Continuous kisspeptin restores luteinizing hormone pulsatility following cessation by a neurokinin b antagonist in female sheep

Iain J. Clarke, Qun Li, Belinda A. Henry, Robert P. Millar

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Pulsatile secretion of the gonadotropin-releasing hormone (GnRH) drives pulsatile secretion of the luteinizing hormone (LH), with evidence that this depends on kisspeptin (Kiss) input to GnRH neurons. Kiss administration causes acute GnRH/LH secretion, and electrophysiological data suggest that Kiss neurons may act in a phasic manner to drive GnRH secretion, but there is not definitive evidence for this. The product of the Kiss-1 gene is proteolytically cleaved to smaller products, and the 10 amino acid C-terminal product (Kiss-10) displays full bioactivity. We have shown previously that continuous delivery of Kiss-10 to anestrous ewes can cause a surge in GnRH secretion and ovulation and increases LH pulse frequency in humans. Here, we tested the hypothesis that continuous Kiss-10 delivery can support pulsatile GnRH/LH secretion in the sheep. Neurokinin B (NKB) provides positive drive to Kiss neurons, so we therefore infused an NKB antagonist (ANT-08) intracerebroventricularly to induce cessation of pulsatile GnRH/LH secretion, with or without concomitant continuous Kiss-10 infusion. ANT-08 suppressed GnRH/LH pulsatility, which was immediately restored with continuous Kiss-10 infusion. These data support the notion that Kiss-10 action is downstream of NKB signaling and that continuous Kiss-10 stimulation of GnRH neurons is sufficient to support a pulsatile pattern of GnRH/LH secretion. This offers further support to the theory that GnRH pulse generation is intrinsic to GnRH neurons and that pulsatile GnRH release can be affected with continuous stimulation by Kiss-10. (Endocrinology 159: 639–646, 2018)

Original languageEnglish
Pages (from-to)639-646
Number of pages8
Issue number2
Publication statusPublished - 1 Feb 2018

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