study investigated the effects of cortisol on the BNC population using immunohistochemistry to count BNCs in ovine placentomes during late gestation and after experimental manipulation of the fetal cortisol level by fetal adrenalectomy and exogenous cortisol infusion. Abolition of the prepartum rise in fetal cortisol prevented the normal decline in BNC numbers towards term. Conversely, raising cortisol levels in immature fetuses to prepartum values prematurely reduced placental BNC numbers. However, a small population of BNC remained, even at the highest cortisol concentrations. When all the data were combined irrespective of treatment or gestational age, there was a significant inverse correlation between fetal plasma cortisol and the number of BNCs in the ovine placenta. These findings show that cortisol regulates the BNC population in ovine placenta during late gestation. They also have important implications for the production of PL and PAG during ovine pregnancy.

Adrenal Glands↗

PubMed2002

Developmental changes in pulmonary and renal angiotensin-converting enzyme concentration in fetal and neonatal horses.

Angiotensin-converting enzyme (ACE) has an active role in the control of blood pressure and body fluid homeostasis both before and after birth. This study investigated the ontogeny of pulmonary and renal ACE concentrations in fetal and neonatal horses. Fetal pulmonary ACE concentration increased from 250 days towards term (c. 335 days). Newborn foals showed significantly higher mean concentrations of pulmonary ACE (4.40 +/- 0.62 nmol min(-1) mg protein(-1)) than both fetuses during late gestation (1.23 +/- 0.51 nmol min(-1) mg protein(-1)) and animals aged 1 day to 2 weeks of postnatal age (0.85 +/- 0.15 nmol min(-1) mg protein(-1)). Renal ACE was detected in fetal horses from 100 days of gestation but showed no developmental trend during the second half of gestation or in early postnatal life. Overall in the fetus, mean concentrations of renal ACE were also approximately 10 times lower than mean pulmonary values. Renal ACE concentration may be related to the functional immaturity of the equine kidneys. The increase in pulmonary ACE concentration seen towards term in the fetal horse may be induced by the prepartum cortisol surge that occurs very close to delivery in this species. Therefore, premature delivery in this species may interrupt the onset of ACE production in the fetal lungs and circumvent the normal maturation of the renin-angiotensin system.

Aging↗

PubMed2002

Thyroid hormones and the mRNA of the GH receptor and IGFs in skeletal muscle of fetal sheep.

Thyroid hormones are required for the normal development of skeletal muscle in utero, although their mechanism of action is poorly understood. The present study examined the effects of the thyroid hormones on the gene expression of the growth hormone receptor (GHR) and the insulin-like growth factors (IGFs) IGF-I and IGF-II, in skeletal muscle of fetal sheep during late gestation (term 145 +/- 2 days) and after manipulation of plasma thyroid hormone concentration. Thyroidectomy at 105-110 days of gestation suppressed muscle GHR and IGF-I gene expression in fetuses studied at 127-130 and 142-145 days. Muscle GHR mRNA abundance remained unchanged with increasing gestational age in intact and thyroidectomized fetuses. In the intact fetuses, a decrease in muscle IGF-I gene expression was observed between 127-130 and 142-145 days, which coincided with the normal prepartum surges in plasma cortisol and triiodothyronine (T3). At 127-130 days, downregulation of muscle IGF-I mRNA abundance was induced prematurely in intact fetuses by an infusion of cortisol for 5 days (2-3 mg x kg(-1) x day(-1) iv), which increased plasma cortisol and T3 concentrations to values seen near term. However, increasing plasma T3 alone by an infusion of T3 for 5 days (8-12 microg x kg(-1) x day(-1) iv) in intact fetuses at this age had no effect on GHR or IGF-I gene expression in skeletal muscle. In the thyroidectomized fetuses, no additional change in the low level of muscle IGF-I mRNA abundance was seen with increasing gestational age, but at 127-130 days, IGF-I gene expression was reduced further when plasma cortisol and T3 concentrations were increased by exogenous cortisol infusion. Muscle IGF-II mRNA abundance was not affected by thyroidectomy, gestational age, or exogenous hormone infusion. These findings show, in the sheep fetus, that thyroid hormones may influence the growth and development of skeletal muscle via changes in the local activity of the somatotrophic axis.

Animals↗

PubMed2002

Plasma leptin concentration in fetal sheep during late gestation: ontogeny and effect of glucocorticoids.

The ontogeny and developmental control of plasma leptin concentration in the fetus are poorly understood. The present study investigated plasma leptin concentration in chronically catheterized sheep fetuses near term, and in neonatal and adult sheep. The effect of glucocorticoids on plasma leptin in utero was examined by fetal adrenalectomy and exogenous cortisol or dexamethasone infusion. In intact, untreated fetuses studied between 130 and 140 d (term, 145 +/- 2 d), plasma leptin concentration increased in association with the prepartum cortisol surge. Positive relationships were observed between plasma leptin in utero and both gestational age and plasma cortisol. Plasma leptin was also inversely correlated with fetal p(a)O(2). The ontogenic rise in plasma leptin was abolished by fetal adrenalectomy. In intact fetuses at 123-127 d, plasma leptin was increased by infusions of cortisol (3-5 mg kg(-1)d(-1), +127 +/- 21%) for 5 d and dexamethasone (45-60 microg kg(-1)d(-1), +268 +/- 61%) for 2 d. However, the cortisol-induced rise in plasma leptin was transient; by the fifth day of infusion, plasma leptin was restored to within the baseline range. These findings show that, in the sheep fetus, an intact adrenal gland is required for the normal ontogenic rise in plasma leptin near term. Furthermore, fetal treatment with exogenous and endogenous glucocorticoids increases circulating leptin concentration in utero.

Adrenalectomy↗

PubMed2002

Regulation of 11 beta-hydroxysteroid dehydrogenase type 2 activity in ovine placenta by fetal cortisol.

The effect of fetal cortisol on the activity of the type 2 isoform of the enzyme, 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD2), was examined in ovine placenta and fetal kidney by measuring tissue 11 beta-HSD2 activity during late gestation when endogenous fetal cortisol levels rise and after exogenous cortisol administration to immature fetuses before the prepartum cortisol surge. Placental 11 beta-HSD2 activity decreased between 128-132 days and term (approximately 145 days of gestation) in association with the normal prepartum increase in fetal plasma cortisol. Raising fetal cortisol levels to prepartum values in the immature fetus at 128--132 days of gestation reduced placental 11 beta-HSD2 activity to term values. In contrast, 11 beta-HSD2 activity in the fetal renal cortex was unaffected by gestational age or cortisol infusion. When all the data were combined, there was an inverse correlation between the log fetal plasma cortisol level at delivery and placental 11 beta-HSD2 activity, expressed both on a weight-specific basis and per mg placental protein. Fetal cortisol therefore appears to be a physiological regulator of placental, but not renal, 11 beta-HSD2 activity in fetal sheep during late gestation. These findings have important implications, not only for glucocorticoid exposure in utero, but also for the local actions of cortisol within the placental tissues that are involved in initiating parturition in the sheep.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗