Kisspeptin Physiology Across Reproductive Development

Kisspeptin 生殖发育的生理学

• 批准号: 8885499
• 负责人: Margaret Flynn Lippincott
• 金额: $ 2.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885499
• 关键词: Adult; Biological Models; Blood specimen; Bolus Infusion; Brain; Child; Childhood; Development; Disease; Enrollment; Estrogens; FDA approved; Failure; Follicle Stimulating Hormone; Frequencies; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Hormones; Human; Hypogonadism; Hypogonadotropism; Individual; Investigational Drugs; Kallmann Syndrome; Knowledge; Lead; Luteinizing Hormone; Modeling; Monitor; Neurons; Neuropeptides; Ovary; Patients; Pharmaceutical Preparations; Physiologic pulse; Physiology; Pituitary Gland; Population; Puberty; Recovery; Reproduction; Research; Sexual Development; Sexual Maturation; Signal Transduction; Stimulus; Testis; Testosterone; Work; egg; hormone deficiency; human GNRH1 protein; human male; hypothalamic pituitary gonadal axis; improved; insight; kisspeptin; public health relevance; reproductive; reproductive development; reproductive function; research study; response; sperm cell; synthetic peptide

DESCRIPTION (provided by applicant): The broad goal of this study is to characterize how sexual maturation transforms the gonadotropin- releasing hormone (GnRH) neuronal response to kisspeptin in the human male. Kisspeptin is essential for pubertal development and regulates reproduction. Kisspeptin stimulates gonadotropin releasing hormone (GnRH) neurons to make GnRH which, in turn, stimulates the pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). LH and FSH signal the ovaries to make estrogen and eggs and the testes to make testosterone and sperm. The proposed research examines how GnRH neuronal responsiveness to kisspeptin changes across sexual maturation in the human. In particular, for Specific Aim #1 the research focuses on how GnRH response to kisspeptin changes before and after sexual maturation. This responsiveness is further characterized in Specific Aim # 2 by examining how GnRH neurons respond to kisspeptin when exposed to sex steroids, such as testosterone. Understanding how kisspeptin signaling to GnRH neurons is modulated will improve knowledge about how kisspeptin works in the brain, and will lead to insights into how puberty begins. The study will enroll a unique subject population, individuals who fail to go through puberty, a condition called idiopathic hypogonadotropic hypogonadism (IHH). This condition, also referred to as GnRH deficiency, has traditionally been considered a lifelong condition. However, our group has shown that over 10% of GnRH "deficient" patients undergo reversal of their hypogonadism, a spontaneous recovery of the hypothalamic- pituitary-gonadal axis with evidence for normal GnRH-induced LH pulse frequency and amplitude. This phenomenon of reversal, in which hypogonadotropic patients essentially undergo spontaneous sexual maturation in adulthood, provides a singular opportunity to explore kisspeptin responsiveness across sexual development (SA#1). Furthermore, the human model of hypogonadotropism allows manipulation of the sex steroid milieu to isolate this factor's effect on kisspeptin signaling (SA#2). The study utilizes the drug, kisspeptin 112-121, a synthetic peptide, which mimics the action of endogenous kisspeptin, and is approved by the FDA to be administered to humans as an investigational new drug. Subjects with IHH will undergo administration of kisspeptin and subsequent monitoring in the form of q 10 minute blood sampling to monitor the subjects' response to kisspeptin. Initially, subjects with IHH, who have not undergone reversal, will be studied off sex steroids. Subsequently, subjects with IHH will return for a repeat bolus of kisspeptin on sex steroids. Finally, a subset of subjects, who undergo reversal of their IHH, will undergo kisspeptin administration in their reversed state. In this way, GnRH neuronal responsiveness to kisspeptin will be examined before and after sexual maturation ("reversal") and on and off sex steroids.

描述（由申请方提供）：本研究的主要目的是描述性成熟如何改变人类男性中促性腺激素释放激素（GnRH）神经元对kisspeptin的反应。Kisspeptin对青春期发育至关重要，并调节生殖。Kisspeptin刺激促性腺激素释放激素（GnRH）神经元以产生GnRH，继而刺激脑下垂体释放促黄体生成激素（LH）和促卵泡激素（FSH）。LH和FSH向卵巢发出信号，使其产生雌激素和卵子，向睾丸发出信号，使其产生睾丸激素和精子。 拟议的研究探讨了GnRH神经元对kisspeptin的反应如何在人类性成熟过程中发生变化。特别是，对于具体目标#1，研究重点是GnRH对kisspeptin的反应在性成熟前后如何变化。这种反应性在《特定目标2》中通过研究GnRH神经元在暴露于性类固醇（如睾酮）时对kisspeptin的反应来进一步表征。了解kisspeptin信号如何调节GnRH神经元将提高kisspeptin如何在大脑中工作的知识，并将导致对青春期如何开始的见解。 该研究将招募一个独特的受试者人群，即未经历青春期的个体，这种疾病称为特发性低促性腺激素性腺功能减退症（IHH）。这种情况，也被称为GnRH缺乏症，传统上被认为是终身疾病。然而，我们的研究小组已经表明，超过10%的GnRH“缺乏”患者的性腺功能减退发生逆转，下丘脑-垂体-性腺轴自发恢复，并有证据表明GnRH诱导的LH脉冲频率和幅度正常。这种逆转现象，其中低促性腺激素患者在成年期基本上经历自发性成熟，提供了探索性发育过程中kisspeptin反应性的独特机会（SA#1）。此外，促性腺功能减退的人模型允许操纵性类固醇环境以分离该因子对kisspeptin信号传导的作用（SA#2）。 该研究利用药物kisspeptin 112-121，一种合成肽，其模拟内源性kisspeptin的作用，并被FDA批准作为研究性新药施用于人类。IHH受试者将接受kisspeptin给药，随后以每10分钟采集一次血样的形式进行监测，以监测受试者对kisspeptin的反应。最初，将对未逆转的IHH受试者进行停用性类固醇的研究。随后，IHH受试者将返回接受重复kisspeptin推注性类固醇。最后，接受IHH逆转的受试者亚组将在逆转状态下接受kisspeptin给药。以这种方式，GnRH神经元对kisspeptin的反应将在性成熟（“逆转”）前后以及性类固醇的使用和停用前后进行检查。