Adrenal Cortex of Fetal Lamb: Changes After Hypophysectomy and Effects of Synacthen on Cytoarchitecture and Secretory Activity

Glucocorticoids are proposed to act as intermediary factors that transcribe the developmental programming sequelae of maternal nutrient restriction (NR). Periconceptional undernutrition of sheep markedly activates fetal hypothalamicpituitary-adrenal (HPA) axis activity leading to preterm birth, while transient undernutrition during late gestation in sheep programs adult HPA axis function. To date, no study has examined resting or stimulated HPA axis function in young adult offspring following a periconceptional nutritional challenge. In the present study, 20 ewes were either periconceptionally undernourished (50% metabolisable energy requirements from days 1 to 30 gestation; NR, nZ8) or fed to control levels (100% requirement; controls, nZ12) to term (147 days gestation). Ewes were blood sampled remotely at 2 and 30 days using automated blood sampling equipment. Thereafter, offspring (controls, nZ6/6 males/females; NR, nZ4/4 males/females) were reared to 1 year of age and on separate days received either an i.v. corticotrophin-releasing hormone (CRH; 0$5 mg/kg) and vasopressin (AVP; 0$1 mg/kg) challenge or a synthetic ACTH i.v. bolus (Synacthen; 1$25 mg/kg), and blood samples were taken (manually and remotely) at appropriate intervals for measurement of plasma ACTH and cortisol accordingly. Resting plasma cortisol, assessed remotely, was similar in ewes during undernutrition (control 18$3G1$4 vs NR 23$4G1$9 nmol/l) and in offspring at 4 months of age (control male 17$6G2$9; control female 17$2G0$4, NR male 16$5G3$1, NR female 21$7G4$0 nmol/l). At 12 months of age, however, resting plasma cortisol was significantly increased in NR females (control male 28$0G1$5, control female 32$9G9, NR male 32G7, NR female 53G10 nmol/l, F 5$7, PZ0$02) despite no difference in plasma ACTH concentration. There was an interaction between nutritional group and gender for both the pituitary and adrenal responses to CRH and AVP, i.e. for controls, females exhibited increased plasma ACTH or cortisol relative to males but for NR this trend was either not present or reversed. The adrenocortical response to synthetic ACTH was gender-dependent only, being greater in female offspring. Combined CRH and AVP provoked a transient hypertension and marked bradycardia in all animals, irrespective of dietary group or gender and could be effectively reproduced by an AVP bolus alone. In conclusion, the present study has shown that periconceptional undernutrition of sheep has only a minor influence on HPA axis function in their young adult offspring when considered alongside the effect of gender per se.

Section: Discussionmentioning

confidence: 99%

Effect of periconceptional undernutrition and gender on hypothalamic–pituitary–adrenal axis function in young adult sheep

Gardner¹,

Bon²,

Dandrea

et al. 2006

“…Cortisol Plasma cortisol concentrations were measured by radioimmunoassay validated for ovine plasma (Robinson et al 1984). The interassay coefficient of variation was 10% and the minimum detectable quantity of cortisol was 1·5 ng/ml.…”

Section: Biochemical Analysesmentioning

confidence: 99%

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

Clarke

Ward²,

Forhead³

et al. 2002

The effect of fetal cortisol on the activity of the type 2 isoform of the enzyme, 11 -hydroxysteroid dehydrogenase (11 -HSD2), was examined in ovine placenta and fetal kidney by measuring tissue 11 -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 -HSD2 activity decreased between 128-132 days and term (]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 -HSD2 activity to term values. In contrast, 11 -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 -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 -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.

“…RIAs Cortisol concentrations were measured by RIA and validated for use with ovine plasma (Robinson et al 1983). The minimum detectable quantity of cortisol was 1·5 ng/ ml and interassay coefficient of variation was 11%.…”

Section: Laboratory Analysesmentioning

confidence: 99%

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

Mostyn¹,

Pearce²,

Budge³

et al. 2003

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.