Kisspeptin Physiology Across Reproductive Development

描述（由申请人提供）：本研究的主要目的是描述人类男性性成熟如何改变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， GnRH反过来刺激垂体释放黄体生成素（LH）和促卵泡激素（FSH）。黄体生成素和卵泡刺激素发出信号，卵巢产生雌激素和卵子，睾丸产生睾丸激素和精子。提出的研究探讨了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Specific Aim #1，研究的重点是GnRH对kisspeptin的反应在性成熟前后的变化。在Specific Aim # 2中，通过检查GnRH神经元在暴露于性类固醇（如睾酮）时对kisspeptin的反应，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被调节的，将提高对kisspeptin在大脑中如何起作用的认识，并将有助于深入了解青春期是如何开始的。这项研究将招募一个独特的受试者群体，这些人没有经历青春期，这种情况被称为特发性促性腺功能减退症（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，下丘脑-垂体-性腺轴的自发恢复，GnRH诱导的LH脉冲频率和幅度正常。这种逆转现象，即促性腺功能低下的患者在成年期基本上经历了自发的性成熟，为探索kisspeptin在性发育中的反应性提供了一个独特的机会（SA#1）。此外，人类促性腺功能低下模型允许操纵性类固醇环境，以分离该因素对kisspeptin信号传导的影响（SA#2）。这项研究使用的药物是kisspeptin 112-121，这是一种合成肽，模仿内源性kisspeptin的作用，已被FDA批准作为一种试验性新药给人服用。IHH患者将接受kisspeptin治疗，并随后以10分钟血样的形式进行监测，以监测受试者对kisspeptin的反应。最初，未接受逆转治疗的IHH患者将停用性类固醇。随后，患有IHH的受试者将在性类固醇上重复注射kisspeptin。最后，一部分接受IHH逆转的受试者将在逆转状态下接受kisspeptin治疗。通过这种方式，GnRH神经元对kisspeptin的反应将在性成熟（“逆转”）前后以及使用和停用性类固醇前后进行检查。

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.