This special issue arises from symposia on GnRH and reproduction presented at the International Congress of Neuroendocrinology in Sydney, August 2014. The symposia and this special issue of Neuroendocrinology bring together a series of new aspects of GnRH research encompassing fundamental studies on the regulation of the GnRH neuron at a molecular and electrophysiological level, through studies on pulsatile gene expression in GnRH-promoter-luciferase transgenic mice, impacts of novel guidance proteins (semaphorins) on GnRH neuron migration, animal models of metabolic, immunological, bacterial and steroidogenic reproductive neuroendocrine programming, to clinical studies on the use of kisspeptin ligands to stimulate or inhibit the reproductive system.
Iremonger and Herbison [1 ]describe their recent research on GnRH neuron dendrites and suggest that GnRH neurons have unique projections to the medium eminence which have both dendritic and axonal properties. This intriguing discovery proposes that this projection (dubbed ‘dendron') facilitates GnRH neurons to ‘multitask and integrate information in ways that would not be possible in a classically envisioned axon projection'. This discovery and proposal promise to revolutionize our understanding of the mechanism of GnRH neuron regulation of reproduction.
Rønnekleiv et al. [2] address the role of ion channels in mediating the effects of estradiol on GnRH and kisspeptin neuron excitability. While the role of kisspeptin as a mediator of estradiol effects on the GnRH neuron is well established, the mechanism whereby estradiol increases the excitability of kisspeptin neurons is poorly understood. Moreover, estradiol acts pre- and postsynaptically on GnRH neurons to upregulate ion channel transcripts which mediate not only the excitability of kisspeptin neurons but also the downstream signaling of kisspeptin on GnRH neurons. Although GnRH neurons appear not to express estrogen nuclear receptor α (ERα), these investigators show that 17β-estradiol and a ligand (STX) for a putative membrane ER, both have membrane-initiated actions to alter GnRH neuron excitability by enhancing ATP-sensitive potassium channels. Their studies have extended our understanding of estradiol action on GnRH neurons and highlight that it modulates the excitability of both kisspeptin and GnRH neurons.
Appropriate GnRH pulse frequency is crucial for reproductive function. Although this has been recognized for many years, the specific identification of the enigmatic pulse generator and the mechanisms involved in pulse generation has not been fully elucidated. Neuron networks in the arcuate nucleus and other brain areas have been implicated. But in addition the GnRH neuron itself appears to secrete in a pulsatile manner independent of upstream regulators. Choe et al. [3] have examined cellular oscillations in individual GnRH neurons and temporal synchronization amongst GnRH neurons using GnRH promoter-driven luciferase-expressing transgenic mice. The luciferase construct is destabilized to facilitate the observation of transient GnRH gene expression. They have thereby demonstrated episodic GnRH gene transcription at the single GnRH neuron level with synchronized multicellular bursts every 2 h. This indicates that in addition to synchronized GnRH secretion there are oscillations in GnRH gene expression which can be demonstrated by the sensitive technology developed by the authors. Pulsatility of GnRH gene expression and GnRH secretion was also demonstrated by pulsatile administration of kisspeptin, but it is uncertain whether kisspeptin neurons are rhythmic in kisspeptin gene expression or secretion. The technology described offers potential for delineating mechanisms involved in GnRH pulsatility.
The role of semaphorin proteins in the development and migration of GnRH neurons is examined by Giacobini [4]. The semaphorin proteins, which contribute to the morphogenesis and homeostasis of a wide range of systems, have been extensively studied as guidance molecules. Recent research has addressed the role of semaphorins in the development of hormone systems as well as their effects on hormone secretion in adulthood. In turn, the activity of hormone systems reciprocally regulates semaphorin expression and function. Recently, research has investigated the molecular mechanisms mediating the effects of semaphorins on the migration, survival and structural and functional plasticity of GnRH neurons. Perturbations in the development of the GnRH neuroendocrine system lead to deranged or absent GnRH secretion, resulting in heterogeneous reproductive disorders such as congenital hypogonadotropic hypogonadism in humans or less overt phenotypes with infertility or subfertility. Studies on the semaphorin function in the reproductive neuroendocrine system therefore promise to be a rich area of enquiry.
Two articles address the vexing and increasing impact of early exposure during development to steroid hormones, endocrine disrupting chemicals, and infectious and inflammatory diseases on subsequent reproductive competence in adulthood. Sominsky et al. [5] investigate the potential role of the early life microbial environment in developmental programming of adult reproductive fitness. Their, and other, laboratories, have demonstrated that acute exposure to an immunological challenge early in life has a robust and prolonged impact on male and female reproductive development. They report that perinatal exposure to an immunological challenge by a bacterial endotoxin, lipopolysaccharide, acts at all levels of the hypothalamic-pituitary-gonadal axis, resulting in long-lasting changes in reproductive function. This adds to the growing literature of impacts of the microbiome on human health.
Cardoso et al. [6] describe an animal model of polycystic ovarian syndrome (PCOS) which employs prenatal exposure to testosterone excess in female sheep. This treatment modality results in adult reproductive disorders which apparently faithfully recapitulate those seen in women with PCOS such as disrupted neuroendocrine feedback mechanisms, increased pituitary sensitivity to GnRH, luteinizing hormone excess, functional hyperandrogenism, and multifollicular ovarian morphology. It also results in insulin resistance, retardation in fetal growth and hypertension. Moreover, these defects are maintained or amplified by postnatal sex steroid administration and the metabolic environment. Their review addresses the steroidal and metabolic contributions to the development and maintenance of the PCOS phenotype in the sheep model. Importantly, the study also looks at effects of prenatal and postnatal treatment with androgen antagonist and/or insulin sensitizer as potential therapies to remedy these dysfunctions.
The discovery of upstream regulators of GnRH and particularly kisspeptin has revealed a plethora of new levels, neural networks and mechanisms of GnRH control. These in turn have opened up new avenues of clinical research which have highlighted potential new therapies using kisspeptin agonists and antagonists. Prague and Dhillo [7] in the final article of this special issue review the enormous strides that have been made in clinical research with kisspeptin and analogs and their potential application. Their group together with those of Seminara and Millar have pioneered the extraordinarily rapid progress in the area. These studies have demonstrated differences in responses to kisspeptin in healthy women during the menstrual cycle, in women with hypothalamic amenorrhea, in women on different steroid hormone regimens, in postmenopausal women, and also in normal, and diabetic and obese men. Other studies have indicated kisspeptin may find application in the induction of ovulation and in normalizing testosterone in diabetic men with low testosterone. Importantly, such applications will have to take into account tachyphylaxis which has been demonstrated on prolonged high-dose kisspeptin in animals and humans. The signaling mechanisms underlying this phenomenon of desensitization have recently been reviewed [8]. This feature of tachyphylaxis has already found practical applications by the development of superactive kisspeptin agonists which are potent inhibitors of testosterone in men, as was described in a previous special issue of Neuroendocrinology [9]. These agonists suppressed LH and testosterone more rapidly and more completely than a GnRH therapeutic agonist used for prostatic cancer, which was somewhat unexpected for an upstream regulator of GnRH, thus underlining the therapeutic potential of kisspeptin analogs.
