title: Exogenous kisspeptin administration as a probe of GnRH neuronal function in patients with idiopathic hypogonadotropic hypogonadism.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  METHODS
  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.
authors.affiliation: Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine (Y-M.C., M.F.L.,V.F.S., C.X.L., L.P., S.B.S.), Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology, Department of Medicine (Y-M.C.), Boston Children's Hospital, Boston, Massachusetts 02115; and Division of Sleep Medicine (J.P.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Yee-Ming
authors.initials: YM
authors.lastname: Chan
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Lippincott
authors.forename: James P
authors.initials: JP
authors.lastname: Butler
authors.forename: Valerie F
authors.initials: VF
authors.lastname: Sidhoum
authors.forename: Cindy X
authors.initials: CX
authors.lastname: Li
authors.forename: Lacey
authors.initials: L
authors.lastname: Plummer
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Seminara
mesh_terms: D000328:Adult; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics*; D006801:Humans; D007006:Hypogonadism / Q000473:pathology*; D059648:Kisspeptins; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000187:drug effects / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D011966:Receptors, LHRH / Q000378:metabolism; D055815:Young Adult
chemical_list: C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; D059648:Kisspeptins; D009419:Nerve Tissue Proteins; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone