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

Narayanaswamy S, Prague JK, Jayasena CN, Papadopoulou DA, Mizamtsidi M, Shah AJ, Bassett P, Comninos AN, Abbara A, Bloom SR, Veldhuis JD, Dhillo WS

The Journal of clinical endocrinology and metabolism5 Jul 2016Cited by 27 (Europe PMC)

PMID27379743PMCIDPMC5010567DOI10.1210/jc.2016-1911PepBankPUB-27379743

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Summary

ContextA 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.ObjectiveTo 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 participantsThis 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 measureAfter 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.ResultsAll 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).ConclusionsOur 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.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study4

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone4

In this study, Kisspeptin-54 (metastin) was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Kisspeptin-54 (metastin).

01HumanNot a test of Kisspeptin-54 (metastin) aloneNon-randomized trialEfficacy outcome
In healthy men, all groups that contained kisspeptin‑54 or naltrexone, alone or in combination, potently increased LH compared with vehicle (P < .001).
In plain wordsIn healthy men, every group given kisspeptin‑54 or naltrexone, alone or together, had a strong rise in luteinising hormone compared with vehicle.
Peptide
Kisspeptin-54 (metastin)
Outcome
IncreaseLH increase in kisspeptin and naltrexone containing groups
Study
n = 5
Comparator
Vehicle
Outcome group
Sex hormones and fertility · Endocrine and hormones
Source sentences
Summary
All kisspeptin and naltrexone containing groups potently increased LH and LH pulsatility (P < .001 vs vehicle).
2 context sentences(design, population, supporting numbers)
Summary · context
Healthy male volunteers (n = 5/group) attended our research facility for eight study visits.
Summary · context
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.
In this study, Kisspeptin-54 (metastin) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Kisspeptin-54 (metastin).
Show in the study text Report a problemFND-2737974301
02HumanNot a test of Kisspeptin-54 (metastin) aloneNon-randomized trialEfficacy outcome
In healthy men, all groups that contained kisspeptin‑54 or naltrexone, alone or in combination, potently increased LH pulsatility compared with vehicle (P < .001).
In plain wordsIn healthy men, every group given kisspeptin‑54 or naltrexone, alone or together, had more luteinising hormone pulses than with vehicle.
Peptide
Kisspeptin-54 (metastin)
Outcome
IncreaseLH pulsatility in kisspeptin and naltrexone containing groups
Study
n = 5
Comparator
Vehicle
Outcome group
Sex hormones and fertility · Endocrine and hormones
Source sentences
Summary
All kisspeptin and naltrexone containing groups potently increased LH and LH pulsatility (P < .001 vs vehicle).
2 context sentences(design, population, supporting numbers)
Summary · context
Healthy male volunteers (n = 5/group) attended our research facility for eight study visits.
Summary · context
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.
In this study, Kisspeptin-54 (metastin) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Kisspeptin-54 (metastin).
Show in the study text Report a problemFND-2737974302
03HumanNot a test of Kisspeptin-54 (metastin) aloneNon-randomized trialEfficacy outcome
In healthy men, the combination of NKB and kisspeptin‑54 produced significantly lower increases in gonadotropins than kisspeptin‑54 alone (P < .01).
In plain wordsIn healthy men, adding NKB to kisspeptin‑54 gave smaller gonadotropin rises than kisspeptin‑54 alone.
Peptide
Kisspeptin-54 (metastin)
Outcome
DecreaseGonadotropin rise with NKB plus kisspeptin-54 versus kisspeptin-54 alone
Study
n = 5
Comparator
Kisspeptin-54 alone
Outcome group
Sex hormones and fertility · Endocrine and hormones
Source sentences
Summary
NKB+KP had significantly lower increases in gonadotropins compared with kisspeptin alone (P < .01).
2 context sentences(design, population, supporting numbers)
Summary · context
Healthy male volunteers (n = 5/group) attended our research facility for eight study visits.
Summary · context
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.
In this study, Kisspeptin-54 (metastin) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Kisspeptin-54 (metastin).
Show in the study text Report a problemFND-2737974303
04HumanNot a test of Kisspeptin-54 (metastin) aloneNon-randomized trialEfficacy outcome
In healthy men, the combination of naltrexone and kisspeptin‑54 was the only group to significantly increase LH pulse amplitude compared with vehicle (P < .001).
In plain wordsIn healthy men, only naltrexone plus kisspeptin‑54 together raised the size of luteinising hormone pulses compared with vehicle.
Peptide
Kisspeptin-54 (metastin)
Outcome
IncreaseLH pulse amplitude with naltrexone plus kisspeptin-54
Study
n = 5
Comparator
Vehicle
Outcome group
Sex hormones and fertility · Endocrine and hormones
Source sentences
Summary
Naltrexone+KP was the only group to significantly increase LH pulse amplitude (P < .001 vs vehicle).
2 context sentences(design, population, supporting numbers)
Summary · context
Healthy male volunteers (n = 5/group) attended our research facility for eight study visits.
Summary · context
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.
In this study, Kisspeptin-54 (metastin) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Kisspeptin-54 (metastin).
Show in the study text Report a problemFND-2737974304

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Version 2Current
13 Oct 2026, 21:44 UTC
Study results updated
Version 1
13 Oct 2026, 16:31 UTC
First added · source update from Europe PMC

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