Effects of maternal cortisol on fetal and neonatal growth and metabolism

母体皮质醇对胎儿和新生儿生长和代谢的影响

• 批准号: 8196958
• 负责人: Maureen Keller-Wood
• 金额: $ 28.89万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-29 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196958
• 关键词: Acceleration; Addison' s disease; Adipose tissue; Adrenal Cortex Hormones; Adrenal Gland Hyperfunction; Adrenal Glands; Adrenal hormone preparation; Adrenalectomy; Affect; Attenuated; Birth; Blood Glucose; Blood Plasma Volume; Blood flow; Cardiac Output; Chronic stress; Clinical; Control Groups; Corticotropin; Cushing Syndrome; Data; Disease; Eating; Fatty acid glycerol esters; Fetal Growth; Fetal Heart; Fetal Weight; Fetus; Gene Expression; Genes; Glucose; Glucose Plasma Concentration; Growth; Growth Factor; Health; Homeostasis; Hydrocortisone; Infusion procedures; Insulin; Insulin-Like Growth Factor I; Ketones; Laboratories; Life; Liver; Maintenance; Malnutrition; Maternal Physiology; Metabolism; Modeling; Neonatal; Normal Range; Nutrient; Obesity; Organ; Perfusion; Physiology; Plasma; Play; Pregnancy; Production; Regulation; Relative (related person); Reporting; Role; SLC2A1 gene; Secondary to; Sheep; Skeletal Muscle; Small for Gestational Age Infant; Testing; Time; Tissues; Triglycerides; Viscera; Visceral; feeding; fetal; fetal blood; glucose metabolism; glucose tolerance; heart dimension/size; improved; maternal stress; neonate; postnatal; pregnant; research study; response; skeletal; skeletal muscle growth

DESCRIPTION (provided by applicant): Maternal cortisol concentrations are normally increased by 2-3 fold in pregnancy. Maternal cortisol levels appear to affect fetal skeletal and visceral growth. Our previous data show reduced growth in fetuses of ewes with either increased or decreased maternal cortisol levels, consistent with clinical reports that either hypoadrenocorticism, Addison's disease, or hyperadrenocorticism, Cushing's syndrome, results in small for gestational age infants. In these studies we will use pregnant sheep in late gestation to test several hypotheses relating to effects of maternal cortisol on fetal growth and on maternal, fetal, and neonatal metabolism. Three groups of ewes will be used: 1) normal intact control ewes, 2) ewes that are adrenalectomized and replaced with cortisol to levels half that of normal pregnancy, but similar to those of normal nonpregnant ewes, 3) ewes infused with cortisol to double normal plasma concentrations relative to the control pregnant ewes. We propose two sets of studies to determine effects on both maternal and fetal physiology, and on neonatal physiology. We will test the hypothesis that reductions in maternal cortisol alter fetal growth and metabolism primarily by reducing maternal volume expansion, and the normal increases in maternal cardiac output and uteroplacental blood flow that are essential for acceleration of fetal growth in the late gestation, and secondarily, by reducing maternal food intake and maternal and fetal glucose concentrations. We also will test the related hypothesis that these changes result in a neonate with proportionate reduction in weight of fetal organs, reduced fat mass and reduced IGF-I expression in adipose tissue and liver. We will also test the hypothesis that fetal adrenal maturation will be slightly accelerated in these fetuses, resulting in slightly earlier delivery as compared to the control groups, and we will test the hypotheses that there will be an impaired insulin response to increases in glucose postnatally in the lambs born of ewes with relative hypoadrenocorticism. In parallel experiments, we will test the hypothesis that increases in maternal cortisol, similar to those produced by chronic stress, do not negatively impact uteroplacental blood flow, but result in reduction in skeletal growth by affects on IGF levels, and will cause organ-specific changes in organ growth and in growth-related genes in the viscera. We also will test the hypothesis that increased feeding in these ewes, in combination with increased maternal cortisol will result in increased maternal and fetal glucose concentrations, with increased adiposity, but reduced neonatal glucose and cortisol concentrations in the period immediately following birth, and reduced glucose tolerance in the first month of life. PUBLIC HEALTH RELEVANCE: Diseases associated with either excess or deficient maternal secretion of the adrenal hormone cortisol have been found to be associated with reduction in fetal growth. Excess secretion of cortisol due to maternal stress has also been suggested as a contributing factor in small for gestational age babies; however, little is known about how changes in maternal cortisol influence either maternal physiology or fetal growth and metabolism. These studies will improve our understanding of the role of the normal increase in maternal cortisol that occurs in healthy pregnancies and how increases or decreases impact both fetal and neonatal growth and metabolism.

描述（由申请人提供）：妊娠期间，孕妇皮质醇浓度通常增加2-3倍。母体皮质醇水平似乎影响胎儿骨骼和内脏生长。我们先前的数据表明，孕妇皮质醇水平升高或降低的母羊的生长降低，这与临床报道相一致，即肾上腺皮质主义，艾迪生氏病或肾上腺皮质高肾上腺皮质主义，Cushing综合征，较小的妊娠婴儿。在这些研究中，我们将在妊娠后期使用怀孕的绵羊来测试与母体皮质醇对胎儿生长以及孕产妇，胎儿和新生儿代谢的影响有关的几种假设。将使用三组母羊：1）正常完整的对照母羊，2）肾上腺切除术并用皮质醇代替的母羊，其水平为正常妊娠的一半，但类似于正常的非怀孕母羊的水平，3）EWES含有皮质醇的EWE，与皮质醇相对于对照组的血浆浓度倍增了皮质醇，相对于对照对照怀孕的EWES双倍。我们提出了两组研究，以确定对孕产妇和胎儿生理的影响以及对新生儿生理的影响。我们将检验以下假设：孕产妇皮质醇的减少主要是通过减少母体体积的膨胀来改变胎儿的生长和代谢，以及孕产妇的心输出量和子宫颅骨血流的正常增加对于妊娠晚期加速胎儿生长至关重要，其次是通过妊娠晚期的加速来加速。我们还将测试相关的假设，即这些变化导致新生儿，胎儿器官的体重比例减少，脂肪质量减少以及脂肪组织和肝脏中IGF-I表达降低。我们还将检验以下假设：这些胎儿在这些胎儿中将稍微加速胎儿肾上腺的成熟，与对照组相比导致稍早的分娩，我们将测试假设，即胰岛素对葡萄糖的增加会受到胰岛素后对葡萄糖的增加的反应，而在羊群中与羊群相对低肾上腺皮质的相对养生会产生的葡萄糖增加。在平行实验中，我们将测试以下假设，即孕妇皮质醇的增加，类似于慢性应激产生的假设，不会对子宫牙科血流产生负面影响，但会导致IGF水平的影响降低骨骼生长，并且会导致器官特异性的器官生长变化和内脏的生长基因。我们还将检验以下假设：这些母羊在这些母羊中的喂养增加与孕妇皮质醇的增加，将导致孕妇和胎儿葡萄糖浓度增加，肥胖增加，但在出生后立即降低了新生儿葡萄糖和皮质醇浓度，并在出生后立即降低了葡萄糖耐受性。公共卫生相关性：已发现与肾上腺激素皮质醇过量或不足的产妇分泌有关的疾病与胎儿生长的减少有关。由于孕产妇而导致的皮质醇分泌过多，这是胎龄婴儿小的促成因素。但是，对于孕产妇皮质醇的变化如何影响孕产妇生理或胎儿生长和代谢几乎没有了解。这些研究将提高我们对健康妊娠中孕妇皮质醇正常增加的作用的理解，以及如何增加或减少胎儿和新生儿的生长和代谢。