Hypothalamic reproductive endocrine pulse generator activity independent of neurokinin b and dynorphin signaling
Author(s)
Type
Journal Article
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.
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.
Date Issued
2019-10-01
Date Acceptance
2019-05-21
Citation
Journal of Clinical Endocrinology and Metabolism (JCEM), 2019, 104 (10), pp.4304-4318
ISSN
0021-972X
Publisher
Oxford University Press
Start Page
4304
End Page
4318
Journal / Book Title
Journal of Clinical Endocrinology and Metabolism (JCEM)
Volume
104
Issue
10
Copyright Statement
Copyright © 2019 Endocrine Society
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/31132118
PII: 5498036
Subjects
ARCUATE NUCLEUS
Endocrinology & Metabolism
FREE ALPHA-SUBUNIT
GONADOTROPIN-RELEASING-HORMONE
IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM
KISSPEPTIN NEURONS
Life Sciences & Biomedicine
LUTEINIZING-HORMONE
OPTOGENETIC ACTIVATION
RECEPTOR ANTAGONISM
Science & Technology
SEXUAL-MATURATION
SMELL IDENTIFICATION TEST
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2019-05-27