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: 7753237
• 负责人: Maureen Keller-Wood
• 金额: $ 30.09万
• 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/7753237
• 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; 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; 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; public health relevance; 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）：怀孕期间母体皮质醇浓度通常会增加 2-3 倍。母体皮质醇水平似乎会影响胎儿骨骼和内脏的生长。我们之前的数据显示，母羊胎儿的生长速度会随着母体皮质醇水平的升高或降低而降低，这与临床报告一致，即肾上腺皮质功能减退（艾迪生氏病）或肾上腺皮质功能亢进（库欣综合征）会导致小于胎龄儿。在这些研究中，我们将使用妊娠晚期的怀孕绵羊来测试与母体皮质醇对胎儿生长以及母体、胎儿和新生儿代谢的影响有关的几个假设。将使用三组母羊：1) 正常完整对照母羊，2) 肾上腺切除并用皮质醇替代的母羊，其水平为正常妊娠的一半，但与正常非妊娠母羊的水平相似，3) 注入皮质醇的母羊为双倍相对于对照怀孕母羊的正常血浆浓度。我们提出了两组研究来确定对母亲和胎儿生理学以及新生儿生理学的影响。我们将检验以下假设：母体皮质醇的减少主要通过减少母体体积膨胀来改变胎儿生长和新陈代谢，以及母体心输出量和子宫胎盘血流量的正常增加，这对于妊娠后期胎儿生长的加速至关重要，其次，通过减少母亲的食物摄入量以及母亲和胎儿的葡萄糖浓度。我们还将检验相关假设，即这些变化导致新生儿胎儿器官重量成比例减少、脂肪量减少以及脂肪组织和肝脏中 IGF-I 表达减少。我们还将检验以下假设：这些胎儿的肾上腺成熟会稍微加速，导致与对照组相比稍早分娩，并且我们将检验以下假设：在出生后，胰岛素对血糖增加的反应会受损。肾上腺皮质功能相对低下的母羊所生的羔羊。在平行实验中，我们将检验以下假设：母体皮质醇的增加（类似于慢性压力产生的皮质醇增加）不会对子宫胎盘血流产生负面影响，但会通过影响 IGF 水平而导致骨骼生长减少，并会导致器官特异性器官生长和内脏生长相关基因的变化。我们还将检验以下假设：增加这些母羊的喂养量，加上母体皮质醇的增加，将导致母体和胎儿的葡萄糖浓度增加，肥胖增加，但出生后不久的新生儿葡萄糖和皮质醇浓度降低，血糖降低生命第一个月的耐受性。公共卫生相关性：已发现与母亲肾上腺激素皮质醇分泌过多或不足相关的疾病与胎儿生长减缓有关。母亲压力导致的皮质醇分泌过多也被认为是小于胎龄儿的一个因素；然而，人们对母体皮质醇的变化如何影响母体生理或胎儿生长和代谢知之甚少。这些研究将提高我们对健康妊娠中母体皮质醇正常增加的作用以及增加或减少如何影响胎儿和新生儿生长和代谢的理解。