Hypothalamic Reproductive Endocrine Pulse Generator Activity Independent of Neurokinin B and Dynorphin Signaling
Hypothalamic Reproductive Endocrine Pulse Generator Activity Independent of Neurokinin B and Dynorphin Signaling
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DOI：
10.1210/jc.2019-00146
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发表时间：
2019-10-01
影响因子：
5.8
通讯作者：
Seminara, Stephanie Beth
中科院分区：
文献类型：
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作者：
Lippincott, Margaret F.;Leon, Silvia;Seminara, Stephanie Beth
背景：Kispeptin-Neurokinin B(NKB)-强啡肽神经元是下丘脑-垂体-性腺轴的关键调节者。NKB和强啡肽被假设为影响GnRH脉冲的频率，而Kispeptin被假设为GnRH脉冲的生成器。目的：探讨NKB在促性腺激素释放激素(GnRH)脉冲生成中的作用，并在完全缺乏NKB的人和小鼠中确定NKB、Kispeptin和强啡肽之间的相互作用。设计：病例/对照。背景：学术医学中心。参与者：NKB编码基因双等位功能丧失突变的血缘家族成员和NKB缺陷小鼠。干预：频繁采血以表征神经内分泌特征和应用Kispeptin、GnRH和纳洛酮(一种用于阻断强啡肽的非特异性阿片受体拮抗剂)。主要观察指标：LH脉特征。结果：缺乏NKB的人表现出缓慢的LH脉频率，以及NKB缺陷小鼠。阿片类拮抗剂可以增加这种作用。缺乏NKB的小鼠也表现出促黄体生成素分泌受损，这种分泌可以通过相同的药物操作来增强。结论：在没有NKB和强啡肽信号的情况下，黄体生成素脉冲的保存表明，这两种多肽对GnRH脉冲的产生和对Kispeptin的反应性都是必不可少的。然而，NKB和强啡肽在GnRH脉冲频率的调制中似乎具有相反的作用。
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.