title: Investigating the KNDy Hypothesis in Humans by Coadministration of Kisspeptin, Neurokinin B, and Naltrexone in Men.
abstract: A subpopulation of hypothalamic neurons colocalize three neuropeptides, namely kisspeptin, neurokinin B (NKB), and dynorphin, collectively termed KNDy neurons. Animal studies suggest they interact to affect pulsatile GnRH release (KNDy hypothesis); kisspeptin stimulates, NKB modulates, and dynorphin (an opioid) inhibits.
  
  
  
  To investigate the KNDy hypothesis in humans, we assessed for the first time the effects of the coadministration of kisspeptin-54, NKB, and an opioid receptor antagonist, naltrexone, on LH pulsatility (surrogate marker for GnRH pulsatility) and gonadotropin release.
  
  
  
  This was an ethically approved prospective, single-blinded, placebo-controlled study. Healthy male volunteers (n = 5/group) attended our research facility for eight study visits.
  
  
  
  After 1 hour of baseline blood sampling, participants received a different intervention at each visit: oral 50 mg naltrexone, 8-hour iv infusions of vehicle, 2.56 nmol/kg · h NKB, 0.1 nmol/kg · h kissspeptin-54 (KP) alone and in combination. Frequent blood sampling to measure plasma gonadotropins and sex steroids was conducted and LH pulsatility was determined using blinded deconvolution analysis.
  
  
  
  All kisspeptin and naltrexone containing groups potently increased LH and LH pulsatility (P < .001 vs vehicle). NKB alone did not affect gonadotropins. NKB+KP had significantly lower increases in gonadotropins compared with kisspeptin alone (P < .01). Naltrexone+KP was the only group to significantly increase LH pulse amplitude (P < .001 vs vehicle).
  
  
  
  Our results suggest significant interactions between the KNDy neuropeptides on LH pulsatility and gonadotropin release in humans. This has important implications for improving our understanding of GnRH pulse generation in humans.
authors.affiliation: Section of Investigative Medicine (S.N., J.K.P., C.N.J., D.A.P., M.M., A.J.S., A.N.C., A.A., S.R.B., W.S.D.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; Statsconsultancy Ltd (P.B.), Amersham, Buckinghamshire HP7 9EN, United Kingdom; and Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Shakunthala
authors.initials: S
authors.lastname: Narayanaswamy
authors.affiliation: Section of Investigative Medicine (S.N., J.K.P., C.N.J., D.A.P., M.M., A.J.S., A.N.C., A.A., S.R.B., W.S.D.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; Statsconsultancy Ltd (P.B.), Amersham, Buckinghamshire HP7 9EN, United Kingdom; and Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Prague
authors.affiliation: Section of Investigative Medicine (S.N., J.K.P., C.N.J., D.A.P., M.M., A.J.S., A.N.C., A.A., S.R.B., W.S.D.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; Statsconsultancy Ltd (P.B.), Amersham, Buckinghamshire HP7 9EN, United Kingdom; and Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Channa N
authors.initials: CN
authors.lastname: Jayasena
authors.affiliation: Section of Investigative Medicine (S.N., J.K.P., C.N.J., D.A.P., M.M., A.J.S., A.N.C., A.A., S.R.B., W.S.D.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; Statsconsultancy Ltd (P.B.), Amersham, Buckinghamshire HP7 9EN, United Kingdom; and Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Papadopoulou
authors.affiliation: Section of Investigative Medicine (S.N., J.K.P., C.N.J., D.A.P., M.M., A.J.S., A.N.C., A.A., S.R.B., W.S.D.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; Statsconsultancy Ltd (P.B.), Amersham, Buckinghamshire HP7 9EN, United Kingdom; and Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Maria
authors.initials: M
authors.lastname: Mizamtsidi
authors.affiliation: Section of Investigative Medicine (S.N., J.K.P., C.N.J., D.A.P., M.M., A.J.S., A.N.C., A.A., S.R.B., W.S.D.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; Statsconsultancy Ltd (P.B.), Amersham, Buckinghamshire HP7 9EN, United Kingdom; and Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Amar J
authors.initials: AJ
authors.lastname: Shah
authors.affiliation: Section of Investigative Medicine (S.N., J.K.P., C.N.J., D.A.P., M.M., A.J.S., A.N.C., A.A., S.R.B., W.S.D.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; Statsconsultancy Ltd (P.B.), Amersham, Buckinghamshire HP7 9EN, United Kingdom; and Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Paul
authors.initials: P
authors.lastname: Bassett
authors.affiliation: Section of Investigative Medicine (S.N., J.K.P., C.N.J., D.A.P., M.M., A.J.S., A.N.C., A.A., S.R.B., W.S.D.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; Statsconsultancy Ltd (P.B.), Amersham, Buckinghamshire HP7 9EN, United Kingdom; and Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Comninos
authors.affiliation: Section of Investigative Medicine (S.N., J.K.P., C.N.J., D.A.P., M.M., A.J.S., A.N.C., A.A., S.R.B., W.S.D.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; Statsconsultancy Ltd (P.B.), Amersham, Buckinghamshire HP7 9EN, United Kingdom; and Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Ali
authors.initials: A
authors.lastname: Abbara
authors.affiliation: Section of Investigative Medicine (S.N., J.K.P., C.N.J., D.A.P., M.M., A.J.S., A.N.C., A.A., S.R.B., W.S.D.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; Statsconsultancy Ltd (P.B.), Amersham, Buckinghamshire HP7 9EN, United Kingdom; and Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bloom
authors.affiliation: Section of Investigative Medicine (S.N., J.K.P., C.N.J., D.A.P., M.M., A.J.S., A.N.C., A.A., S.R.B., W.S.D.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; Statsconsultancy Ltd (P.B.), Amersham, Buckinghamshire HP7 9EN, United Kingdom; and Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
authors.affiliation: Section of Investigative Medicine (S.N., J.K.P., C.N.J., D.A.P., M.M., A.J.S., A.N.C., A.A., S.R.B., W.S.D.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; Statsconsultancy Ltd (P.B.), Amersham, Buckinghamshire HP7 9EN, United Kingdom; and Endocrine Research Unit (J.D.V.), Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Waljit S
authors.initials: WS
authors.lastname: Dhillo
mesh_terms: D000328:Adult; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects*; D006062:Gonadotropins / Q000378:metabolism*; D006801:Humans; D059648:Kisspeptins / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000008:administration & dosage*; D009292:Narcotic Antagonists / Q000008:administration & dosage; D015287:Neurokinin B / Q000008:administration & dosage*; D018377:Neurotransmitter Agents / Q000008:administration & dosage; D011446:Prospective Studies; D016037:Single-Blind Method
chemical_list: D006062:Gonadotropins; C106628:KISS1 protein, human; D059648:Kisspeptins; D009292:Narcotic Antagonists; D018377:Neurotransmitter Agents; D009271:Naltrexone; D015287:Neurokinin B