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

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.

Definition of the hypothalamic GnRH pulse generator in mice

“…It remains that the mechanisms responsible for the synchronization of ARN KISS neurons are unknown. Similarly, it is unclear how gonadal steroids and neuronal inputs proposed to mediate multiple different homeostatic and external influences upon pulsatility (14) interact with ARN KISS neurons. It is expected that the further elucidation of both the intra-and intercellular mechanics of the ARN KISS pulse generator will provide a robust framework for advancing strategies aimed at regulating LH pulse frequency in the clinic.…”

“…Humans and rodents with global deletions or mutations in kisspeptin or the kisspeptin receptor fail to exhibit normal pulsatile luteinizing hormone (LH) secretion (9,10,12,13). Of the two kisspeptin neuron populations that innervate GnRH neurons, particular attention has focused upon the arcuate nucleus kisspeptin (ARN KISS ) neurons in terms of pulse generation (14,15). Investigators have shown that ARN KISS neurons coexpress a variety of different neurotransmitters, including glutamate, neurokinin B, and dynorphin (15,16), for which these cells also express functional receptors (17,18).…”

Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility

“…The endocrine components of the reproductive system are hierarchically organized and integrated in a classical endocrine feedback loop. The HPG axis is active during development and shortly after birth, silenced during childhood by inhibitory neurotransmitters, and reawakened at the onset of puberty by pulsatile secretion of gonadotropin-releasing hormone (GnRH), a decapeptide that is synthesized by neurons located in the mediobasal hypothalamus (2,3). During development, GnRH neurons originate from the olfactory placode of the olfactory system and migrate to the hypothalamus, where they control reproduction by secreting GnRH into a capillary network that transmits GnRH to the anterior pituitary to stimulate secretion of follicle-stimulating hormone (FSH, encoded by Fshb) and luteinizing hormone (LH, encoded by Lhb).…”

Congenital Adrenal Hyperplasia

“…Multiple neuroendocrine and environmental signals influence the function of the GnRH neurons. 51 GnRH pulse frequency is deciphered by the pituitary to generate preferential LH or FSH secretion. Indeed LH secretion has been used as a proximate indicator of GnRH pulses.…”