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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：
8736944
负责人：
Angela Delaney Freedman
金额：
$ 42.72万
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/8736944
关键词：
Adult Affect Animal Model Anosmia Anovulation Auditory Award Biochemical Biological Biology Blood specimen Candidate Disease Gene Characteristics Child Childhood Chronic Clinical Clinical Protocols Clinical Research Clinical Trials Cognition Collaborations Defect Delayed Puberty Development Diagnostic Diagnostic Procedure Disease Disease model Dose Endocrine Enrollment Event Family Family member Female Fertility Follicle Stimulating Hormone Frequencies Functional disorder Funding Gatekeeping General Hospitals Genes Genetic Genotype Goals Gonadal Steroid Hormones Gonadotropin Hormone Releasing Hormone Gonadotropins Growth Heterogeneity Hormones Hour Human Hyperandrogenism Hypogonadism Hypothalamic structure Individual Infusion procedures Inherited Insulin Resistance Investigation KISS1 gene KISS1R gene Kidney Klinefelter&apos s Syndrome Knowledge Lead Learning Light Luteinizing Hormone Massachusetts Menstrual cycle Molecular Mutation National Institute of Mental Health Neonatal Neurocognitive Neurologic Neurons Neuropeptides Neurosecretory Systems Obesity Oligonucleotides Pathway interactions Patients Pattern Peptides Phase Phenotype Physiologic pulse Physiological Physiology Pituitary Gland Polycystic Ovary Syndrome Postmenopause Precocious Puberty Protocols documentation Puberty Rare Diseases Regulation Reproduction Reproductive Endocrinology Research Role Safety Sampling Studies Sexual Maturation Signal Transduction Site Syndrome Techniques Therapeutic Intervention Time Translational Research United States National Institutes of Health Variant Woman base bench to bedside desensitization exome gene discovery genetic analysis genetic linkage analysis genetic variant hormone deficiency hormone regulation human disease human female hypothalamic pituitary gonadal axis insight interest kisspeptin male meetings member novel novel diagnostics novel therapeutic intervention patient population programs receptor reproductive reproductive development skeletal tool volunteer

项目摘要

The Role of Gonadotropin Pulsations in the Regulation of Puberty and Fertility The key initiating factors for reproductive development remain among the great mysteries of pediatric and reproductive endocrinology. The onset of puberty is initiated by pulsatile secretion of GnRH from the hypothalamus. GnRH secretion is fully active during the neonatal period, quiescent throughout most of childhood, and is reactivated at the time of puberty to induce sexual maturation and subsequent fertility. The neuroendocrine factors leading to these events remain largely unknown. Isolated deficiency of GnRH results in the rare clinical syndrome of isolated hypogonadotropic hypogonadism (IHH), where decreased secretion of GnRH results in impaired secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. The resultant hypogonadism presents with delayed, incomplete, or absent sexual maturation. In addition, non-reproductive phenotypic features of this spectrum have been identified in some individuals, including anosmia, auditory defects, and skeletal, neurological and renal anomalies. Defining the physiology of GnRH secretion is critical to understanding the clinical heterogeneity of IHH, particularly in light of emerging gene discoveries that elucidate genotype-phenotype correlations. Our collaboration has resulted in the addition of the NIH as the second site in an existing protocol at MGH to phenotypically characterize subjects with IHH. Clinical studies are now actively underway, enrolling males and females with clinical signs suggestive of IHH for comprehensive phenotyping to include neuroendocrine profiling via an LH pulsatility study and identification of other non-reproductive findings. We have seen a broad range of LH pulsatility patterns and other features that will be investigated in the context of genetic variants, where identified, in order to increase our understanding of the ontogeny of these disorders. Combining our effort with the established protocol and recruitment mechanisms at MGH has also allowed us to maximize the number of subjects with this rare disorder that can be evaluated. In addition, we are now including neurocognitive phenotyping of these subjects, in collaboration with Jay Giedds research group (NIMH), to determine the effect of sex steroid hormone deficiency during puberty on adult cognition. We are utilizing the disease model of IHH to increase our understanding of the physiology of GnRH secretion, including unknown aspects of GnRH biology that may be illuminated through the non-reproductive characteristics of these patients. Examining the baseline characteristics of subjects with isolated GnRH deficiency will allow us to make genotype-phenotype correlations that will expand our current paradigm of the hypothalamic-pituitary-gonadal axis, which may have important implications for human disorders of puberty and fertility. The Molecular Basis of Inherited Reproductive Disorders Human and animal models have identified a number of genes responsible for IHH, 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. Recent evidence has expanded our understanding of this spectrum of disorders to include oligo-digenic inheritence, as well as reversibility of the condition, and has provided insight into developmental pathways involved in the ontogeny of GnRH neurons. Genetic analysis of subjects with unknown mutations is likely to yield important insights into additional pathways involved in the regulation of GnRH secretion, as was the case with the identification of mutations in the kisspeptin receptor (KISS1R, or GPR54) in families with IHH, leading to the emergence of kisspeptin (KISS1) as an important gatekeeper of puberty. This is merely one example among many critical discoveries that have been made in this field through molecular exploration. We are conducting genetic investigations of subjects with IHH and their family members to characterize further the phenotypic effect of previously described genetic variants, as well as to identify novel genes involved in congenital GnRH deficiency using candidate gene and whole exome approaches, as well as linkage analysis. We are also conducting these molecular investigations in individuals with precocious puberty as well as delayed puberty, even in the absence of meeting diagnostic criteria for IHH, in order to explore the molecular mechanisms underlying these more common variants of pubertal development. Patients with IHH provide a unique human disease model, which will elucidate the physiology of GnRH secretion, including the neuroendocrine regulation of GnRH secretion. Examining the genetic characteristics of subjects with isolated GnRH deficiency, as well as other pubertal disorders, and correlating these findings with detailed phenotypic characteristics 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 from neurons in the hypothalamus. 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. Polycystic ovary syndrome (PCOS) is a common condition characterized by ovulatory dysfunction and hyperandrogenism, and is frequently associated with obesity and insulin resistance. 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. Here, we also seek 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. In collaboration with Stephanie Seminara, and funded through the NIH Bedside-to-Bench Award program, we are developing a new clinical trial to explore the use of continuous kisspeptin to manipulate the reproductive cascade in healthy female volunteers, as well as in women with chronic anovulation due to PCOS. Our approved clinical protocol involves the study of 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. Subsequently, the peptide will be given to women in the periovulatory phase of the menstrual cycle and to women with PCOS. Subjects will undergo a frequent blood sampling study to determine the effect of a 24-hour infusion of kisspeptin on GnRH-induced LH pulsatility. In summary, this study utilizes a cutting-edge physiologic tool to answer key questions about the neuroendocrine control of reproduction in the human female. The information gained from these protocols has the potential to significantly broaden our knowledge of the neuroendocrine control of human reproduction.