Hypothalamic reproductive endocrine pulse generator activity independent of neurokinin B and dynorphin signaling

Research output: Contribution to journalArticle

Authors

  • Margaret F Lippincott
  • Silvia León
  • Yee-ming Chan
  • Chrysanthi Fergani
  • Rajae Talbi
  • I Sadaf Farooqi
  • Christopher M Jones
  • Susan E Stewart
  • Trevor R Cole
  • Ei Terasawa
  • Janet E Hall
  • Natalie D Shaw
  • Victor M Navarro
  • Stephanie Beth Seminara

External organisations

  • Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA
  • Division of Endocrinology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
  • Division of Endocrinology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA
  • University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom
  • Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin
  • Wisconsin National Primate Research Center, Madison, Wisconsin
  • Birmingham Women's and Children's NHS Foundation Trust
  • University Hospital Birmingham NHS Foundation Trust
  • University of Leeds

Abstract

Context
Kisspeptin–neurokinin B (NKB)–dynorphin neurons are critical regulators of the hypothalamic–pituitary–gonadal axis. NKB and dynorphin are hypothesized to influence the frequency of GnRH pulses, whereas kisspeptin is hypothesized to be a generator of the GnRH pulse. How these neuropeptides interact remains unclear.
Objective
To probe the role of NKB in GnRH pulse generation and to determine the interactions between NKB, kisspeptin, and dynorphin in humans and mice with a complete absence of NKB.
Design
Case/control.
Setting
Academic medical center.
Participants
Members of a consanguineous family bearing biallelic loss-of-function mutations in the gene encoding NKB and NKB-deficient mice.
Interventions
Frequent blood sampling to characterize neuroendocrine profile and administration of kisspeptin, GnRH, and naloxone, a nonspecific opioid receptor antagonist used to block dynorphin.
Main Outcome Measures
LH pulse characteristics.
Results
Humans lacking NKB demonstrate slow LH pulse frequency, which can be increased by opioid antagonism. Mice lacking NKB also demonstrate impaired LH secretion, which can be augmented with an identical pharmacologic manipulation. Both mice and humans with NKB deficiency respond to exogenous kisspeptin.
Conclusion
The preservation of LH pulses in the absence of NKB and dynorphin signaling suggests that both peptides are dispensable for GnRH pulse generation and kisspeptin responsiveness. However, NKB and dynorphin appear to have opposing roles in the modulation of GnRH pulse frequency.

Details

Original languageEnglish
Pages (from-to)4304-4318
Number of pages15
JournalJournal of Clinical Endocrinology and Metabolism
Volume104
Issue number10
Early online date27 May 2019
Publication statusPublished - 1 Oct 2019