Effects of maternal cortisol on fetal and neonatal growth and metabolism

描述（由申请人提供）：孕妇皮质醇浓度通常增加2-3倍。母亲的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的皮质醇水平升高或降低，母羊的胎儿生长减慢，这与临床报告一致，肾上腺皮质功能低下（Addison's病）或肾上腺皮质功能亢进（Cushing's综合征）导致胎龄婴儿小。在这些研究中，我们将使用妊娠后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)正常的、完整的对照母羊；2)肾上腺切除的母羊，用皮质醇替代正常妊娠母羊的水平，使其达到正常妊娠母羊的一半，但与正常未怀孕母羊的水平相似；3)向母羊注入皮质醇，使其相对于对照妊娠母羊的正常血浆浓度翻倍。我们提出两组研究，以确定对母亲和胎儿生理和新生儿生理的影响。我们将测试母体皮质醇的减少改变胎儿生长和代谢的假设，主要是通过减少母体体积扩张，以及母体心输出量和子宫胎盘血流量的正常增加（这是妊娠后期加速胎儿生长所必需的），其次是通过减少母体食物摄入量和母体和胎儿葡萄糖浓度。我们还将检验相关的假设，即这些变化导致新生儿的胎儿器官重量成比例地减少，脂肪量减少，脂肪组织和肝脏中IGF-I的表达减少。我们还将验证这样的假设，即这些胎儿的胎儿肾上腺成熟会略微加快，导致与对照组相比分娩时间略早。我们还将验证这样的假设，即相对肾上腺皮质功能低下的母羊所生的羊羔，在出生后血糖升高时，胰岛素反应会受损。在平行实验中，我们将验证这样的假设，即母体皮质醇的增加，类似于慢性应激所产生的皮质醇的增加，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，并会导致器官生长和内脏生长相关基因的器官特异性变化。我们还将测试这样一个假设：母羊喂养增加，与母羊皮质醇增加相结合，会导致母羊和胎儿葡萄糖浓度增加，肥胖增加，但在出生后立即降低新生儿葡萄糖和皮质醇浓度，并降低出生后第一个月的葡萄糖耐量。公共卫生相关性：与母体肾上腺激素皮质醇分泌过多或不足相关的疾病已被发现与胎儿生长减少有关。由于母亲压力导致的皮质醇分泌过多也被认为是小胎龄婴儿的一个因素；然而，关于母体皮质醇的变化如何影响母体生理或胎儿生长和代谢，我们知之甚少。这些研究将提高我们对健康妊娠中母体皮质醇正常增加的作用的理解，以及皮质醇的增加或减少如何影响胎儿和新生儿的生长和代谢。

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.