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Endocrine Abstracts (2016) 44 OC1.3 | DOI: 10.1530/endoabs.44.OC1.3

1Imperial College, London, UK; 2Statsconsultancy Ltd, Amersham, Buckinghamshire, UK; 3Mayo Clinic, Rochester, Minnesota, USA.

Background: Hypothalamic KNDy neurons have recently been identified as key regulators of reproductive function by releasing three neuropeptides namely kisspeptin, neurokinin B (NKB) and dynorphin. Animal studies show they interact to control pulsatile GnRH release, which is vital for fertility. In animals, kisspeptin stimulates, NKB modulates and the opioid dynorphin inhibits GnRH pulsatility. However, the interaction of these peptides has never been studied in humans. To investigate the importance of KNDy neuropeptides for the first time in humans, we assessed the effects of co-administration of kisspeptin-54, NKB and an opioid antagonist naltrexone on LH pulsatility (a surrogate marker of GnRH pulsatility) and gonadotrophin release.

Methods: We conducted an ethically approved prospective, single-blinded placebo-controlled study. Healthy male volunteers (n=5/group) attended our research facility for 8 study visits and received a different treatment intervention at each visit: oral 50 mg naltrexone (NAL), 8 h intravenous infusions of vehicle, 2.56 nmol/kg per h NKB (NKB) or 0.1 nmol/kg per h kissspeptin-54 (KP) alone and in combination. The treatment intervention was started after 1 h of baseline blood sampling. Frequent blood sampling to measure serum gonadotrophins and sex steroids was conducted for 8 h. LH pulsatility was determined using blinded deconvolution analysis.

Results: All kisspeptin and naltrexone containing groups potently increased serum LH and LH pulsatility (P<0.001 vs vehicle). NKB alone did not affect serum gonadotrophin levels. NKB+KP had significantly smaller increases in gonadotrophin levels when compared with kisspeptin alone (P<0.01). NAL+KP was the only combination to significantly increase LH pulse amplitude (P<0.001 vs vehicle).

Conclusions: Our results show for the first time in humans significant interactions between the KNDy neuropeptides on LH pulsatility and gonadotrophin release in humans. This data has important implications for improving our understanding of GnRH pulse generation and therapeutic implications for treating patients with reproductive failure and infertility.

Volume 44

Society for Endocrinology BES 2016

Brighton, UK
07 Nov 2016 - 09 Nov 2016

Society for Endocrinology 

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