Effects of maternal cortisol on fetal and neonatal growth and metabolism

描述(申请人提供)：孕妇的皮质醇浓度在怀孕期间通常会增加2-3倍。孕妇的皮质醇水平似乎会影响胎儿骨骼和内脏的发育。我们先前的数据显示，母体皮质醇水平升高或降低的母羊胚胎生长减少，这与临床报告一致，即肾上腺皮质功能减退(Addison病)或肾上腺皮质功能亢进(库欣综合征)导致小于胎龄的婴儿。在这些研究中，我们将使用妊娠晚期的绵羊来检验与母体皮质醇对胎儿生长以及对母体、胎儿和新生儿代谢的影响有关的几个假说。将使用三组母羊：1)正常完整的对照母羊，2)切除肾上腺并用皮质醇取代的母羊，其水平是正常妊娠的一半，但与正常未怀孕的母羊相似，3)注入皮质醇的母羊血浆浓度是对照怀孕母羊的两倍。我们提出了两组研究，以确定对母体和胎儿生理学以及对新生儿生理学的影响。我们将验证这一假设，即母体皮质醇的减少主要通过减少母体的体积扩张，以及母体心输出量和子宫胎盘血流量的正常增加来改变胎儿的生长和代谢，这是在妊娠晚期加速胎儿生长所必需的，其次是通过减少母体的食物摄入量以及母体和胎儿的葡萄糖浓度。我们还将检验相关假设，即这些变化会导致新生儿胎儿器官重量成比例减少，脂肪质量减少，脂肪组织和肝脏中IGF-I的表达减少。我们还将测试这样的假设，即这些胎儿的肾上腺成熟将略有加快，导致与对照组相比略微提前分娩，我们将测试相对肾上腺皮质功能低下的母羊出生的羔羊出生后对葡萄糖增加的胰岛素反应受损的假设。在平行实验中，我们将检验这样一个假设，即与慢性应激产生的皮质醇增加类似，母亲皮质醇的增加不会对子宫胎盘血流产生负面影响，但会通过影响IGF水平导致骨骼生长减少，并将导致器官生长和内脏生长相关基因的器官特有变化。我们还将测试这样一种假设，即增加这些母羊的喂养，加上母羊皮质醇的增加，将导致母羊和胎儿血糖浓度增加，肥胖增加，但在出生后立即降低新生儿血糖和皮质醇浓度，并在出生后第一个月降低葡萄糖耐量。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有关的疾病与胎儿生长发育减慢有关。母亲压力造成的皮质醇过度分泌也被认为是小于胎龄儿的一个促成因素；然而，关于母亲皮质醇的变化如何影响母亲的生理或胎儿的生长和新陈代谢，人们知之甚少。这些研究将提高我们对健康妊娠中母体皮质醇正常升高的作用以及增加或减少如何影响胎儿和新生儿的生长和代谢的理解。

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.