Investigating the KNDy hypothesis in humans by coadministration of kisspeptin, neurokinin B, and naltrexone in men

Shakunthala Narayanaswamy, Julia K. Prague, Channa N. Jayasena, Deborah A. Papadopoulou, Maria Mizamtsidi, Amar J. Shah, Paul Bassett, Alexander N. Comninos, Ali Abbara, Stephen R. Bloom, Johannes D. Veldhuis, Waljit S. Dhillo

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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, placebocontrolled study. Healthymalevolunteers (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 50mgnaltrexone, 8-hour iv infusions of vehicle, 2.56 nmol/kg · hNKB, 0.1 nmol/kg · hkissspeptin-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.

Original languageEnglish (US)
Pages (from-to)3429-3436
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Issue number9
StatePublished - Sep 2016

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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