Kisspeptin Physiology Across Reproductive Development

Kisspeptin 生殖发育的生理学

• 批准号: 8716915
• 负责人: Margaret Flynn Lippincott
• 金额: $ 6.1万
• 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/8716915
• 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（由申请人提供）：本研究的主要目标是描述性成熟如何改变人类男性促性腺激素释放激素（GnRH）神经元对 Kisspeptin 的反应。 Kisspeptin 对于青春期发育和调节生殖至关重要。 Kisspeptin 刺激促性腺激素释放激素 (GnRH) 神经元产生 GnRH，进而刺激垂体释放黄体生成素 (LH) 和卵泡刺激素 (FSH)。 LH 和 FSH 向卵巢发出信号，以产生雌激素和卵子，并向睾丸发出信号，以产生睾酮和精子。 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，对于特定目标#1，研究重点是 GnRH 对 Kisspeptin 的反应在性成熟前后如何变化。具体目标#2 通过检查 GnRH 神经元在暴露于睾酮等性类固醇时如何对 Kisspeptin 做出反应，进一步表征了这种反应性。了解 Kisspeptin 向 GnRH 神经元发出的信号是如何调节的，将提高人们对 Kisspeptin 如何在大脑中发挥作用的了解，并有助于深入了解青春期如何开始。 该研究将招募一个独特的受试者群体，即未能度过青春期的个体，这种情况称为特发性低促性腺激素性性腺功能减退症（IHH）。这种情况也称为 GnRH 缺乏症，传统上被认为是终生疾病。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了逆转，即下丘脑-垂体-性腺轴的自发恢复，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，其中促性腺激素低下的患者在成年后基本上经历了自发性成熟，为探索 Kisspeptin 在性发育过程中的反应性提供了一个独特的机会 (SA#1)。此外，促性腺激素低下的人类模型允许操纵性类固醇环境来分离该因素对 Kisspeptin 信号传导的影响 (SA#2)。 该研究使用了 Kisspeptin 112-121 药物，这是一种合成肽，可模仿内源性 Kisspeptin 的作用，并已获得 FDA 批准作为研究性新药用于人体。患有 IHH 的受试者将接受 Kisspeptin 给药，并随后以每 10 分钟抽血一次的形式进行监测，以监测受试者对 Kisspeptin 的反应。最初，未经历逆转的 IHH 受试者将在停用性类固醇的情况下进行研究。随后，患有 IHH 的受试者将返回并重复注射 Kisspeptin 和性类固醇。最后，一部分经历 IHH 逆转的受试者将在逆转状态下接受 Kisspeptin 给药。通过这种方式，将在性成熟之前和之后（“逆转”）以及使用和关闭性类固醇的情况下检查 GnRH 神经元对 Kisspeptin 的反应性。