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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Endocrine Society
2016
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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 |
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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 |
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