Review
Control of GnRH secretion: One step back

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Abstract

The reproductive system is controlled by gonadotropin releasing hormone (GnRH) secretion from the brain, which is finely modulated by a number of factors including gonadal sex steroids. GnRH cells do not express estrogen receptor α, but feedback is transmitted by neurons that are at least ‘one step back’ from the GnRH cells. Modulation by season, stress and nutrition are effected by neuronal pathways that converge on the GnRH cells. Kisspeptin and gonadotropin inhibitory hormone (GnIH) neurons are regulators of GnRH secretion, the former being a major conduit for transmission of sex steroid feedback. GnIH cells project to GnRH cells and may play a role in the seasonal changes in reproductive activity in sheep. GnIH also modulates the action of GnRH at the level of the pituitary gonadotrope. This review focuses on the role that kisspeptin and GnIH neurons play, as modulators that are ‘one step back’ from GnRH neurons.

Research highlights

Kisspeptin cells express estrogen and progesterone receptors and relay feedback to GnRH cells. ► Kisspeptin cells also produce dynorphin and neurokinin B, which regulate GnRH cells. ► Gonadotropin inhibitory hormone (GnIH) negatively regulates GnRH cells. ► GnIH is a powerful negative regulator of pituitary gonadotropes. ► GnIH increases feeding; it may be a molecular switch for reproduction vs feeding.

Introduction

The original finding of Harris [53], that electrical stimulation of the brain caused ovulation in the rabbit, instigated his lifelong mission to delineate the means by which pituitary gonadotropin secretion is stimulated. This culminated in the development of the neurohumoral theory [54] which relies upon a unique anatomical arrangement in the median eminence and a highly efficient conduit of multiple signals from various types of hypothalamic cells to their respective target cells in the anterior pituitary. The early work of Harris and others, which led to the formulation of the neurohumoral theory was well reviewed by Donovan [42] in an earlier Harris Memorial Lecture.

Whereas it became apparent that neurohumoral factors were produced by the hypothalamus and reached the anterior pituitary gland by way of the hypophysial portal blood system, it was not until the chemical identification of such factors that proof of such ‘messengers’ was obtained. The purification of thyrotropin releasing hormone (TRH) [14], [16] from hypothalamic extracts was closely followed by discovery of gonadotropin releasing hormone (GnRH) [2], [86], [107]. Proof of secretion of GnRH into the portal system was provided by the technically challenging studies of Fink and colleagues [106]. Original work in the non-human primate provided evidence that the pattern of secretion of luteinizing hormone (LH) was pulsatile [40]. Ultimately, the exact relationship between the secretion of GnRH and that of LH from the pituitary was revealed with the creation of a model in sheep that allowed concomitant serial sampling of hypophysial portal blood and jugular venous blood in conscious, sentient sheep [20], [29]. This allowed the full description of the hypothalamo-pituitary–gonadal (HPG) axis, outlining how GnRH action is modulated at the level of the pituitary gonadotrope and how feedback effects of gonadal hormones modulate the secretion of GnRH and the gonadotrophins [23]. The measurement of GnRH secretion also allowed definition of physiological and environmental factors that regulate reproduction at the level of the GnRH system. This included revelation of the effects of gonadectomy [20], photoperiod/season [72], stress [92], stress levels of cortisol [89], immune response [69] and gonadal steroid feedback [25], [71] on GnRH secretion. One of the most fundamental aspects of the operation of the HPG axis is the means by which sex steroids act to modulate GnRH secretion and this took some time to resolve. Since GnRH cells do not possess the relevant sex steroid receptors [57], significant efforts were made in various laboratories and species over decades (1970s to 2003) to identify steroid-receptive elements in the brain that relayed feedback information to the GnRH cells. Various cell types were found to express estrogen, progesterone and androgen receptors, but evidence of a major conduit remained elusive [127]. A significant advance was the discovery that the kisspeptin receptor (and by implication, its ligand, kisspeptin) was essential for normal reproduction [39], [108]. Intense investigation over the past 7 years strongly suggests that sex steroid feedback regulation of GnRH cells is predominantly exerted via kisspeptin cells, although many other cell types in the brain also play a role. These cells are at least ‘one step back’ from the GnRH cells, allowing for integration of information of steroid feedback, season, stress, immune status, nutritional status, etc. to be synthesized by the GnRH cells and converted to a singular output of the brain that drives the reproductive system. Thus, serial and neuronal systems converge on the GnRH cells to determine the output of these cells in terms of secretion.

A major focus of this review is the role of kisspeptin in the regulation of the GnRH system, especially in relation to work done in the ovine model. The reader is also referred to other recent reviews on the function of kisspeptin [19], [90], [112]. Another recently recognized modulator of reproductive function is gonadotropin inhibitory hormone (GnIH). Whereas the prevailing view was that the secretion of GnRH was the singular means by which the brain controls the reproductive system, the existence of an inhibitory system was also entertained. Gonadal factors such as luteinizing hormone release-inhibiting factor (LHRIF) [62] were proposed. Another inhibitory factor, gonadotropin surge inhibiting factor (GnSIF) [37], suppresses LH secretion with or without any effect on FSH. This latter is a protein produced by ovarian follicles, not the brain [83], but there was no convincing evidence of hypothalamic factor that negatively regulated the reproductive axis until 2000. The discovery that GnIH was present in the hypothalamus of the quail [131] and that it acted as a negative regulator of reproduction was, therefore, an important advance in our knowledge. Whilst evidence that GnIH is an important facet of the HPG axis in mammals has been tardy, work over the last few years has escalated its importance. Like kisspeptin, GnIH is an RF-amide peptide and it exerts negative effects on GnRH cells [43] and, at least in some species, the gonadotropes [33]. Recent and extensive reviews on the role of GnIH in mammals are also available [32], [77], [111], [129], [130] and this review will focus mainly on work in relation to GnIH function that has been carried out in sheep. The following review will consider the evidence that GnIH cells are also ‘one step back’ from GnRH cells and play a major role in the regulation of GnRH secretion as well as acting on the pituitary gonadotropes, in sheep at least, to negatively regulate gonadotropin synthesis and secretion.

Section snippets

Inherent properties of GnRH cells

Andrew and Dudek [5] showed that magnocellular neuroendocrine cells possess inherent phasic firing patterns [5] and this was extended to a demonstration of the same in GnRH cells when the ‘labeling’ of cells by incorporation of green fluorescent protein genes through transgenics provided a means of recording from single units in vitro [79]. Others showed that multi-unit activity of the hypothalamus correlated with pulsatile LH secretion in rats [74], sheep [126] and non-human primates [138].

Regulation of GnRH cells by neuronal systems within the brain

Given that GnRH cells operate in a phasic manner, the modulation of ultradian secretion becomes highly relevant, since this dictates reproductive function. Such a system allows for alterations in frequency and amplitude with exquisite precision; variation in these two parameters allows very fine tuning of GnRH output. The question then becomes one of how such modulation is effected. Afferents neurons that provide either direct or indirect input to GnRH cell bodies are important in this regard,

Kisspeptin

As indicated above, the revelation that kisspeptins and the kisspeptin receptor GPR54 are essential for reproductive function was a major advance in reproductive neuroendocrinology. Hereafter in this review (unless stated otherwise), ‘kisspeptin’ will refer to the 10-amino acid form, although it is recognized that larger forms of the post-translational product of the Kiss1 gene are equally effective [65], [75]. Mass spectrometry analysis of the arcuate nucleus of the sheep brain indicates the

Gonadotropin inhibitory hormone (GnIH)

GnIH was identified as an hypothalamic factor that inhibits the HPG axis in the quail [131] and a large body of work has established this is as a bone fide regulatory peptide in avian species [128]. Original work by Hinuma et al. [60] identified the GnIH gene in mammals at the same time, but invoked a role in the control of prolactin secretion. The presence of orthologues of GnIH in the brains of various species as now been reported [32], [111]. These have been named RF-amide related peptides

Conclusions

In the last decade, the emergence of kisspeptin and GnIH as major neuroendocrine regulators of reproduction, the latter having gained acceptance only in the last few years. This has led to a significant revision of our understanding as to how reproduction is controlled by the brain, especially through the feedback effects of gonadal steroids. The accumulated data on the role of kisspeptin is far more extensive than that for GnIH and further work is required to understand the degree to which

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