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

S Narayanaswamy, JK Prague… - The Journal of …, 2016 - academic.oup.com
S Narayanaswamy, JK Prague, CN Jayasena, DA Papadopoulou, M Mizamtsidi, AJ Shah…
The Journal of Clinical Endocrinology & Metabolism, 2016academic.oup.com
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 …
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.
Oxford University Press