Yee-Ming Chan1,2, Margaret F Lippincott1, Temitope O Kusa1, Stephanie B Seminara1. 1. Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. 2. Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
Abstract
BACKGROUND: The neuropeptide kisspeptin stimulates luteinizing hormone (LH) secretion in healthy adults but not in adults with idiopathic hypogonadotropic hypogonadism. We hypothesized that, in children presenting with delayed or stalled puberty, kisspeptin would elicit LH secretion in those children found on detailed nighttime neuroendocrine profiling to have evidence of emerging reproductive endocrine function. METHODS: Eleven boys and four girls were admitted overnight to assess LH secretion at baseline, after a single intravenous bolus of kisspeptin, and after a single intravenous bolus of gonadotropin-releasing hormone (GnRH). Subjects then received exogenous pulsatile GnRH for 6 days and returned for a second visit to measure responses to kisspeptin and GnRH after this pituitary "priming." Responses to kisspeptin and GnRH were also measured in 5 healthy men. RESULTS: Of the 15 children with delayed/stalled puberty, 6 exhibited at least one spontaneous LH pulse overnight; all of these subjects had clear responses to kisspeptin, as did one additional subject. Seven subjects had no response to kisspeptin, and one subject exhibited an intermediate response. In the children who responded to kisspeptin, the responses had features comparable to those of adult men. CONCLUSION: In this first report of kisspeptin administration to pediatric subjects to our knowledge, children with delayed/stalled puberty showed a wide range of responses, with some showing a robust response and others showing little to no response. Further follow-up will determine whether responses to kisspeptin predict future pubertal entry for children with delayed puberty. TRIAL REGISTRATION: ClinicalTrials.gov NCT01438034 and NCT01952782. FUNDING: NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD043341, R01 HD090071, P50 HD028138), NIH National Center for Advancing Translational (UL1 TR001102), NIH National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK007028), the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery, Harvard Catalyst, Doris Duke Charitable Foundation (award 2013110), Charles H. Hood Foundation, Robert and Laura Reynolds MGH Research Scholar Program, and Harvard University. These funding sources had no role in the design of this study and did not have any role in conducting the study, analyses, interpretation of the data, or the decision to submit results.
BACKGROUND: The neuropeptide kisspeptin stimulates luteinizing hormone (LH) secretion in healthy adults but not in adults with idiopathic hypogonadotropic hypogonadism. We hypothesized that, in children presenting with delayed or stalled puberty, kisspeptin would elicit LH secretion in those children found on detailed nighttime neuroendocrine profiling to have evidence of emerging reproductive endocrine function. METHODS: Eleven boys and four girls were admitted overnight to assess LH secretion at baseline, after a single intravenous bolus of kisspeptin, and after a single intravenous bolus of gonadotropin-releasing hormone (GnRH). Subjects then received exogenous pulsatile GnRH for 6 days and returned for a second visit to measure responses to kisspeptin and GnRH after this pituitary "priming." Responses to kisspeptin and GnRH were also measured in 5 healthy men. RESULTS: Of the 15 children with delayed/stalled puberty, 6 exhibited at least one spontaneous LH pulse overnight; all of these subjects had clear responses to kisspeptin, as did one additional subject. Seven subjects had no response to kisspeptin, and one subject exhibited an intermediate response. In the children who responded to kisspeptin, the responses had features comparable to those of adult men. CONCLUSION: In this first report of kisspeptin administration to pediatric subjects to our knowledge, children with delayed/stalled puberty showed a wide range of responses, with some showing a robust response and others showing little to no response. Further follow-up will determine whether responses to kisspeptin predict future pubertal entry for children with delayed puberty. TRIAL REGISTRATION: ClinicalTrials.gov NCT01438034 and NCT01952782. FUNDING: NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD043341, R01 HD090071, P50 HD028138), NIH National Center for Advancing Translational (UL1 TR001102), NIH National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK007028), the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery, Harvard Catalyst, Doris Duke Charitable Foundation (award 2013110), Charles H. Hood Foundation, Robert and Laura Reynolds MGH Research Scholar Program, and Harvard University. These funding sources had no role in the design of this study and did not have any role in conducting the study, analyses, interpretation of the data, or the decision to submit results.
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