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The Regulation of Pubertal Onset and Reproductive Development

青春期开始和生殖发育的调节

基本信息

批准号：
9150171
负责人：
Angela Delaney Freedman
金额：
$ 26.99万
依托单位：
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9150171
关键词：
Accounting Affect Age Amenorrhea Animal Model Anosmia Anovulation Auditory Award Biochemical Biological Brain Candidate Disease Gene Characteristics Child Clinical Clinical Protocols Collaborations Data Data Analyses Defect Delayed Puberty Development Diagnostic Procedure Disease Dose Endocrine Enrollment Exercise Extended Family Family Fertility Frequencies Functional Magnetic Resonance Imaging Functional disorder Funding Gender General Hospitals General Population Genes Genetic Genetic study Genomics Genotype Goals Gonadal Steroid Hormones Gonadotropin Hormone Releasing Hormone Gonadotropins Growth Heterogeneity Hormones Hour Human Hyperandrogenism Hypothalamic structure Individual Infusion procedures Inheritance Patterns Inherited Investigation Kallmann Syndrome Kidney Lead Learning Light Malnutrition Massachusetts Mental disorders Molecular Multicenter Studies Mutation National Institute of Child Health and Human Development Neurocognitive Neurocognitive Deficit Neurologic Neuropeptides Neurosecretory Systems Oligonucleotides Pathway interactions Patients Pattern Peptides Phenotype Physiologic pulse Physiology Pilot Projects Play Polycystic Ovary Syndrome Postmenopause Precocious Puberty Predisposition Prevalence Psychological Stress Puberty Race Recruitment Activity Regulation Reproduction Research Personnel Role Safety Sequence Analysis Sexual Maturation Signal Transduction Subgroup Symptoms Techniques Therapeutic Intervention Translational Research United States National Institutes of Health Variant Woman base bench to bedside clinical phenotype cohort desensitization exome sequencing gene discovery gene function genetic variant hormone deficiency hormone regulation human subject hypothalamic pituitary gonadal axis insight interest kisspeptin member memory recognition negative emotional state neurocognitive test novel novel diagnostics novel therapeutic intervention patient population physiologic stressor premature proband psychologic pubertal timing receptor reproductive reproductive development sex skeletal spatiotemporal

项目摘要

The Role of Gonadotropin Pulsations in the Regulation of Puberty and Fertility At one extreme of pubertal development, isolated deficiency of GnRH results in a spectrum of rare clinical disorders of isolated GnRH deficiency (IGD), also known as idiopathic hypogonadotropic hypogonadism (IHH), which presents with delayed, incomplete, or absent sexual maturation. Defining the physiology of GnRH secretion is critical to understanding the clinical heterogeneity of IGD, particularly in light of emerging gene discoveries that aim to elucidate genotype-phenotype correlations. Non-reproductive phenotypic features have been identified in some individuals, including anosmia, auditory defects, and skeletal, neurological and renal anomalies. These additional features may be the key to determining the developmental function of genes implicated in this spectrum of disorders. Our clinical protocol, which is a multicenter study in collaboration with the REU at MGH has identified a broad range of LH pulsatility patterns and other features that are being investigated in the context of genetic variants, where identified, in order to increase our understanding of the ontogeny of these disorders. Our phenotyping efforts have identified that uterine anomalies may represent a novel non-reproductive feature of IGD, which is now being investigated in our genetic study (below) to determine whether there is a common molecular cause for these phenotypes. We have also initiated a pilot study to determine the prevalence of psychiatric disorders and symptoms of negative emotional states in our cohort, compared with healthy controls, in order to determine whether there are previously unidentified psychological features in need of further investigation. Neurocognitive Effects of Sex Hormone Deficiency at or Before Puberty There is little existing evidence for the neurocognitive effects of delayed puberty. We have performed neurocognitive testing and structural and functional MRI on subjects with IGD, compared with healthy controls matched for age, sex, and race. Accounting for gender, our preliminary findings suggested that in both sexes, pubertal sex steroid deficiency contributes to persistent structural and functional brain differences as well as to neurocognitive deficits primarily involving spatial ability and recognition memory, providing direct evidence in humans about the critical spatiotemporal role played by appropriately timed pubertal sex steroids during normal brain development. Final analysis of the preliminary cohort in this study is underway. The Molecular Basis of Inherited Reproductive Disorders Human and animal models have identified a number of genes responsible for IGD, but more than half of patients with clinical evidence of the disorder do not have a detectable mutation. In addition, there is significant clinical heterogeneity among affected individuals, including members of the same family harboring the same mutations, which is often explained by oligo-digenic inheritance patterns. Whole exome sequencing (WES) has been performed in the Molecular Genomics Lab (NICHD) on 28 probands, including several extended families to identify novel genes responsible for IGD. Data analysis is underway, and our findings are likely to yield important insights into additional pathways involved in the regulation of GnRH secretion. In addition, we have also performed WES in several families with IGD and known uterine anomalies, based on our discovery of several patients with this phenotypic combination. Analysis of these data has the potential to identify a new non-reproductive feature of IGD, as well as a novel molecular pathway involved in the regulation of GnRH secretion and uterine development. We have also been investigating genetic variants in 14 genes known to cause IGD in a subgroup of individuals with functional GnRH deficiency, resulting in hypothalamic amenorrhea (HA). We aim to determine whether variants in the IGD genes are over-represented in individuals with HA, compared to the general population. If the data support our hypothesis, this would provide further evidence that heterozygous variants in these genes may confer an increased susceptibility to developing HA in the setting of physiologic stressors, such as nutritional deficiency, extreme exercise, or psychological stress. At the other extreme of pubertal development are patients with premature reactivation of hypothalamic GnRH secretion, resulting in idiopathic central precocious puberty (CPP). There is evidence that familial cases account for anywhere from 20-45% of CPP, with most studies describing autosomal dominant inheritance patterns. Far less is known about the molecular basis of CPP, and it was only within the past year that convincing evidence for a causative mutation was identified, using WES, in MKRN3 (Abreu, AP, et al, N Engl J Med, 2013). Candidate gene approaches have not been successful in identifying the molecular basis of this disorder, and an unbiased approach to gene discovery seems more likely to achieve the goal of identifying novel candidate genes responsible for premature GnRH secretion in CPP. We are now actively recruiting familial cases of idiopathic CPP to undergo WES analysis. We have established collaborations with investigators both locally and internationally to increase enrollment, and we anticipate performing WES analysis on this cohort in the coming year. Examining the genetic characteristics of subjects with pubertal disorders will reveal insights into the mechanisms underlying the reawakening of the hypothalamic-pituitary-gonadal axis at puberty. This will provide opportunities for new diagnostic capabilities and therapeutic interventions for disorders of puberty and reproduction. Blockade of Kisspeptin Signaling in Women The neuropeptide hormone kisspeptin potently stimulates secretion of GnRH. While single doses of kisspeptin stimulate the reproductive endocrine axis, animal models suggest that continuous administration of kisspeptin paradoxically suppresses the reproductive endocrine axis temporarily through desensitization of the kisspeptin receptor. By administering 24-hour infusions of kisspeptin to healthy women and to patients with reproductive disorders, we hope to learn more about the role of kisspeptin both in normal physiology and in pathological conditions, such as polycystic ovary syndrome (PCOS), a common condition characterized by ovulatory dysfunction and hyperandrogenism. Among other disturbances of hormonal regulation, patients with PCOS have high amplitude, high frequency LH pulses which may contribute to the oligo-anovulation characteristic of this disorder. In collaboration with Stephanie Seminara, and funded through an NIH Bedside-to-Bench Award, we are investigating healthy postmenopausal women to determine the safety of continuous kisspeptin administration in women and the proper dose and conditions required to achieve desensitization of the kisspeptin receptor. Once these conditions are established, we plan to administer the peptide to women with PCOS to determine if abnormal kisspeptin signaling is involved in these disturbed endocrine dynamics, as greater understanding of how kisspeptin modulates GnRH secretion in this condition could lead to novel therapeutic interventions for this patient population.