Kisspeptin Signaling in Reproductive Biology
http://link.springer.com/book/10.1007/978-1-4614-6199-9/page/1
http://link.springer.com/book/10.1007/978-1-4614-6199-9/page/1
MESO-Rx
Anabolic Steroids
Kisspeptin
- Thread starter The_Skeptic
- Start date
Kanda S, Akazome Y, Mitani Y, Okubo K, Oka Y. Neuroanatomical evidence that kisspeptin directly regulates isotocin and vasotocin neurons. PLoS One 2013;8(4):e62776. PLOS ONE: Neuroanatomical Evidence That Kisspeptin Directly Regulates Isotocin and Vasotocin Neurons
Neuropeptide kisspeptin has been suggested to be an essential central regulator of reproduction in response to changes in serum gonadal steroid concentrations. However, in spite of wide kisspeptin receptor distribution in the brain, especially in the preoptic area and hypothalamus, the research focus has mostly been confined to the kisspeptin regulation on GnRH neurons. Here, by using medaka whose kisspeptin (kiss1) neurons have been clearly demonstrated to be regulated by sex steroids, we analyzed the anatomical distribution of kisspeptin receptors Gpr54-1 and Gpr54-2. Because the both receptors were shown to be activated by kisspeptins (Kiss1 and Kiss2), we analyzed the anatomical distribution of the both receptors by in situ hybridization. They were mainly expressed in the ventral telencephalon, preoptic area, and hypothalamus, which have been suggested to be involved in homeostatic functions including reproduction. First, we found gpr54-2 mRNA expression in nucleus preopticus pars magnocellularis and demonstrated that vasotocin and isotocin (Vasopressin and Oxytocin ortholog, respectively) neurons express gpr54-2 by dual in situ hybridization. Given that kisspeptin administration increases serum oxytocin and vasopressin concentration in mammals, the present finding are likely to be vertebrate-wide phenomenon, although direct regulation has not yet been demonstrated in mammals. We then analyzed co-expression of kisspeptin receptors in three types of GnRH neurons. It was clearly demonstrated that gpr54-expressing cells were located adjacent to GnRH1 neurons, although they were not GnRH1 neurons themselves. In contrast, there was no gpr54-expressing cell in the vicinities of neuromodulatory GnRH2 or GnRH3 neurons. From these results, we suggest that medaka kisspeptin neurons directly regulate some behavioral and neuroendocrine functions via vasotocin/isotocin neurons, whereas they do not regulate hypophysiotropic GnRH1 neurons at least in a direct manner. Thus, direct kisspeptin regulation of GnRH1 neurons proposed in mammals may not be the universal feature of vertebrate kisspeptin system in general.
Neuropeptide kisspeptin has been suggested to be an essential central regulator of reproduction in response to changes in serum gonadal steroid concentrations. However, in spite of wide kisspeptin receptor distribution in the brain, especially in the preoptic area and hypothalamus, the research focus has mostly been confined to the kisspeptin regulation on GnRH neurons. Here, by using medaka whose kisspeptin (kiss1) neurons have been clearly demonstrated to be regulated by sex steroids, we analyzed the anatomical distribution of kisspeptin receptors Gpr54-1 and Gpr54-2. Because the both receptors were shown to be activated by kisspeptins (Kiss1 and Kiss2), we analyzed the anatomical distribution of the both receptors by in situ hybridization. They were mainly expressed in the ventral telencephalon, preoptic area, and hypothalamus, which have been suggested to be involved in homeostatic functions including reproduction. First, we found gpr54-2 mRNA expression in nucleus preopticus pars magnocellularis and demonstrated that vasotocin and isotocin (Vasopressin and Oxytocin ortholog, respectively) neurons express gpr54-2 by dual in situ hybridization. Given that kisspeptin administration increases serum oxytocin and vasopressin concentration in mammals, the present finding are likely to be vertebrate-wide phenomenon, although direct regulation has not yet been demonstrated in mammals. We then analyzed co-expression of kisspeptin receptors in three types of GnRH neurons. It was clearly demonstrated that gpr54-expressing cells were located adjacent to GnRH1 neurons, although they were not GnRH1 neurons themselves. In contrast, there was no gpr54-expressing cell in the vicinities of neuromodulatory GnRH2 or GnRH3 neurons. From these results, we suggest that medaka kisspeptin neurons directly regulate some behavioral and neuroendocrine functions via vasotocin/isotocin neurons, whereas they do not regulate hypophysiotropic GnRH1 neurons at least in a direct manner. Thus, direct kisspeptin regulation of GnRH1 neurons proposed in mammals may not be the universal feature of vertebrate kisspeptin system in general.
Popa SM, Moriyama RM, Caligioni CS, et al. Redundancy in Kiss1 Expression Safeguards Reproduction in the Mouse. Endocrinology. http://endo.endojournals.org/content/early/2013/06/03/en.2013-1222.abstract (Redundancy in Kiss1 Expression Safeguards Reproduction in the Mouse)
Kisspeptin (Kiss1) signaling to gonadotropin releasing hormone neurons is widely acknowledged to be a prerequisite for puberty and reproduction. Animals lacking functional genes for either kisspeptin or its receptor exhibit low gonadotropin secretion and infertility.
Paradoxically, a recent study reported that genetic ablation of nearly all Kiss1-expressing neurons (Kiss1 neurons) does not impair reproduction, arguing that neither Kiss1 neurons nor their products are essential for sexual maturation. We posited that only minute quantities of kisspeptin are sufficient to support reproduction. If this were the case, animals having dramatically reduced Kiss1 expression might retain fertility — testifying to the redundancy of Kiss1 neurons and their products.
To test this hypothesis and to determine whether males and females differ in the required amount of kisspeptin needed for reproduction, we used a mouse (Kiss1-CreGFP) that has a severe reduction in Kiss1 expression. Mice that are heterozygous and homozygous for this allele (Kiss1Cre/+ and Kiss1Cre/Cre) have ?50% and 95% reductions in Kiss1 transcript, respectively.
We found that although male Kiss1Cre/Cre mice sire normal-sized litters, female Kiss1Cre/Cre mice exhibit significantly impaired fertility and ovulation. These observations suggest that males require only 5% of normal Kiss1 expression to be reproductively competent, whereas females require higher levels for reproductive success.
Kisspeptin (Kiss1) signaling to gonadotropin releasing hormone neurons is widely acknowledged to be a prerequisite for puberty and reproduction. Animals lacking functional genes for either kisspeptin or its receptor exhibit low gonadotropin secretion and infertility.
Paradoxically, a recent study reported that genetic ablation of nearly all Kiss1-expressing neurons (Kiss1 neurons) does not impair reproduction, arguing that neither Kiss1 neurons nor their products are essential for sexual maturation. We posited that only minute quantities of kisspeptin are sufficient to support reproduction. If this were the case, animals having dramatically reduced Kiss1 expression might retain fertility — testifying to the redundancy of Kiss1 neurons and their products.
To test this hypothesis and to determine whether males and females differ in the required amount of kisspeptin needed for reproduction, we used a mouse (Kiss1-CreGFP) that has a severe reduction in Kiss1 expression. Mice that are heterozygous and homozygous for this allele (Kiss1Cre/+ and Kiss1Cre/Cre) have ?50% and 95% reductions in Kiss1 transcript, respectively.
We found that although male Kiss1Cre/Cre mice sire normal-sized litters, female Kiss1Cre/Cre mice exhibit significantly impaired fertility and ovulation. These observations suggest that males require only 5% of normal Kiss1 expression to be reproductively competent, whereas females require higher levels for reproductive success.
Irfan S, Ehmcke J, Wahab F, Shahab M, Schlatt S. Intratesticular action of kisspeptin in rhesus monkey (Macaca mulatta). Andrologia. http://onlinelibrary.wiley.com/doi/10.1111/and.12121/abstract
Kisspeptin-Kiss1R signalling in mammals has been implicated as an integral part of the reproductive cascade. Kisspeptinergic neurons upstream of GnRH neurons are involved in the activation of the hypothalamic GnRH pulse generator during pubertal onset. Thus, the major research focus has been on the central effects of kisspeptin.
The demonstration of the presence of KissR expression in human testes suggests additional unknown actions of kisspeptin-KISS1R signalling at the distal component of the male reproductive axis. Here, researchers explored the impact of kisspeptin at the testis in the adult male rhesus monkey.
They employed the clamped monkey model to assess the intratesticular actions of kisspeptin. Plasma testosterone and LH levels were monitored in four adult male monkeys.
The peripheral administration of human kisspeptin-10 (50 mug, iv bolus) caused a single LH pulse, which was followed by a robust increase in plasma testosterone levels sustained for at least 180 min.
This response was abolished when kisspeptin was administered to GnRH receptor antagonist (acyline) pre-treated animals. However, kisspeptin administration significantly (P < 0.005) elevated hCG-stimulated testosterone levels in acyline pre-treated monkeys when compared with saline+ hCG treatment.
These results revealed a novel peripheral facet of kisspeptin signalling.
Kisspeptin-Kiss1R signalling in mammals has been implicated as an integral part of the reproductive cascade. Kisspeptinergic neurons upstream of GnRH neurons are involved in the activation of the hypothalamic GnRH pulse generator during pubertal onset. Thus, the major research focus has been on the central effects of kisspeptin.
The demonstration of the presence of KissR expression in human testes suggests additional unknown actions of kisspeptin-KISS1R signalling at the distal component of the male reproductive axis. Here, researchers explored the impact of kisspeptin at the testis in the adult male rhesus monkey.
They employed the clamped monkey model to assess the intratesticular actions of kisspeptin. Plasma testosterone and LH levels were monitored in four adult male monkeys.
The peripheral administration of human kisspeptin-10 (50 mug, iv bolus) caused a single LH pulse, which was followed by a robust increase in plasma testosterone levels sustained for at least 180 min.
This response was abolished when kisspeptin was administered to GnRH receptor antagonist (acyline) pre-treated animals. However, kisspeptin administration significantly (P < 0.005) elevated hCG-stimulated testosterone levels in acyline pre-treated monkeys when compared with saline+ hCG treatment.
These results revealed a novel peripheral facet of kisspeptin signalling.
Millar RP, Newton CL. Current and future applications of GnRH, kisspeptin and neurokinin B analogues. Nat Rev Endocrinol. Current and future applications of GnRH, kisspeptin and neurokinin B analogues : Abstract : Nature Reviews Endocrinology
Reproductive hormones affect all stages of life from gamete production, fertilization, fetal development and parturition, neonatal development and puberty through to adulthood and senescence. The reproductive hormone cascade has, therefore, been the target for the development of numerous drugs that modulate its activity at many levels. As the central regulator of the cascade, gonadotropin-releasing hormone (GnRH) agonists and antagonists have found extensive applications in treating a wide range of hormone-dependent diseases, such as precocious puberty, prostate cancer, benign prostatic hyperplasia, endometriosis and uterine fibroids, as well as being an essential component of in vitro fertilization protocols. The neuroendocrine peptides that regulate GnRH neurons, kisspeptin and neurokinin B, have also been identified as therapeutic targets, and novel agonists and antagonists are being developed as modulators of the cascade upstream of GnRH. Here, we review the development and applications of analogues of the major neuroendocrine peptide regulators of the reproductive hormone cascade: GnRH, kisspeptin and neurokinin B.
Reproductive hormones affect all stages of life from gamete production, fertilization, fetal development and parturition, neonatal development and puberty through to adulthood and senescence. The reproductive hormone cascade has, therefore, been the target for the development of numerous drugs that modulate its activity at many levels. As the central regulator of the cascade, gonadotropin-releasing hormone (GnRH) agonists and antagonists have found extensive applications in treating a wide range of hormone-dependent diseases, such as precocious puberty, prostate cancer, benign prostatic hyperplasia, endometriosis and uterine fibroids, as well as being an essential component of in vitro fertilization protocols. The neuroendocrine peptides that regulate GnRH neurons, kisspeptin and neurokinin B, have also been identified as therapeutic targets, and novel agonists and antagonists are being developed as modulators of the cascade upstream of GnRH. Here, we review the development and applications of analogues of the major neuroendocrine peptide regulators of the reproductive hormone cascade: GnRH, kisspeptin and neurokinin B.
Tariq A, Shahab M, Clarke I, et al. Kiss1 and Kiss1 receptor expression in the rhesus monkey testis: a possible local regulator of testicular function. Central European Journal of Biology 2013;8(10):968-74. Kiss1 and Kiss1 receptor expression in the rhesus monkey testis: a possible local regulator of testicular function - Springer
Background - Kisspeptin, a KISS1 gene product, stimulates GnRH neurons in the hypothalamus, but some recent studies have also suggested a direct effect on gonads. We aimed to localise Kiss and Kiss1 receptor (Kiss1r) in adult rhesus monkey testis.
Experimental Procedures - Expression of Kiss1 and Kiss1r was detected in testicular tissue of rhesus monkey using immunohistochemistry and reverse transcriptase PCR (RT-PCR). Dual immunohistochemistry was used to colocalize Kiss1 with germ cell marker T4 and Kiss1r with inhibin (Sertoli cell marker) using specific antibodies for all. Immunohistochemistry of testis was conducted on formaldehyde fixed tissues using 5 µ thick sections. Using gene specific primers, RT-PCR was carried out to find expression of Kiss1 and Kiss1r mRNAs in testis.
Results - Kiss1 immunoreactivity was localised to spermatocytes and spermatids and Kiss1r was observed in spermatocytes and Sertoli cells. Double-label immunohistochemistry co-localized Kiss1 and T4 in spermatids and Kiss1r and inhibin were co-localized in Sertoli cells. RT-PCR showed mRNA expression of Kiss1 and Kiss1r in adult rhesus monkey testis.
Conclusions - Present results indicate for the first time the presence of Kiss1 and Kiss1r in adult primate testis. These suggest a possible autocrine/paracrine role of kisspeptin in non-human primate testis. Kiss1-Kiss1r in testis suggests possible direct involvement in the regulatory network involved in spermatogenesis.
Background - Kisspeptin, a KISS1 gene product, stimulates GnRH neurons in the hypothalamus, but some recent studies have also suggested a direct effect on gonads. We aimed to localise Kiss and Kiss1 receptor (Kiss1r) in adult rhesus monkey testis.
Experimental Procedures - Expression of Kiss1 and Kiss1r was detected in testicular tissue of rhesus monkey using immunohistochemistry and reverse transcriptase PCR (RT-PCR). Dual immunohistochemistry was used to colocalize Kiss1 with germ cell marker T4 and Kiss1r with inhibin (Sertoli cell marker) using specific antibodies for all. Immunohistochemistry of testis was conducted on formaldehyde fixed tissues using 5 µ thick sections. Using gene specific primers, RT-PCR was carried out to find expression of Kiss1 and Kiss1r mRNAs in testis.
Results - Kiss1 immunoreactivity was localised to spermatocytes and spermatids and Kiss1r was observed in spermatocytes and Sertoli cells. Double-label immunohistochemistry co-localized Kiss1 and T4 in spermatids and Kiss1r and inhibin were co-localized in Sertoli cells. RT-PCR showed mRNA expression of Kiss1 and Kiss1r in adult rhesus monkey testis.
Conclusions - Present results indicate for the first time the presence of Kiss1 and Kiss1r in adult primate testis. These suggest a possible autocrine/paracrine role of kisspeptin in non-human primate testis. Kiss1-Kiss1r in testis suggests possible direct involvement in the regulatory network involved in spermatogenesis.
Semaan SJ, Kauffman AS. Emerging concepts on the epigenetic and transcriptional regulation of the Kiss1 gene. International Journal of Developmental Neuroscience 2013;31(6):452-62. Emerging concepts on the epigenetic and transcriptional regulation of the Kiss1 gene
Kisspeptin and its receptor have been implicated as critical regulators of reproductive physiology, with humans and mice without functioning kisspeptin systems displaying severe pubertal and reproductive defects. Alterations in the expression of Kiss1 (the gene encoding kisspeptin) over development, along with differences in Kiss1 expression between the sexes in adulthood, may be critical for the maturation and functioning of the neuroendocrine reproductive system and could possibly contribute to pubertal progression, sex differences in luteinizing hormone secretion, and other facets of reproductive physiology.
It is therefore essential to understand how Kiss1 gene expression develops and what possible regulatory mechanisms govern the modulation of its expression. A number of recent studies, primarily in rodent or cell line models, have focused on the contributions of epigenetic mechanisms to the regulation of Kiss1 gene expression; thus far, mechanisms such as DNA methylation, histone acetylation, and histone methylation have been investigated.
This review discusses the most recent findings on the epigenetic control of Kiss1 expression in adulthood, the evidence for epigenetic factors affecting Kiss1 expression during puberty and development, and findings regarding the contribution of epigenetics to the sexually dimorphic expression of Kiss1 in the hypothalamus.
Kisspeptin and its receptor have been implicated as critical regulators of reproductive physiology, with humans and mice without functioning kisspeptin systems displaying severe pubertal and reproductive defects. Alterations in the expression of Kiss1 (the gene encoding kisspeptin) over development, along with differences in Kiss1 expression between the sexes in adulthood, may be critical for the maturation and functioning of the neuroendocrine reproductive system and could possibly contribute to pubertal progression, sex differences in luteinizing hormone secretion, and other facets of reproductive physiology.
It is therefore essential to understand how Kiss1 gene expression develops and what possible regulatory mechanisms govern the modulation of its expression. A number of recent studies, primarily in rodent or cell line models, have focused on the contributions of epigenetic mechanisms to the regulation of Kiss1 gene expression; thus far, mechanisms such as DNA methylation, histone acetylation, and histone methylation have been investigated.
This review discusses the most recent findings on the epigenetic control of Kiss1 expression in adulthood, the evidence for epigenetic factors affecting Kiss1 expression during puberty and development, and findings regarding the contribution of epigenetics to the sexually dimorphic expression of Kiss1 in the hypothalamus.
Hrabovszky E, Liposits Z. Afferent Neuronal Control of Type-I Gonadotropin Releasing Hormone Neurons in the Human. Front Endocrinol (Lausanne) 2013;4:130. http://www.frontiersin.org/Journal/10.3389/fendo.2013.00130/full
Understanding the regulation of the human menstrual cycle represents an important ultimate challenge of reproductive neuroendocrine research. However, direct translation of information from laboratory animal experiments to the human is often complicated by strikingly different and unique reproductive strategies and central regulatory mechanisms that can be present in even closely related animal species.
In all mammals studied so far, type-I gonadotropin releasing hormone (GnRH) synthesizing neurons form the final common output way from the hypothalamus in the neuroendocrine control of the adenohypophysis.
Under various physiological and pathological conditions, hormonal and metabolic signals either regulate GnRH neurons directly or act on upstream neuronal circuitries to influence the pattern of pulsatile GnRH secretion into the hypophysial portal circulation.
Neuronal afferents to GnRH cells convey important metabolic-, stress-, sex steroid-, lactational-, and circadian signals to the reproductive axis, among other effects.
This article gives an overview of the available neuroanatomical literature that described the afferent regulation of human GnRH neurons by peptidergic, monoaminergic, and amino acidergic neuronal systems. Recent studies of human genetics provided evidence that central peptidergic signaling by kisspeptins and neurokinin B (NKB) play particularly important roles in puberty onset and later, in the sex steroid-dependent feedback regulation of GnRH neurons.
This review article places special emphasis on the topographic distribution, sexual dimorphism, aging-dependent neuroanatomical changes, and plastic connectivity to GnRH neurons of the critically important human hypothalamic kisspeptin and NKB systems.
Understanding the regulation of the human menstrual cycle represents an important ultimate challenge of reproductive neuroendocrine research. However, direct translation of information from laboratory animal experiments to the human is often complicated by strikingly different and unique reproductive strategies and central regulatory mechanisms that can be present in even closely related animal species.
In all mammals studied so far, type-I gonadotropin releasing hormone (GnRH) synthesizing neurons form the final common output way from the hypothalamus in the neuroendocrine control of the adenohypophysis.
Under various physiological and pathological conditions, hormonal and metabolic signals either regulate GnRH neurons directly or act on upstream neuronal circuitries to influence the pattern of pulsatile GnRH secretion into the hypophysial portal circulation.
Neuronal afferents to GnRH cells convey important metabolic-, stress-, sex steroid-, lactational-, and circadian signals to the reproductive axis, among other effects.
This article gives an overview of the available neuroanatomical literature that described the afferent regulation of human GnRH neurons by peptidergic, monoaminergic, and amino acidergic neuronal systems. Recent studies of human genetics provided evidence that central peptidergic signaling by kisspeptins and neurokinin B (NKB) play particularly important roles in puberty onset and later, in the sex steroid-dependent feedback regulation of GnRH neurons.
This review article places special emphasis on the topographic distribution, sexual dimorphism, aging-dependent neuroanatomical changes, and plastic connectivity to GnRH neurons of the critically important human hypothalamic kisspeptin and NKB systems.
Roa J. Role of GnRH Neurons and Their Neuronal Afferents as Key Integrators between Food Intake Regulatory Signals and the Control of Reproduction. Int J Endocrinol. 2013:518046. Role of GnRH Neurons and Their Neuronal Afferents as Key Integrators between Food Intake Regulatory Signals and the Control of Reproduction
Reproductive function is regulated by a plethora of signals that integrate physiological and environmental information. Among others, metabolic factors are key components of this circuit since they inform about the propitious timing for reproduction depending on energy availability. This information is processed mainly at the hypothalamus that, in turn, modulates gonadotropin release from the pituitary and, thereby, gonadal activity. Metabolic hormones, such as leptin, insulin, and ghrelin, act as indicators of the energy status and convey this information to the reproductive axis regulating its activity. In this review, we will analyse the central mechanisms involved in the integration of this metabolic information and their contribution to the control of the reproductive function. Particular attention will be paid to summarize the participation of GnRH, Kiss1, NPY, and POMC neurons in this process and their possible interactions to contribute to the metabolic control of reproduction.
Reproductive function is regulated by a plethora of signals that integrate physiological and environmental information. Among others, metabolic factors are key components of this circuit since they inform about the propitious timing for reproduction depending on energy availability. This information is processed mainly at the hypothalamus that, in turn, modulates gonadotropin release from the pituitary and, thereby, gonadal activity. Metabolic hormones, such as leptin, insulin, and ghrelin, act as indicators of the energy status and convey this information to the reproductive axis regulating its activity. In this review, we will analyse the central mechanisms involved in the integration of this metabolic information and their contribution to the control of the reproductive function. Particular attention will be paid to summarize the participation of GnRH, Kiss1, NPY, and POMC neurons in this process and their possible interactions to contribute to the metabolic control of reproduction.
Matsui H, Asami T. Effects and Therapeutic Potentials of Kisspeptin Analogs: Regulation of the Hypothalamic-Pituitary-Gonadal Axis. Neuroendocrinology. Neuroendocrinology - Effects and Therapeutic Potentials of Kisspeptin Analogs: Regulation of the Hypothalamic-Pituitary-Gonadal Axis - Abstract - Karger Publishers
The hypothalamic peptide kisspeptin/metastin, an endogenous ligand of the G-protein coupled receptor KISS1R, plays a critical role in controlling GnRH release from hypothalamic GnRH neurons and thereby regulates hypothalamic-pituitary-gonadal functions. Although the therapeutic potential of kisspeptin is attractive, its susceptibility to proteolytic degradation limits its utility.
To overcome this, KISS1R agonists or antagonists as peptide analogs or small molecules have been investigated. Kisspeptin analogs have been most extensively studied by reducing the length of the peptide from the original 54 amino acids to 10 amino acids or less and by substituting key amino acid residues. Two investigational kisspeptin agonist analogs have been evaluated in clinical studies in men; in agreement with animal studies, abrupt elevations in gonadotropin and testosterone levels as were observed an acute effect, followed by rapid reductions in these hormones as a chronic effect. Some studies of small-molecule KISS1R antagonists have also been published.
In this review, we present a brief overview on kisspeptin/KISS1R physiology in reproductive functions and summarize the available knowledge of both agonists and antagonists. We also focus on the kisspeptin agonist analogs by summarizing key pharmacological findings from both clinical and pre-clinical studies, and discuss their potential therapeutic utility. (c) 2014 S. Karger AG, Basel.
The hypothalamic peptide kisspeptin/metastin, an endogenous ligand of the G-protein coupled receptor KISS1R, plays a critical role in controlling GnRH release from hypothalamic GnRH neurons and thereby regulates hypothalamic-pituitary-gonadal functions. Although the therapeutic potential of kisspeptin is attractive, its susceptibility to proteolytic degradation limits its utility.
To overcome this, KISS1R agonists or antagonists as peptide analogs or small molecules have been investigated. Kisspeptin analogs have been most extensively studied by reducing the length of the peptide from the original 54 amino acids to 10 amino acids or less and by substituting key amino acid residues. Two investigational kisspeptin agonist analogs have been evaluated in clinical studies in men; in agreement with animal studies, abrupt elevations in gonadotropin and testosterone levels as were observed an acute effect, followed by rapid reductions in these hormones as a chronic effect. Some studies of small-molecule KISS1R antagonists have also been published.
In this review, we present a brief overview on kisspeptin/KISS1R physiology in reproductive functions and summarize the available knowledge of both agonists and antagonists. We also focus on the kisspeptin agonist analogs by summarizing key pharmacological findings from both clinical and pre-clinical studies, and discuss their potential therapeutic utility. (c) 2014 S. Karger AG, Basel.
Grachev P, Millar RP, O'Byrne KT. The Role of Neurokinin B Signalling in Reproductive Neuroendocrinology. Neuroendocrinology. Neuroendocrinology - The Role of Neurokinin B Signalling in Reproductive Neuroendocrinology - Abstract - Karger Publishers
The KNDy neuropeptides, K isspeptin, N eurokinin B (NKB) and Dy norphin A (Dyn), have been implicated in regulating pulsatile luteinising hormone (LH) secretion. Studies of the interactions between KNDy signalling systems, however, are currently few. Although the stimulatory effect of kisspeptin and inhibitory effect of Dyn on the GnRH pulse generator are widely accepted, the effects of NKB in rodents are variable and sometimes controversial.
Literature describing increased LH secretion in response to NKB receptor agonism predominates, and is in line with human physiology, as well as the pathophysiology of pubertal failure associated with disruption of NKB signalling. However the robust suppression of the LH pulse, induced by the same treatment under hypoestrogenic conditions, may hold clues as to the mechanisms of reproductive inhibition under pathological conditions.
This review discusses the recent evidence for this paradox and outlines a revised working model incorporating the mechanisms by which KNDy neuropeptides modulate the reproductive axis.
The KNDy neuropeptides, K isspeptin, N eurokinin B (NKB) and Dy norphin A (Dyn), have been implicated in regulating pulsatile luteinising hormone (LH) secretion. Studies of the interactions between KNDy signalling systems, however, are currently few. Although the stimulatory effect of kisspeptin and inhibitory effect of Dyn on the GnRH pulse generator are widely accepted, the effects of NKB in rodents are variable and sometimes controversial.
Literature describing increased LH secretion in response to NKB receptor agonism predominates, and is in line with human physiology, as well as the pathophysiology of pubertal failure associated with disruption of NKB signalling. However the robust suppression of the LH pulse, induced by the same treatment under hypoestrogenic conditions, may hold clues as to the mechanisms of reproductive inhibition under pathological conditions.
This review discusses the recent evidence for this paradox and outlines a revised working model incorporating the mechanisms by which KNDy neuropeptides modulate the reproductive axis.
Noel SD, Abreu AP, Xu S, et al. TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH-deficient patients. The FASEB Journal. TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH-deficient patients
Neurokinin B (NKB) and its G-protein-coupled receptor, NK3R, have been implicated in the neuroendocrine control of GnRH release; however, little is known about the structure-function relationship of this ligand-receptor pair. Moreover, loss-of-function NK3R mutations cause GnRH deficiency in humans.
Using missense mutations in NK3R we previously identified in patients with GnRH deficiency, we demonstrate that Y256H and Y315C NK3R mutations in the fifth and sixth transmembrane domains (TM5 and TM6), resulted in reduced whole-cell (79.3±7.2%) or plasma membrane (67.3±7.3%) levels, respectively, compared with wild-type (WT) NK3R, with near complete loss of inositol phosphate (IP) signaling, implicating these domains in receptor trafficking, processing, and/or stability.
We further demonstrate in a FRET-based assay that R295S NK3R, in the third intracellular loop (IL3), bound NKB but impaired dissociation of Gq-protein subunits from the receptor compared with WT NK3R, which showed a 10.0 ± 1.3% reduction in FRET ratios following ligand binding, indicating activation of Gq-protein signaling.
Interestingly, R295S NK3R, identified in the heterozygous state in a GnRH-deficient patient, also interfered with dissociation of G proteins and IP signaling from wild-type NK3R, indicative of dominant-negative effects. Collectively, our data illustrate roles for TM5 and TM6 in NK3R trafficking and ligand binding and for IL3 in NK3R signaling.
Neurokinin B (NKB) and its G-protein-coupled receptor, NK3R, have been implicated in the neuroendocrine control of GnRH release; however, little is known about the structure-function relationship of this ligand-receptor pair. Moreover, loss-of-function NK3R mutations cause GnRH deficiency in humans.
Using missense mutations in NK3R we previously identified in patients with GnRH deficiency, we demonstrate that Y256H and Y315C NK3R mutations in the fifth and sixth transmembrane domains (TM5 and TM6), resulted in reduced whole-cell (79.3±7.2%) or plasma membrane (67.3±7.3%) levels, respectively, compared with wild-type (WT) NK3R, with near complete loss of inositol phosphate (IP) signaling, implicating these domains in receptor trafficking, processing, and/or stability.
We further demonstrate in a FRET-based assay that R295S NK3R, in the third intracellular loop (IL3), bound NKB but impaired dissociation of Gq-protein subunits from the receptor compared with WT NK3R, which showed a 10.0 ± 1.3% reduction in FRET ratios following ligand binding, indicating activation of Gq-protein signaling.
Interestingly, R295S NK3R, identified in the heterozygous state in a GnRH-deficient patient, also interfered with dissociation of G proteins and IP signaling from wild-type NK3R, indicative of dominant-negative effects. Collectively, our data illustrate roles for TM5 and TM6 in NK3R trafficking and ligand binding and for IL3 in NK3R signaling.
Wahab F, Atika B, Huma T, Shahab M. Primate HPT Axis Response to the Peripheral Kisspeptin Challenge Under Different Time Periods of Food Restriction in Monkeys. Horm Metab Res. https://www.thieme-connect.de/ejournals/abstract/10.1055/s-0033-1363263
Metabolism and reproduction are closely linked. Both long- and short-term fasting-induced metabolic deficiency suppresses reproductive function in mammals. Recently, we have shown that 48-h fasting-induced metabolic deficiency attenuates the reproductive axis responsiveness to peripheral kisspeptin injection in the sexually mature monkeys. But currently there is no data to show whether shorter time periods of fasting also alter the reproductive axis responsiveness to kisspeptin. Therefore, this study was aimed to examine the reproductive axis responsiveness to kisspeptin administration in the adult male rhesus monkey fasted for 12-, 18-, and 24h. Intravenous boli of vehicle (1ml) and human kisspeptin-10 (KP10; 50mug) were given to 5 intact sexually mature male rhesus monkeys in both fasting (12-, 18-, 24-h) and ad libitum feeding conditions. Specific immunoassays were used to determine plasma hormones concentrations. KP10 injection highly stimulated testosterone secretion in all conditions. However, mean testosterone concentrations in 3-h post-KP10 injection period were significantly (p<0.01) decreased in 18- and 24-h fasted monkeys when compared to 12-h fasted and fed monkeys. Moreover, 18- and 24-h fasting conditions also significantly (p<0.05) delayed the duration to the first significant increase in T levels after KP10 injection. Vehicle injection did not alter these parameters in any conditions. Present results indicate that 18- and 24-h fasting conditions suppressed the testosterone response to KP10 administration both in initiation and quantity. These results suggest that 18- and 24-h fasting-induced inhibition of the reproductive functions in the mature male macaque may partly involve attenuation in the reproductive axis responsiveness to endogenous kisspeptin stimulation.
Metabolism and reproduction are closely linked. Both long- and short-term fasting-induced metabolic deficiency suppresses reproductive function in mammals. Recently, we have shown that 48-h fasting-induced metabolic deficiency attenuates the reproductive axis responsiveness to peripheral kisspeptin injection in the sexually mature monkeys. But currently there is no data to show whether shorter time periods of fasting also alter the reproductive axis responsiveness to kisspeptin. Therefore, this study was aimed to examine the reproductive axis responsiveness to kisspeptin administration in the adult male rhesus monkey fasted for 12-, 18-, and 24h. Intravenous boli of vehicle (1ml) and human kisspeptin-10 (KP10; 50mug) were given to 5 intact sexually mature male rhesus monkeys in both fasting (12-, 18-, 24-h) and ad libitum feeding conditions. Specific immunoassays were used to determine plasma hormones concentrations. KP10 injection highly stimulated testosterone secretion in all conditions. However, mean testosterone concentrations in 3-h post-KP10 injection period were significantly (p<0.01) decreased in 18- and 24-h fasted monkeys when compared to 12-h fasted and fed monkeys. Moreover, 18- and 24-h fasting conditions also significantly (p<0.05) delayed the duration to the first significant increase in T levels after KP10 injection. Vehicle injection did not alter these parameters in any conditions. Present results indicate that 18- and 24-h fasting conditions suppressed the testosterone response to KP10 administration both in initiation and quantity. These results suggest that 18- and 24-h fasting-induced inhibition of the reproductive functions in the mature male macaque may partly involve attenuation in the reproductive axis responsiveness to endogenous kisspeptin stimulation.
Kotani M, Katagiri F, Hirai T, Kagawa J. Plasma kisspeptin levels in male cases with hypogonadism. Endocr J. https://www.jstage.jst.go.jp/article/endocrj/advpub/0/advpub_EJ14-0137/_pdf
The hypothalamic hormone kisspeptin (metastin) regulates human reproduction by modulating gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin is detected in peripheral blood, although GnRH is not.
In this study, we measured plasma kisspeptin levels in four male cases with hypogonadism and seven normal male controls using enzyme immunoassay (EIA) to elucidate the clinical implications of kisspeptin levels in male hypogonadism.
The results showed a variety of plasma kisspeptin levels: 6.0 fmol/ml in a male with isolated hypogonadotropic hypogonadism (IHH), 43.2 fmol/ml in a male with Kallmann's syndrome, 40.7 fmol/ml in a male with azoospermia, 323.2 fmol/ml in a male with hypergonadotropic hypogonadism, and 12.3 +/- 2.5 fmol/ml (mean +/- SD) in seven normal controls.
Except for the case with IHH, the plasma kisspetin levels were elevated in the three cases with Kallmann's syndrome, azoospermia, and hypergonadotropic hypogonadism. The reason why the three cases had high values was their lesions were downstream of the kisspeptin neuron in the hypothalamic-pituitary-gonadal axis, suggesting that elevated kisspeptin levels were implicated in hypothalamic kisspeptin secretion under decreased negative feedback of gonadal steroids.
The result that the plasma kisspeptin levels were decreased by gonadotropin therapy in the case with Kallmann's syndrome supported this hypothesis.
In conclusion, to measure plasma kisspeptin levels could be useful for better understanding of male hypogonadism.
The hypothalamic hormone kisspeptin (metastin) regulates human reproduction by modulating gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin is detected in peripheral blood, although GnRH is not.
In this study, we measured plasma kisspeptin levels in four male cases with hypogonadism and seven normal male controls using enzyme immunoassay (EIA) to elucidate the clinical implications of kisspeptin levels in male hypogonadism.
The results showed a variety of plasma kisspeptin levels: 6.0 fmol/ml in a male with isolated hypogonadotropic hypogonadism (IHH), 43.2 fmol/ml in a male with Kallmann's syndrome, 40.7 fmol/ml in a male with azoospermia, 323.2 fmol/ml in a male with hypergonadotropic hypogonadism, and 12.3 +/- 2.5 fmol/ml (mean +/- SD) in seven normal controls.
Except for the case with IHH, the plasma kisspetin levels were elevated in the three cases with Kallmann's syndrome, azoospermia, and hypergonadotropic hypogonadism. The reason why the three cases had high values was their lesions were downstream of the kisspeptin neuron in the hypothalamic-pituitary-gonadal axis, suggesting that elevated kisspeptin levels were implicated in hypothalamic kisspeptin secretion under decreased negative feedback of gonadal steroids.
The result that the plasma kisspeptin levels were decreased by gonadotropin therapy in the case with Kallmann's syndrome supported this hypothesis.
In conclusion, to measure plasma kisspeptin levels could be useful for better understanding of male hypogonadism.
‘‘KNDy Neuron’’ Model for GnRH Regulation and Steroid Feedback
In the hypothalamus, KNDy neurons located within the arcuate nuclei via bilateral/ autosynaptic innervation can trigger kisspeptin (Kiss) secretion through type 3 neurokinin receptor (NK3R) activation caused by local release of neurokinin B (NKB).
Kiss output from KNDy neurons through activation of its cognate receptor GPR54 not only stimulates GnRH neurons with cell bodies located in the preoptic area, but also trigger GnRH secretion into portal blood through direct innervation of GnRH nerve terminals located in the median eminence.
Besides the stimulatory action of NKB, dynorphin A (Dyn) secretion from KNDy neurons, presumably via mediation of a yet unidentified interneuron with j-type opioid receptor (KOR) expression, can exert a negative feedback to inhibit both basal as well as NKB-induced Kiss release.
The functional interplay of the NKB/NK3R system and Dyn/KOR system in the arcuate nuclei can regulate GnRH secretion into hypophysial portal blood, which then controls the pulsatility of LH release from the pituitary into systemic circulation.
The neuronal circuitry in the arcuate nuclei with KNDy neurons as a major component also serves as the major target for negative feedback by sex steroids including estrogen and progesterone.
Other than the KNDy neurons, GnRH neurons within the preoptic area also receive the signal input of Kiss neurons located in the anteroventral periventricular nuclei, which are believed to be the target site within the hypothalamus responsible for positive feedback of estrogen observed during the preovulatory period (e.g., in rodents).
Hu G, Lin C, He M, Wong AO. Neurokinin B and Reproductive Functions: - "KNDy Neuron" Model in Mammals and the Emerging Story in Fish. Gen Comp Endocrinol. https://www.sciencedirect.com/science/article/pii/S0016648014003207
In mammals, neurokinin B (NKB), the gene product of the tachykinin family member TAC3, is known to be a key regulator for episodic release of luteinizing hormone (LH).
Its regulatory actions are mediated by a subpopulation of kisspeptin neurons within the arcuate nucleus with co-expression of NKB and dynorphin A (commonly called the "KNDy neurons").
By forming an "autosynaptic feedback loop" within the hypothalamus, the KNDy neurons can modulate gonadotropin-releasing hormone (GnRH) pulsatility and subsequent LH release in the pituitary.
NKB regulation of LH secretion has been recently demonstrated in zebrafish, suggesting that the reproductive functions of NKB may be conserved from fish to mammals. Interestingly, the TAC3 genes in fish not only encode the mature peptide of NKB but also a novel tachykinin-like peptide, namely NKB-related peptide (or neurokinin F).
Recent studies in zebrafish also reveal the neuroanatomy of TAC3/kisspeptin system within the fish brain is quite different from that of mammals.
In this article, the current ideas of "KNDy neuron" model for GnRH regulation and steroid feedback, other reproductive functions of NKB including its local actions in the gonad and placenta, the revised model of tachykinin evolution from invertebrates to vertebrates, as well as the emerging story of the two TAC3 gene products in fish, NKB and NKB-related peptide, will be reviewed with stress on the areas with interesting questions for future investigations.
In the hypothalamus, KNDy neurons located within the arcuate nuclei via bilateral/ autosynaptic innervation can trigger kisspeptin (Kiss) secretion through type 3 neurokinin receptor (NK3R) activation caused by local release of neurokinin B (NKB).
Kiss output from KNDy neurons through activation of its cognate receptor GPR54 not only stimulates GnRH neurons with cell bodies located in the preoptic area, but also trigger GnRH secretion into portal blood through direct innervation of GnRH nerve terminals located in the median eminence.
Besides the stimulatory action of NKB, dynorphin A (Dyn) secretion from KNDy neurons, presumably via mediation of a yet unidentified interneuron with j-type opioid receptor (KOR) expression, can exert a negative feedback to inhibit both basal as well as NKB-induced Kiss release.
The functional interplay of the NKB/NK3R system and Dyn/KOR system in the arcuate nuclei can regulate GnRH secretion into hypophysial portal blood, which then controls the pulsatility of LH release from the pituitary into systemic circulation.
The neuronal circuitry in the arcuate nuclei with KNDy neurons as a major component also serves as the major target for negative feedback by sex steroids including estrogen and progesterone.
Other than the KNDy neurons, GnRH neurons within the preoptic area also receive the signal input of Kiss neurons located in the anteroventral periventricular nuclei, which are believed to be the target site within the hypothalamus responsible for positive feedback of estrogen observed during the preovulatory period (e.g., in rodents).
Hu G, Lin C, He M, Wong AO. Neurokinin B and Reproductive Functions: - "KNDy Neuron" Model in Mammals and the Emerging Story in Fish. Gen Comp Endocrinol. https://www.sciencedirect.com/science/article/pii/S0016648014003207
In mammals, neurokinin B (NKB), the gene product of the tachykinin family member TAC3, is known to be a key regulator for episodic release of luteinizing hormone (LH).
Its regulatory actions are mediated by a subpopulation of kisspeptin neurons within the arcuate nucleus with co-expression of NKB and dynorphin A (commonly called the "KNDy neurons").
By forming an "autosynaptic feedback loop" within the hypothalamus, the KNDy neurons can modulate gonadotropin-releasing hormone (GnRH) pulsatility and subsequent LH release in the pituitary.
NKB regulation of LH secretion has been recently demonstrated in zebrafish, suggesting that the reproductive functions of NKB may be conserved from fish to mammals. Interestingly, the TAC3 genes in fish not only encode the mature peptide of NKB but also a novel tachykinin-like peptide, namely NKB-related peptide (or neurokinin F).
Recent studies in zebrafish also reveal the neuroanatomy of TAC3/kisspeptin system within the fish brain is quite different from that of mammals.
In this article, the current ideas of "KNDy neuron" model for GnRH regulation and steroid feedback, other reproductive functions of NKB including its local actions in the gonad and placenta, the revised model of tachykinin evolution from invertebrates to vertebrates, as well as the emerging story of the two TAC3 gene products in fish, NKB and NKB-related peptide, will be reviewed with stress on the areas with interesting questions for future investigations.
Demirbilek H, Nuri Ozbek M, Demir K, et al. Normosmic idiopathic hypogonadotrophic hypogonadism due to a novel homozygous nonsense c.C969A (p.Y323X) mutation in the KISS1R gene in three unrelated families. Clinical Endocrinology. http://onlinelibrary.wiley.com/doi/10.1111/cen.12618/abstract
Objective The spectrum of genetic alterations in cases of hypogonadotrophic hypogonadism continues to expand. However, KISS1R mutations remain rare. The aim of the present study was to understand the molecular basis of normosmic idiopathic hypogonadotrophic hypogonadism.
Methods Clinical characteristics, hormonal studies, and genetic analyses of seven cases with idiopathic normosmic hypogonadotrophic hypogonadism (nIHH) from three unrelated consanguineous families are presented.
Results One male presented with absence of pubertal onset and required surgery for severe penoscrotal hypospadias and cryptorchidism whilst other two males had absence of pubertal onset.
Two out of four female cases required replacement therapy for pubertal onset and maintenance whereas the other two had spontaneous pubertal onset but incomplete maturation. In sequence analysis, we identified a novel homozygous nonsense (p.Y323X) mutation (c.C969A) in the last exon of the KISS1R gene in all clinically affected cases.
Conclusions We identified a homozygous nonsense mutation in the KISS1R gene in three unrelated families with nIHH, which enabled us to observe the phenotypic consequences of this rare condition.
Escape from nonsense-mediated decay, and thus production of abnormal proteins, may account for the variable severity of the phenotype. Although KISS1R mutations are extremely rare and can cause a heterogeneous phenotype, analysis of the KISS1R gene should be a part of genetic analysis of patients with nIHH, to allow better understanding of phenotype-genotype relationship of KISS1R mutations and the underlying genetic basis of patients with nIHH. This article is protected by copyright. All rights reserved.
Objective The spectrum of genetic alterations in cases of hypogonadotrophic hypogonadism continues to expand. However, KISS1R mutations remain rare. The aim of the present study was to understand the molecular basis of normosmic idiopathic hypogonadotrophic hypogonadism.
Methods Clinical characteristics, hormonal studies, and genetic analyses of seven cases with idiopathic normosmic hypogonadotrophic hypogonadism (nIHH) from three unrelated consanguineous families are presented.
Results One male presented with absence of pubertal onset and required surgery for severe penoscrotal hypospadias and cryptorchidism whilst other two males had absence of pubertal onset.
Two out of four female cases required replacement therapy for pubertal onset and maintenance whereas the other two had spontaneous pubertal onset but incomplete maturation. In sequence analysis, we identified a novel homozygous nonsense (p.Y323X) mutation (c.C969A) in the last exon of the KISS1R gene in all clinically affected cases.
Conclusions We identified a homozygous nonsense mutation in the KISS1R gene in three unrelated families with nIHH, which enabled us to observe the phenotypic consequences of this rare condition.
Escape from nonsense-mediated decay, and thus production of abnormal proteins, may account for the variable severity of the phenotype. Although KISS1R mutations are extremely rare and can cause a heterogeneous phenotype, analysis of the KISS1R gene should be a part of genetic analysis of patients with nIHH, to allow better understanding of phenotype-genotype relationship of KISS1R mutations and the underlying genetic basis of patients with nIHH. This article is protected by copyright. All rights reserved.
Navarro V, Bosch M, Leon S, et al. The Integrated Hypothalamic Tachykinin-Kisspeptin System as a Central Coordinator for Reproduction. Endocrinology. http://press.endocrine.org/doi/abs/10.1210/en.2014-1651
Tachykinins are comprised of the family of related peptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). NKB has emerged as regulator of kisspeptin release in the arcuate nucleus (ARC), whereas the roles of SP and NKA in reproduction remain unknown. This work explores the roles of SP and NKA in the central regulation of GnRH release. First, central infusion of specific agonists for the receptors of SP (NK1R), NKA (NK2R) and NKB (NK3R) each induced gonadotropin release in adult male and ovariectomized, estradiol-replaced female mice, which was absent in Kiss1r-/- mice, indicating a kisspeptin-dependent action. The NK2R agonist, however, decreased LH release in ovariectomized-sham replaced females, as documented for NK3R agonists but in contrast to the NK1R agonist, which further increased LH release. Second, Tac1 (encoding SP and NKA) expression in the ARC and ventromedial (VMN) nuclei was inhibited by circulating estradiol but did not co-localize with Kiss1 mRNA. Third, about half of isolated ARC Kiss1 neurons expressed Tacr1 (NK1R) and 100% Tacr3 (NK3R); for anteroventral-periventricular Kiss1 neurons and GnRH neurons, approximately one-fourth expressed Tacr1 and one-tenth Tacr3; Tacr2 (NK2R) expression was absent in all cases. Overall, these results identify a potent regulation of gonadotropin release by the SP/NK1R and NKA/NK2R systems in the presence of kisspeptin-Kiss1r signaling, indicating that they may, along with NKB/NK3R, control GnRH release, at least in part through actions on Kiss1 neurons.
Tachykinins are comprised of the family of related peptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). NKB has emerged as regulator of kisspeptin release in the arcuate nucleus (ARC), whereas the roles of SP and NKA in reproduction remain unknown. This work explores the roles of SP and NKA in the central regulation of GnRH release. First, central infusion of specific agonists for the receptors of SP (NK1R), NKA (NK2R) and NKB (NK3R) each induced gonadotropin release in adult male and ovariectomized, estradiol-replaced female mice, which was absent in Kiss1r-/- mice, indicating a kisspeptin-dependent action. The NK2R agonist, however, decreased LH release in ovariectomized-sham replaced females, as documented for NK3R agonists but in contrast to the NK1R agonist, which further increased LH release. Second, Tac1 (encoding SP and NKA) expression in the ARC and ventromedial (VMN) nuclei was inhibited by circulating estradiol but did not co-localize with Kiss1 mRNA. Third, about half of isolated ARC Kiss1 neurons expressed Tacr1 (NK1R) and 100% Tacr3 (NK3R); for anteroventral-periventricular Kiss1 neurons and GnRH neurons, approximately one-fourth expressed Tacr1 and one-tenth Tacr3; Tacr2 (NK2R) expression was absent in all cases. Overall, these results identify a potent regulation of gonadotropin release by the SP/NK1R and NKA/NK2R systems in the presence of kisspeptin-Kiss1r signaling, indicating that they may, along with NKB/NK3R, control GnRH release, at least in part through actions on Kiss1 neurons.
Dubois SL, Acosta-Martinez M, DeJoseph MR, et al. Positive, but not negative feedback actions of estradiol in female mice require estrogen receptor α (ERα) in kisspeptin neurons. Endocrinology. http://press.endocrine.org/doi/abs/10.1210/en.2014-1851
Hypothalamic kisspeptin (Kiss1) neurons express estrogen receptor α (ERα) and exert control over GnRH/LH secretion in female rodents.
It has been proposed that estradiol (E2) activation of ERα in kisspeptin neurons in the arcuate nucleus (ARC) suppresses GnRH/LH secretion (negative feedback), while E2 activation of ERα in kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) mediates the release of preovulatory GnRH/LH surges (positive feedback).
To test these hypotheses, we generated mice bearing kisspeptin cell-specific deletion of ERα (KERαKO) and treated them with E2 regimens that evoke either negative or positive feedback actions on GnRH/LH secretion.
Using negative feedback regimens, as expected, E2 effectively suppressed LH levels in ovariectomized (OVX) wild-type (WT) mice to the levels seen in ovary-intact mice.
Surprisingly, however, despite the fact that E2 regulation of Kiss1 mRNA expression was abrogated in both the ARC and AVPV of KERαKO mice, E2 also effectively decreased LH levels in OVX KERαKO mice to the levels seen in ovary-intact mice.
Conversely, using a positive feedback regimen, E2 stimulated LH surges in WT mice, but had no effect in KERαKO mice.
These experiments clearly demonstrate that ERα in kisspeptin neurons is required for the positive, but not negative feedback actions of E2 on GnRH/LH secretion in adult female mice.
It remains to be determined if the failure of KERαKO mice to exhibit GnRH/LH surges reflects the role of ERα in the development of kisspeptin neurons, in the active signaling processes leading to the release of GnRH/LH surges, or both.
Hypothalamic kisspeptin (Kiss1) neurons express estrogen receptor α (ERα) and exert control over GnRH/LH secretion in female rodents.
It has been proposed that estradiol (E2) activation of ERα in kisspeptin neurons in the arcuate nucleus (ARC) suppresses GnRH/LH secretion (negative feedback), while E2 activation of ERα in kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) mediates the release of preovulatory GnRH/LH surges (positive feedback).
To test these hypotheses, we generated mice bearing kisspeptin cell-specific deletion of ERα (KERαKO) and treated them with E2 regimens that evoke either negative or positive feedback actions on GnRH/LH secretion.
Using negative feedback regimens, as expected, E2 effectively suppressed LH levels in ovariectomized (OVX) wild-type (WT) mice to the levels seen in ovary-intact mice.
Surprisingly, however, despite the fact that E2 regulation of Kiss1 mRNA expression was abrogated in both the ARC and AVPV of KERαKO mice, E2 also effectively decreased LH levels in OVX KERαKO mice to the levels seen in ovary-intact mice.
Conversely, using a positive feedback regimen, E2 stimulated LH surges in WT mice, but had no effect in KERαKO mice.
These experiments clearly demonstrate that ERα in kisspeptin neurons is required for the positive, but not negative feedback actions of E2 on GnRH/LH secretion in adult female mice.
It remains to be determined if the failure of KERαKO mice to exhibit GnRH/LH surges reflects the role of ERα in the development of kisspeptin neurons, in the active signaling processes leading to the release of GnRH/LH surges, or both.
Bhattacharya M, Babwah AV. Kisspeptin: Beyond the Brain. Endocrinology. http://press.endocrine.org/doi/abs/10.1210/en.2014-1915
The hypothalamic-based kisspeptin signaling system is a major positive regulator of the neuroendocrine-reproductive axis in mammals. Over the last decade, major advances have been made in understanding how this signaling system is regulated and how it can be manipulated clinically to achieve beneficial outcomes in treating sex steroid-dependent disorders.
Interestingly, kisspeptin was not first identified as a regulator of fertility. Instead, about seven years earlier KISS1 was reported to be expressed in non-metastatic melanoma cells and was subsequently demonstrated to act as a powerful suppressor of the metastatic potential of malignant melanoma cells.
Since this discovery, numerous studies have demonstrated the expression of the kisspeptin signaling system at several peripheral sites implicating it in biological processes such as the regulation of ovarian function, embryo implantation, placentation, angiogenesis, insulin secretion and kidney development.
While much work remains to be done to assess how important kisspeptin signaling is in regulating some of these processes, for other processes recent studies have made tremendous strides towards such an assessment.
Using mice lacking Kiss1 and Kiss1r alleles, researchers have provided compelling evidence for kisspeptin playing a major role in regulating breast cancer metastasis, oocyte survival, follicular maturation, ovulation and embryo implantation.
This review critically discusses the findings from these as well as other studies which suggest roles for kisspeptin in regulating important physiological processes beyond the brain. It also discusses the challenges that lie ahead in determining whether findings made with animal models are relevant in humans.
The hypothalamic-based kisspeptin signaling system is a major positive regulator of the neuroendocrine-reproductive axis in mammals. Over the last decade, major advances have been made in understanding how this signaling system is regulated and how it can be manipulated clinically to achieve beneficial outcomes in treating sex steroid-dependent disorders.
Interestingly, kisspeptin was not first identified as a regulator of fertility. Instead, about seven years earlier KISS1 was reported to be expressed in non-metastatic melanoma cells and was subsequently demonstrated to act as a powerful suppressor of the metastatic potential of malignant melanoma cells.
Since this discovery, numerous studies have demonstrated the expression of the kisspeptin signaling system at several peripheral sites implicating it in biological processes such as the regulation of ovarian function, embryo implantation, placentation, angiogenesis, insulin secretion and kidney development.
While much work remains to be done to assess how important kisspeptin signaling is in regulating some of these processes, for other processes recent studies have made tremendous strides towards such an assessment.
Using mice lacking Kiss1 and Kiss1r alleles, researchers have provided compelling evidence for kisspeptin playing a major role in regulating breast cancer metastasis, oocyte survival, follicular maturation, ovulation and embryo implantation.
This review critically discusses the findings from these as well as other studies which suggest roles for kisspeptin in regulating important physiological processes beyond the brain. It also discusses the challenges that lie ahead in determining whether findings made with animal models are relevant in humans.
Similar threads
