Developmental Origins of Polycystic Ovary Syndrome: Very Early Phenotypes During the Mini Puberty of Infancy and Beyond

多囊卵巢综合症的发育起源：婴儿期迷你青春期及以后的早期表型

基本信息

批准号：
10631920
负责人：
Laura C Torchen
金额：
$ 66.91万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10631920
关键词：
2 year old Adult Affect Age Age Months Androgens Animal Model Animals Blood capillaries Blood specimen Body fat C-Peptide Characteristics Cluster Analysis Collection Creatinine Data Daughter Development Disease Endocrine System Diseases Enrollment Exposure to Female First Degree Relative Functional disorder Genetic Predisposition to Disease Genetic Risk Glucose Goals Gonadal Steroid Hormones Gonadotropins Growth Health Height Heritability Hormone secretion Hormones Infant Insulin Investigation Life Longitudinal Studies Measurement Measures Metabolic Metabolic Pathway Methods Mothers Neurosecretory Systems Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Pathogenesis Phenotype Polycystic Ovary Syndrome Pregnancy Prevalence Prevention Puberty Reporting Research Risk Sampling Second Pregnancy Trimester Serum Sex Hormone-Binding Globulin Study models Subgroup Susceptibility Gene Syndrome Testing Testosterone Time Urine Weight Woman adiponectin age group cohort critical developmental period endophenotype fetal genetic architecture genetic variant genome wide association study girls hypothalamic pituitary gonadal axis infancy insight insulin secretion insulin sensitivity male metabolic phenotype minimally invasive mullerian-inhibiting hormone neonatal period neuroendocrine phenotype novel offspring programs prospective reproductive reproductive hormone steroid hormone steroid hormone metabolism subfertility trait

项目摘要

PROJECT SUMMARY Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders in women of reproductive age and is associated with significant negative reproductive and metabolic outcomes. As PCOS is highly heritable, daughters of affected women have increased risk, with reported prevalence rates as high as ~70%. Several studies have established that distinct reproductive and metabolic phenotypes can be observed in PCOS daughters prior to puberty, suggesting the pathogenesis of PCOS begins at an early developmental stage in these at-risk girls. Further, studies in animal models of PCOS have demonstrated that exposure to androgens or anti-Mullerian hormone (AMH) during critical developmental periods such as fetal life, the neonatal period, or puberty can program the offspring to develop the reproductive and/or metabolic phenotypes of PCOS during reproductive maturity. Prior to puberty, the hypothalamic-pituitary-gonadal (HPG) axis is quiescent, except during the “mini puberty of infancy”, a transient developmental stage during the first several months of life. The HPG axis is active during this time and gonadotropin and sex steroids reach pubertal levels. Our overarching hypothesis is that mini puberty will unmask an early reproductive phenotype in daughters of women with PCOS, characterized by alterations in gonadotropin and AMH secretion. Studies during this very early age have been limited due to the challenges of pursuing invasive testing in this age group. We will employ minimally invasive methods which will allow us to examine early metabolic and reproductive phenotypes in PCOS daughters without risk of harm to these young girls. Three Aims will test the hypotheses that: 1) PCOS daughters have a distinct reproductive phenotype during the mini puberty of infancy characterized by increased gonadotropin and AMH levels and decreased sex hormone binding globulin (SHBG); 2) PCOS daughters will develop a metabolic phenotype characterized by increased body fat accrual and decreased insulin sensitivity in the first two years of life; 3) LH and AMH levels in PCOS daughters during the mini puberty of infancy will be positively associated with maternal testosterone and AMH levels and negatively associated with maternal insulin sensitivity and adiponectin levels during the second trimester of gestation. We will enroll 120 women with PCOS and 120 control women early in their second trimester of pregnancy. We will measure reproductive hormones and markers of insulin sensitivity and secretion in these women between 24 and 28 weeks gestation. We will collect timed urine samples for assessment of C-peptide, gonadotropin secretion, and steroid hormone metabolism in their infant daughters at 1, 2, and 3 months of age. We will obtain measures of adiposity and capillary blood samples for measurement of SHBG, AMH, and adiponectin at 3, 6, 12, 18, and 24 months of age in the infant daughters. If the Aims are achieved, the impact of this research will result in a paradigm shift in our understanding of the early mechanisms of PCOS. Through the proposed study, we will also establish a cohort for continued longitudinal studies in girls at increased risk for PCOS.

项目概要多囊卵巢综合症（PCOS）是育龄妇女最常见的内分泌疾病之一年龄，与显着的负面生殖和代谢结果相关，因为多囊卵巢综合症的发病率很高。由于遗传因素，受影响妇女的女儿患病风险增加，据报道患病率高达 70% 左右。多项研究已经证实，多囊卵巢综合征中可以观察到不同的生殖和代谢表型青春期前的女儿，表明多囊卵巢综合症的发病机制始于女孩的早期发育阶段此外，对多囊卵巢综合症动物模型的研究表明，接触雄激素。或抗缪勒氏管激素（AMH）在关键发育时期，如胎儿期、新生儿期或青春期可以对后代进行编程，使其在青春期期间发展出 PCOS 的生殖和/或代谢表型。青春期之前，下丘脑-垂体-性腺 (HPG) 轴处于静止状态，除非在青春期期间。 “婴儿期的迷你青春期”是生命最初几个月的一个短暂的发育阶段。在此期间，轴处于活跃状态，促性腺激素和性类固醇达到青春期的总体水平。假设是，迷你青春期将揭示多囊卵巢综合症女性的女儿的早期生殖表型，其特点是促性腺激素和 AMH 分泌的改变，在这个很小的时候就已经进行了研究。由于在这个年龄段进行侵入性检测的挑战，我们将采用微创检测。这些方法将使我们能够检查多囊卵巢综合症女儿的早期代谢和生殖表型，而无需三个目标将检验这些年轻女孩受到伤害的风险：1) 多囊卵巢综合症的女儿有一个独特的特征。婴儿期迷你青春期的生殖表型，以促性腺激素和 AMH 增加为特征水平和性激素结合球蛋白（SHBG）下降；2）多囊卵巢综合症的女儿会出现代谢紊乱；表型的特点是在头两年体内脂肪累积增加和胰岛素敏感性降低 3) PCOS 女儿在婴儿期迷你青春期的 LH 和 AMH 水平呈正相关与母体睾酮和 AMH 水平呈负相关，与母体胰岛素敏感性呈负相关我们将招募 120 名 PCOS 女性和 120 名对照女性。我们将测量怀孕中期的女性的生殖激素和标记物。这些妊娠 24 至 28 周期间的女性的胰岛素敏感性和分泌情况我们将收集定时尿液。用于评估婴儿 C 肽、促性腺激素分泌和类固醇激素代谢的样本我们将对 1、2 和 3 个月大的女儿进行肥胖测量和毛细血管血样测量。测量女婴 3、6、12、18 和 24 个月时的 SHBG、AMH 和脂联素。如果目标实现了，这项研究的影响将导致我们对早期研究的理解发生范式转变。通过拟议的研究，我们还将建立一个持续纵向队列。针对多囊卵巢综合症风险增加的女孩的研究。