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. 2019 Oct 1;104(10):4304-4318.
doi: 10.1210/jc.2019-00146.

Hypothalamic Reproductive Endocrine Pulse Generator Activity Independent of Neurokinin B and Dynorphin Signaling

Margaret F Lippincott  1 , Silvia León  2 , Yee-Ming Chan  1   3 , Chrysanthi Fergani  2 , Rajae Talbi  2 , I Sadaf Farooqi  4 , Christopher M Jones  5 , Wiebke Arlt  6   7   8 , Susan E Stewart  9   10 , Trevor R Cole  9   10   11 , Ei Terasawa  12   13 , Janet E Hall  1 , Natalie D Shaw  1 , Victor M Navarro  2 , Stephanie Beth Seminara  1
Affiliations

Hypothalamic Reproductive Endocrine Pulse Generator Activity Independent of Neurokinin B and Dynorphin Signaling

Margaret F Lippincott et al. J Clin Endocrinol Metab. .

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.

Trial registration: ClinicalTrials.gov NCT00914823 NCT01952782 NCT00494169.

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Figures

Figure 1.
Figure 1.
Baseline neuroendocrine profiling. (A) Study schema. (B) Study subjects with IHH who underwent 8-h sampling between 2010 and 2011. (C) Healthy sister in early follicular phase (EFP). Arrowheads indicate LH pulses detected by the algorithm. E2, estradiol; P, progesterone; q10 min, every 10 min.
Figure 2.
Figure 2.
Baseline studies with response to kisspeptin and GnRH. (A) Study schema. (B) Study subjects. Arrowheads indicate LH pulses detected by the algorithm. E2, estradiol; G, GnRH IVB (75 ng/kg); K, kp-10 by IVB (subscript indicates the dose: 1, 0.24 nmol/kg; 2, 0.72 nmol/kg; 3, 2.4 nmol/kg); q10 min, every 10 min.
Figure 3.
Figure 3.
Response to kisspeptin infusion and GnRH. (A) Study schema. (B) Study subject. Arrowheads indicate LH pulses detected by the algorithm. E2, estradiol; G, GnRH IVB (75 ng/kg); q10 min, every 10 min.
Figure 4.
Figure 4.
Neuropeptide administration with response to kisspeptin and GnRH. (A) Study schema. (B) Study subjects. Arrowheads indicate LH pulses detected by the algorithm. E2, estradiol; G, GnRH IVB (75 ng/kg); K, kp-10 by IVB (subscript indicates the dose: 1, 0.24 nmol/kg; 2, 0.72 nmol/kg; 3, 2.4 nmol/kg); q10 min, every 10 min.
Figure 5.
Figure 5.
Kisspeptin administration to Tac2 KO mice and littermate controls across sexual development. Dashed line indicates kisspeptin administration. LH values are mean ± SEM for each time point.
Figure 6.
Figure 6.
LH pulse profile (A and D) and the effects of NLX (B, C, E, and F) in adult OVX WT and Tac2 KO mice. (A and D) LH pulses 120 min before NLX injection, and 180 min after NLX injection. The NLX injection is indicated by arrows. Arrowheads indicate the LH pulses. (B and E) Changes in LH secretion (mean ± SEM) 60 min before and 120 min after NLX in WT and OVX Tac2 KO mice, respectively. (C and F) The effects of NLX treatment on LH release are also shown as mean ± SEM from 20 min before (Pre NLX) and 20 min after NLX injection (Post NLX). *P < 0.05, Student t test.
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