Review Article | Published:

Control of puberty onset and fertility by gonadotropin-releasing hormone neurons

Nature Reviews Endocrinology volume 12, pages 452466 (2016) | Download Citation

Abstract

The gonadotropin-releasing hormone (GnRH) neuronal network generates pulse and surge modes of gonadotropin secretion critical for puberty and fertility. The arcuate nucleus kisspeptin neurons that innervate the projections of GnRH neurons in and around their neurosecretory zone are key components of the pulse generator in all mammals. By contrast, kisspeptin neurons located in the preoptic area project to GnRH neuron cell bodies and proximal dendrites and are involved in surge generation in female rodents (and possibly other species). The hypothalamic–pituitary–gonadal axis develops embryonically but, apart from short periods of activation immediately after birth, remains suppressed through a combination of gonadal and non-gonadal mechanisms. At puberty onset, the pulse generator reactivates, probably owing to progressive stimulatory influences on GnRH neurons from glial and neurotransmitter signalling, and the re-emergence of stimulatory arcuate kisspeptin input. In females, the development of pulsatile gonadotropin secretion enables final maturation of the surge generator that ultimately triggers the first ovulation. Representation of the GnRH neuronal network as a series of interlocking functional modules could help conceptualization of its functioning in different species. Insights into pulse and surge generation are expected to aid development of therapeutic strategies ameliorating pubertal disorders and infertility in the clinic.

Key points

  • Gonadotropin-releasing hormone (GnRH) neurons exhibit many unique morphological features, including a blended dendrite–axon (dendron) that projects to the median eminence to secrete GnRH into the pituitary portal system

  • Kisspeptin neurons in the arcuate nucleus probably represent a key component of an extrinsic pulse generator that drives pulsatile GnRH secretion in all mammals

  • The preovulatory luteinizing hormone surge is driven by high follicular-phase oestradiol levels that act variably upon the neuronal surge generator and the pituitary gland among spontaneously ovulating mammals

  • Re-emergence of pulsatile GnRH secretion at puberty requires gonadal and non-gonadal mechanisms involving linear maturation of glial and afferent inputs alongside the resurgence of an excitatory kisspeptin input

  • The GnRH neuronal network can be represented by a hierarchical modular design in which functional modules appropriate to the needs of specific mammalian species can be included

  • A variety of genetic mutations affect fertility, either by altering the GnRH neuron migratory pathway or by disrupting the GnRH neuron and its key neuronal regulators

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Acknowledgements

Studies in the laboratory of A.E.H. were supported by the New Zealand Health Research Council and the Royal Society Marsden Fund. A.E.H. thanks all past and present members of his laboratory for many stimulating discussions and experimental work that has aimed to advance understanding of the gonadotropin-releasing hormone neuron. Long-standing research collaborations with U. Boehm (University of Saarland, Germany), R. Campbell (University of Otago, New Zealand), B. Colledge (University of Cambridge, UK), D. Grattan (University of Otago, New Zealand) and G. Schütz (Heidelberg University, Germany) have also been invaluable.

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  1. Centre for Neuroendocrinology and Department of Physiology, University of Otago School of Medical Sciences, Dunedin 9054, New Zealand.

    • Allan E. Herbison

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The author declares no competing financial interests.

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Correspondence to Allan E. Herbison.

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https://doi.org/10.1038/nrendo.2016.70

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