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

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Authors

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

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Oxford University Press

Abstract

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.

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Keywords

Gonadotropin-releasing hormone (GnRH), Luteinizing hormone (LH), Kisspeptin (Kiss), Neurokinin B (NKB), Intravenous infusion, In vivo, GnRH/LH secretion, Pulse generation, Ovariectomized ewes, Hypogonadotropic hypogonadism, Arcuate nucleus, Hypophyseal portal blood

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Citation

Clarke, I.J., Li, Q., Henry, B.A. & Millar, R.P. 2018, 'Continuous kisspeptin restores luteinizing hormone pulsatility following cessation by a neurokinin B antagonist in female sheep', Endocrinology, vol. 159, no. 2, pp. 639-646.