Cargando…

Investigating the KNDy Hypothesis in Humans by Coadministration of Kisspeptin, Neurokinin B, and Naltrexone in Men

CONTEXT: 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...

Descripción completa

Detalles Bibliográficos
Autores principales: Narayanaswamy, Shakunthala, Prague, Julia K., Jayasena, Channa N., Papadopoulou, Deborah A., Mizamtsidi, Maria, Shah, Amar J., Bassett, Paul, Comninos, Alexander N., Abbara, Ali, Bloom, Stephen R., Veldhuis, Johannes D., Dhillo, Waljit S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Endocrine Society 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010567/
https://www.ncbi.nlm.nih.gov/pubmed/27379743
http://dx.doi.org/10.1210/jc.2016-1911
_version_ 1782451698485166080
author Narayanaswamy, Shakunthala
Prague, Julia K.
Jayasena, Channa N.
Papadopoulou, Deborah A.
Mizamtsidi, Maria
Shah, Amar J.
Bassett, Paul
Comninos, Alexander N.
Abbara, Ali
Bloom, Stephen R.
Veldhuis, Johannes D.
Dhillo, Waljit S.
author_facet Narayanaswamy, Shakunthala
Prague, Julia K.
Jayasena, Channa N.
Papadopoulou, Deborah A.
Mizamtsidi, Maria
Shah, Amar J.
Bassett, Paul
Comninos, Alexander N.
Abbara, Ali
Bloom, Stephen R.
Veldhuis, Johannes D.
Dhillo, Waljit S.
author_sort Narayanaswamy, Shakunthala
collection PubMed
description CONTEXT: 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. OBJECTIVE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTION AND MAIN OUTCOME MEASURE: 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. RESULTS: 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). CONCLUSIONS: 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.
format Online
Article
Text
id pubmed-5010567
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Endocrine Society
record_format MEDLINE/PubMed
spelling pubmed-50105672016-09-13 Investigating the KNDy Hypothesis in Humans by Coadministration of Kisspeptin, Neurokinin B, and Naltrexone in Men Narayanaswamy, Shakunthala Prague, Julia K. Jayasena, Channa N. Papadopoulou, Deborah A. Mizamtsidi, Maria Shah, Amar J. Bassett, Paul Comninos, Alexander N. Abbara, Ali Bloom, Stephen R. Veldhuis, Johannes D. Dhillo, Waljit S. J Clin Endocrinol Metab Original Articles CONTEXT: 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. OBJECTIVE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTION AND MAIN OUTCOME MEASURE: 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. RESULTS: 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). CONCLUSIONS: 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. Endocrine Society 2016-09 2016-07-05 /pmc/articles/PMC5010567/ /pubmed/27379743 http://dx.doi.org/10.1210/jc.2016-1911 Text en https://creativecommons.org/licenses/by/4.0/ This article has been published under the terms of the Creative Commons Attribution License (CC-BY; https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s).
spellingShingle Original Articles
Narayanaswamy, Shakunthala
Prague, Julia K.
Jayasena, Channa N.
Papadopoulou, Deborah A.
Mizamtsidi, Maria
Shah, Amar J.
Bassett, Paul
Comninos, Alexander N.
Abbara, Ali
Bloom, Stephen R.
Veldhuis, Johannes D.
Dhillo, Waljit S.
Investigating the KNDy Hypothesis in Humans by Coadministration of Kisspeptin, Neurokinin B, and Naltrexone in Men
title Investigating the KNDy Hypothesis in Humans by Coadministration of Kisspeptin, Neurokinin B, and Naltrexone in Men
title_full Investigating the KNDy Hypothesis in Humans by Coadministration of Kisspeptin, Neurokinin B, and Naltrexone in Men
title_fullStr Investigating the KNDy Hypothesis in Humans by Coadministration of Kisspeptin, Neurokinin B, and Naltrexone in Men
title_full_unstemmed Investigating the KNDy Hypothesis in Humans by Coadministration of Kisspeptin, Neurokinin B, and Naltrexone in Men
title_short Investigating the KNDy Hypothesis in Humans by Coadministration of Kisspeptin, Neurokinin B, and Naltrexone in Men
title_sort investigating the kndy hypothesis in humans by coadministration of kisspeptin, neurokinin b, and naltrexone in men
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010567/
https://www.ncbi.nlm.nih.gov/pubmed/27379743
http://dx.doi.org/10.1210/jc.2016-1911
work_keys_str_mv AT narayanaswamyshakunthala investigatingthekndyhypothesisinhumansbycoadministrationofkisspeptinneurokininbandnaltrexoneinmen
AT praguejuliak investigatingthekndyhypothesisinhumansbycoadministrationofkisspeptinneurokininbandnaltrexoneinmen
AT jayasenachannan investigatingthekndyhypothesisinhumansbycoadministrationofkisspeptinneurokininbandnaltrexoneinmen
AT papadopouloudeboraha investigatingthekndyhypothesisinhumansbycoadministrationofkisspeptinneurokininbandnaltrexoneinmen
AT mizamtsidimaria investigatingthekndyhypothesisinhumansbycoadministrationofkisspeptinneurokininbandnaltrexoneinmen
AT shahamarj investigatingthekndyhypothesisinhumansbycoadministrationofkisspeptinneurokininbandnaltrexoneinmen
AT bassettpaul investigatingthekndyhypothesisinhumansbycoadministrationofkisspeptinneurokininbandnaltrexoneinmen
AT comninosalexandern investigatingthekndyhypothesisinhumansbycoadministrationofkisspeptinneurokininbandnaltrexoneinmen
AT abbaraali investigatingthekndyhypothesisinhumansbycoadministrationofkisspeptinneurokininbandnaltrexoneinmen
AT bloomstephenr investigatingthekndyhypothesisinhumansbycoadministrationofkisspeptinneurokininbandnaltrexoneinmen
AT veldhuisjohannesd investigatingthekndyhypothesisinhumansbycoadministrationofkisspeptinneurokininbandnaltrexoneinmen
AT dhillowaljits investigatingthekndyhypothesisinhumansbycoadministrationofkisspeptinneurokininbandnaltrexoneinmen