Exogenous Kisspeptin Administration as a Probe of GnRH Neuronal Function in Patients With Idiopathic Hypogonadotropic Hypogonadism
Year: 2014
Type: article
Study design: Clinical Trial
Abstract: CONTEXT: Idiopathic hypogonadotropic hypogonadism (IHH) results from defective synthesis, secretion, or action of GnRH. Kisspeptin is a potent stimulus for GnRH secretion. OBJECTIVE: We probed the functional capacity of the GnRH neuronal network in patients with IHH. PARTICIPANTS: Eleven subjects with congenital IHH (9 men and 2 women) and one male subject who underwent reversal of IHH were studied. Six of the twelve subjects had an identified genetic cause of their IHH: KAL1 (n = 1), FGFR1 (n = 3), PROKR2 (n = 1), GNRHR (n = 1). INTERVENTION: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to intravenous boluses of kisspeptin (0.24 nmol/kg) and GnRH (75 ng/kg) both pre- and post-six days of treatment with exogenous GnRH (25 ng/kg sc every 2 h). RESULTS: All subjects with abiding IHH failed to demonstrate a GnRH-induced LH response to exogenous kisspeptin. In contrast, the subject who achieved reversal of his hypogonadotropism demonstrated a robust response to kisspeptin. CONCLUSIONS: The functional capacity of the GnRH neuronal network in IHH patients is impaired, as evidenced by their inability to respond to the same dose of kisspeptin that effects a robust GnRH-induced LH response in healthy men and luteal-phase women. This impairment is observed across a range of genotypes, suggesting that it reflects a fundamental property of GnRH neuronal networks that have not been properly engaged during pubertal development. In contrast, a patient who had experienced reversal of his hypogonadotropism responded to exogenous kisspeptin.
DOI: 10.1210/jc.2014-2233
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Doris Duke Charitable Foundation, Massachusetts General Hospital, Harvard Catalyst, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, NIH Clinical Center, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1019374866, G1159328635, G140944187, G221159913, Northwest Genomics Center, ARRA - NHLBI Lung Cohorts Sequencing Project, G2700825495, Kisspeptin and Neurokinin B: Physiology in Monkey to Pathophysiology in Human, Harvard Clinical and Translational Science Center (UL1), G406748190, Kisspeptin Physiology Across Reproductive Development, G4741304744, G4757947361, ARRA - NHLBI Lung Cohorts Sequencing Project, REPRODUCTIVE ENDOCRINE SCIENCES CENTER, Harvard Reproductive Endocrine Sciences Center, G5945347341, WHI Sequencing Project (WHISP), Harvard Clinical and Translational Science Center (UL1), G843766559, Harvard Reproductive Endocrine Sciences Center, Child Health Research Career Development Award (CHRCDA) Program (K12), Training Program in Endocrinology
OpenAlex ID: W2169232963