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.
Sexual development in childhood remains poorly understood: some children develop too early, others too late or not at all. This research study investigates how the hormone kisspeptin, a naturally occurring neuropeptide, stimulates the brain during sexual development. The proposed research will provide new information about how kisspeptin creates signals in the brain which ultimately lead to reproductive function, and may help develop new treatments for reproductive disorders.