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  1. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] The Role of Kiss1 Neurons As Integrators of Endocrine, Metabolic, and Environmental Factors in the Hypothalamic-Pituitary-Gonadal Axis

    Kisspeptin-GPR54 signaling in the hypothalamus is required for reproduction and fertility in mammals. Kiss1 neurons are key regulators of gonadotropin-releasing hormone (GnRH) release and modulation of the hypothalamic-pituitary-gonadal (HPG) axis.

    Arcuate Kiss1 neurons project to GnRH nerve terminals in the median eminence, orchestrating the pulsatile secretion of luteinizing hormone (LH) through the intricate interaction between GnRH pulse frequency and the pituitary gonadotrophs.

    Arcuate Kiss1 neurons, also known as KNDy neurons in rodents and ruminants because of their co-expression of neurokinin B and dynorphin represent an ideal hub to receive afferent inputs from other brain regions in response to physiological and environmental changes, which can regulate the HPG axis.

    This review will focus on studies performed primarily in rodent and ruminant species to explore potential afferent inputs to Kiss1 neurons with emphasis on the arcuate region but also considering the rostral periventricular region of the third ventricle (RP3V).

    Specifically, we will discuss how these inputs can be modulated by hormonal, metabolic, and environmental factors to control gonadotropin secretion and fertility. We also summarize the methods and techniques that can be used to study functional inputs into Kiss1 neurons.

    Yeo SH, Colledge WH. The Role of Kiss1 Neurons As Integrators of Endocrine, Metabolic, and Environmental Factors in the Hypothalamic-Pituitary-Gonadal Axis. Frontiers in endocrinology 2018;9:188. https://www.frontiersin.org/articles/10.3389/fendo.2018.00188/full
     
  2. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] Comninos AN, Dhillo WS. Emerging Roles of Kisspeptin in Sexual and Emotional Brain Processing. Neuroendocrinology 2018;106:195-202. Emerging Roles of Kisspeptin in Sexual and Emotional Brain Processing

    The emergence of kisspeptin as a crucial regulator of the hypothalamo-pituitary-gonadal (HPG) axis over the last 14 years has answered many questions as to the control of reproductive hormone secretion from the hypothalamus.

    More recently, the role of kisspeptin outside the HPG axis has received increasing attention in the hope of delineating the pathways linking various sensory and social behaviours to reproduction.

    These studies, in a range of species from zebrafish to humans, have identified a role for kisspeptin in behavioural networks related to reproduction including olfaction, audition, fear, anxiety, mood, and sexual arousal.

    The available evidence suggests that extrahypothalamic kisspeptin signalling encourages positive aspects of emotional and sexual brain processing in a presumed drive towards reproduction and ultimately maintenance of the species at a population level.

    In this review, we examine these studies, which collectively propose that kisspeptin may integrate sexual and emotional brain processing with the control of the HPG axis.

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  3. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] Kisspeptin and the Control of Emotions, Mood and Reproductive Behaviour

    Reproduction is fundamental for the survival of all species and requires meticulous synchronisation of a diverse complement of neural, endocrine and related behaviours. The reproductive hormone kisspeptin (encoded by the KISS1/kiss1 gene), is now a well-established orchestrator of reproductive hormones, acting upstream of gonadotrophin releasing hormone (GnRH) at the apex of the hypothalamic-pituitary-gonadal (HPG) reproductive axis.

    Beyond the hypothalamus, kisspeptin is also expressed in limbic and paralimbic brain regions, which are areas of the neurobiological network implicated in sexual and emotional behaviours. We are now forming a more comprehensive appreciation of extra-hypothalamic kisspeptin signalling and the complex role of kisspeptin as an upstream mediator of reproductive behaviours, including olfactory-driven partner preference, copulatory behaviour, audition, mood and emotion. An increasing body of research from zebrafish to humans has implicated kisspeptin in the integration of reproductive hormones with an overall positive influence on these reproductive behaviours.

    In this review, we critically appraise the current literature regarding kisspeptin and its control of reproductive behaviour. Collectively, these data significantly enhance our understanding of the integration of reproductive hormones and behaviour and provide the foundation for kisspeptin-based therapies to treat related disorders of body and mind.

    Mills EG, Dhillo WS, Comninos AN. Kisspeptin and the control of emotions, mood and reproductive behaviour. Journal of Endocrinology 2018. Kisspeptin and the control of emotions, mood and reproductive behaviour
     
  4. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] The Role of Kisspeptin Neurons in Reproduction and Metabolism

    Kisspeptin is a neuropeptide with a critical role in the function of the hypothalamic–pituitary–gonadal (HPG) axis. Kisspeptin is produced by two major populations of neurons located in the hypothalamus, the rostral periventricular region of the third ventricle (RP3V) and arcuate nucleus (ARC).

    These neurons project to and activate gonadotrophin-releasing hormone (GnRH) neurons (acting via the kisspeptin receptor, Kiss1r) in the hypothalamus and stimulate the secretion of GnRH.

    Gonadal sex steroids stimulate kisspeptin neurons in the RP3V, but inhibit kisspeptin neurons in the ARC, which is the underlying mechanism for positive- and negative feedback respectively, and it is now commonly accepted that the ARC kisspeptin neurons act as the GnRH pulse generator.

    Due to kisspeptin’s profound effect on the HPG axis, a focus of recent research has been on afferent inputs to kisspeptin neurons and one specific area of interest has been energy balance, which is thought to facilitate effects such as suppressing fertility in those with under- or severe over-nutrition.

    Alternatively, evidence is building for a direct role for kisspeptin in regulating energy balance and metabolism. Kiss1r-knockout (KO) mice exhibit increased adiposity and reduced energy expenditure.

    Although the mechanisms underlying these observations are currently unknown, Kiss1r is expressed in adipose tissue and potentially brown adipose tissue (BAT) and Kiss1rKO mice exhibit reduced energy expenditure.

    Recent studies are now looking at the effects of kisspeptin signalling on behaviour, with clinical evidence emerging of kisspeptin affecting sexual behaviour, further investigation of potential neuronal pathways are warranted.

    Harter CJL, Kavanagh GS, Smith JT. The role of kisspeptin neurons in reproduction and metabolism. Journal of Endocrinology 2018;238:R173-R83. The role of kisspeptin neurons in reproduction and metabolism
     
  5. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Trevisan CM, Montagna E, de Oliveira R, et al. Kisspeptin/GPR54 System: What Do We Know About Its Role in Human Reproduction? Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology 2018;49:1259-76. Kisspeptin/GPR54 System: What Do We Know About Its Role in Human Reproduction?

    Kisspeptin is involved in the control of human reproduction bridging the gap between the sex steroid levels and feedback mechanisms that control the gonadotropin releasing hormone (GnRH) secretion; however, studies considering this peptide and infertility are limited.

    We conducted a review and critical assessment of available evidence considering kisspeptin structure, physiology, function in puberty and reproduction, its role in assisted reproduction treatments, kisspeptin dosage and the impact on KISS1 and GPR54 genes.

    Literature searches were conducted in PubMed using keywords related to:
    (i) kisspeptin or receptors, kisspeptin-1
    (ii) reproduction or infertility or fertility
    (iii) gene and
    (iv) dosage or measurement or quantification or serum level, in human.

    Kisspeptin is a product of KISS1 gene that binds to a G-protein-coupled receptor (GPR54/KISS1R) stimulating the release of GnRH by hypothalamic neurons, leading to secretion of pituitary gonadotropins (LH and FSH) and sexual steroids, which in turn will act in the gonads to produce the gametes.

    Kisspeptin is being recognized as a crucial regulator of the onset of puberty, the regulation of sex hormone mediated secretion of gonadotropins, and the control of fertility. Inactivating and activating mutations in both KISS1 or GPR54 genes were associated with hypogonadotropic hypogonadism and precocious puberty.

    Despite this, studies considering kisspeptin and infertility are scarce. The understanding of the role of kisspeptin may lead to its use as a biomarker in infertility treatments and use in controlled ovarian hyperstimulation.
     
  6. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] The Roles of Kisspeptin In the Mechanism Underlying Reproductive Functions In Mammals

    Kisspeptin, identified as a natural ligand of GPR54 in 2001, is now considered as a master regulator of puberty and subsequent reproductive functions in mammals. Our previous studies using Kiss1 knockout (KO) rats clearly demonstrated the indispensable role of kisspeptin in gonadotropin-releasing hormone (GnRH)/gonadotropin secretion. In addition, behavioral analyses of Kiss1 KO rats revealed an organizational effect of kisspeptin on neural circuits controlling sexual behaviors.

    Our studies using transgenic mice carrying a region-specific Kiss1 enhancer-driven reporter gene provided a clue as to the mechanism by which estrogen regulates Kiss1 expression in hypothalamic kisspeptin neurons. Analyses of Kiss1 expression and gonadotropin secretion during the pubertal transition shed light on the mechanism triggering GnRH/gonadotropin secretion at the onset of puberty in rats.

    Here, we summarize data obtained from the aforementioned studies and revisit the physiological roles of kisspeptin in the mechanism underlying reproductive functions in mammals.

    Uenoyama Y, Inoue N, Maeda K-i, Tsukamura H. The roles of kisspeptin in the mechanism underlying reproductive functions in mammals. Journal of Reproduction and Development 2018;advpub. The roles of kisspeptin in the mechanism underlying reproductive functions in mammals
     
  7. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] The Multiple Facets of Kisspeptin Activity in Biological Systems

    In 1996, as part of a screen for anti-metastatic genes, a novel gene termed Kiss1 was found to be expressed in non-metastatic melanoma cell lines (1). Its 54 amino-acid product, Kisspeptin-54 (Kp-54), was originally called metastin for its ability to inhibit cancer metastasis through the activation of a G protein coupled receptor, previously known as GPR54, and currently renamed the Kisspeptin receptor (KISS1R) (2, 3).

    Kp-54 is the longest cleavage product of the Kisspeptin precursor protein, but there are shorter active peptides [i.e., Kp-14, Kp-13, and Kp-10], all capable of binding to KISS1R (3). Since the tissue distribution of KISS1R was very similar in mammalian and non-mammalian vertebrates, especially in the brain, it was suggested that kisspeptins not only acted as metastasis suppressors, but also were a new family of evolutionarily conserved biological modulators (4).

    In both rodents and humans, genetic ablation or inactivating mutations of the Kiss1/Kiss1R genes cause lack of sexual maturation and hypogonadotropic hypogonadism. Conversely, functionally activating mutations of Kiss1/Kiss1R genes cause precocious puberty (5, 6).

    Thus, most studies have focused on the involvement of Kisspeptin activity in the central control of reproduction, through the regulation of hypothalamic Gonadotropin Releasing Hormone (GnRH) neurons, which depends on the hormonal milieu, energy homeostasis, and environmental factors (7).

    The twelve articles in this Research Topic provide a comprehensive insight into the wider physiological actions of Kisspeptin beyond the reproductive system including cancer, metabolism and neuroscience and also highlight the role of Kisspeptins in non-mammalian species.

    Chianese R, Colledge WH, Fasano S, Meccariello R. Editorial: The Multiple Facets of Kisspeptin Activity in Biological Systems. Frontiers in endocrinology 2018;9:727. Editorial: The Multiple Facets of Kisspeptin Activity in Biological Systems
     
  8. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Nishizawa N, Asami T, Nishibori K, et al. A new class of pentapeptide KISS1 receptor agonists with hypothalamic-pituitary-gonadal axis activation. Bioorganic & medicinal chemistry letters 2018. https://www.sciencedirect.com/science/article/pii/S0960894X18309508?via=ihub

    The kisspeptin (Kp, Kp-54, metastin)/KISS1R system plays crucial roles in regulating the secretion of gonadotropin-releasing hormone.

    Continuous administration of nonapeptide Kp analogs caused plasma testosterone depletion, whereas bolus administration caused strong plasma testosterone elevation in male rats.

    To develop a new class of small peptide drugs, we focused on stepwise N-terminal truncation of Kp analogs and discovered potent pentapeptide analogs. Benzoyl-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (16) exhibited high agonist activity for KISS1R and excellent metabolic stability in rat serum.

    A single injection of a 4-pyridyl analog (19) at the N-terminus of 16 into male Sprague Dawley rats caused a robust increase in plasma luteinizing hormone levels, but unlike continuous administration of nonapeptide Kp analogs, continuous administration of 19 maintained moderate testosterone levels in rats.

    These results indicated that small peptide drugs can be successfully developed for treating sex hormone deficiency.
     
  9. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Moore AM, Coolen LM, Porter DT, Goodman RL, Lehman MN. KNDy Cells Revisited. Endocrinology 2018;159:3219-34. KNDy Cells Revisited

    In the past decade since kisspeptin/neurokinin B/dynorphin (KNDy) cells were first identified in the mammalian hypothalamus, a plethora of new research has emerged adding insights into the role of this neuronal population in reproductive neuroendocrine function, including the basis for GnRH pulse generation and the mechanisms underlying the steroid feedback control of GnRH secretion.

    In this mini-review, we provide an update of evidence regarding the roles of KNDy peptides and their postsynaptic receptors in producing episodic GnRH release and assess the relative contribution of KNDy neurons to the "GnRH pulse generator." In addition, we examine recent work investigating the role of KNDy neurons as mediators of steroid hormone negative feedback and review evidence for their involvement in the preovulatory GnRH/LH surge, taking into account species differences that exist among rodents, ruminants, and primates.

    Finally, we summarize emerging roles of KNDy neurons in other aspects of reproductive function and in nonreproductive functions and discuss critical unresolved questions in our understanding of KNDy neurobiology.
     
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  10. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Mechanism of Pulsatile GnRH Release in Primates: Unresolved Questions

    Highlights
    · Pulsatile release of GnRH is indispensable for reproductive function.
    · This article reviews current concept and unresolved issues on the mechanism of GnRH pulse generation.

    The pulsatility of GnRH release is essential for reproductive function. The key events in reproductive function, such as puberty onset and ovulatory cycles, are regulated by the frequency and amplitude modulation of pulsatile GnRH release. Abnormal patterns of GnRH pulsatility are seen in association with disease states, such as polycystic ovarian syndrome and anorexia nervosa.

    Recent studies with physiological, track-tracing, optogenetic and electrophysiological recording experiments indicate that a group of kisspeptin neurons in the arcuate nucleus (ARC) of the hypothalamus are responsible for pulsatile GnRH release.

    Thus, the kisspeptin neuron in the ARC has been called the “GnRH pulse-generator.” However, a few pieces of evidence do not quite fit into this concept. This article reviews some old works and discusses unresolved issues on the mechanism of GnRH pulse generation.

    Terasawa E. Mechanism of pulsatile GnRH release in primates: Unresolved questions. Molecular and cellular endocrinology 2019:110578. http://www.sciencedirect.com/science/article/pii/S0303720719302801
     

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