ABSTRACT
Kisspeptin (KP) and neurokinin B (NKB) are neuropeptides that govern the reproductive endocrine axis through regulating hypothalamic gonadotropin-releasing hormone (GnRH) neuronal activity and pulsatile GnRH secretion. Their critical role in reproductive health was first identified after inactivating variants in genes encoding for KP or NKB signaling were shown to result in congenital hypogonadotropic hypogonadism and a failure of pubertal development. Over the past 2 decades since their discovery, a wealth of evidence from both basic and translational research has laid the foundation for potential therapeutic applications. Beyond KP's function in the hypothalamus, it is also expressed in the placenta, liver, pancreas, adipose tissue, bone, and limbic regions, giving rise to several avenues of research for use in the diagnosis and treatment of pregnancy, metabolic, liver, bone, and behavioral disorders. The role played by NKB in stimulating the hypothalamic thermoregulatory center to mediate menopausal hot flashes has led to the development of medications that antagonize its action as a novel nonsteroidal therapeutic agent for this indication. Furthermore, the ability of NKB antagonism to partially suppress (but not abolish) the reproductive endocrine axis has supported its potential use for the treatment of various reproductive disorders including polycystic ovary syndrome, uterine fibroids, and endometriosis. This review will provide a comprehensive up-to-date overview of the preclinical and clinical data that have paved the way for the development of diagnostic and therapeutic applications of KP and NKB.
Subject(s)
Kisspeptins , Neurokinin B , Pregnancy , Female , Humans , Neurokinin B/genetics , Neurokinin B/metabolism , Kisspeptins/therapeutic use , Gonadotropin-Releasing Hormone/metabolism , Reproduction/physiology , HypothalamusABSTRACT
Endometriosis and polycystic ovary syndrome (PCOS) are two common female reproductive disorders with a significant impact on the health and quality of life of women affected. A novel hypothesis by evolutionary biologists suggested that these two diseases are inversely related to one another, representing a pair of diametrical diseases in terms of opposite alterations in reproductive physiological processes but also contrasting phenotypic traits. However, to fully explain the phenotypic features observed in women with these conditions, we need to establish a potential nexus system between the reproductive system and general biological functions. The recent discovery of kisspeptin as pivotal mediator of internal and external inputs on the hypothalamic-pituitary-gonadal axis has led to a new understanding of the neuroendocrine upstream regulation of the human reproductive system. In this review, we summarize the current knowledge on the physiological roles of kisspeptin in human reproduction, as well as its involvement in complex biological functions such as metabolism, inflammation and pain sensitivity. Importantly, these functions are known to be dysregulated in both PCOS and endometriosis. Within the evolving scientific field of "kisspeptinology", we critically discuss the clinical relevance of these discoveries and their potential translational applications in endometriosis and PCOS. By exploring the possibilities of manipulating this complex signaling system, we aim to pave the way for novel targeted therapies in these reproductive diseases.
Subject(s)
Endometriosis , Polycystic Ovary Syndrome , Female , Humans , Polycystic Ovary Syndrome/metabolism , Kisspeptins/metabolism , Kisspeptins/therapeutic use , Quality of Life , Reproduction/physiologyABSTRACT
Importance: The human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to low sexual desire; the most prevalent psychological form is hypoactive sexual desire disorder (HSDD), which affects 8% of men but currently has no effective pharmacological treatment options. The reproductive neuropeptide kisspeptin offers a putative therapeutic target, owing to emerging understanding of its role in reproductive behavior. Objective: To determine the physiological, behavioral, neural, and hormonal effects of kisspeptin administration in men with HSDD. Design, Setting, and Participants: This double-blind, 2-way crossover, placebo-controlled randomized clinical trial was performed at a single academic research center in the UK. Eligible participants were right-handed heterosexual men with HSDD. Physiological, behavioral, functional magnetic resonance imaging (fMRI), and hormonal analyses were used to investigate the clinical and mechanistic effects of kisspeptin administration in response to visual sexual stimuli (short and long video tasks). The trial was conducted between January 11 and September 15, 2021, and data analysis was performed between October and November 2021. Interventions: Participants attended 2 study visits at least 7 days apart, in balanced random order, for intravenous infusion of kisspeptin-54 (1 nmol/kg/h) for 75 minutes or for administration of a rate-matched placebo. Main Outcomes and Measures: Changes in (1) brain activity on whole-brain analysis, as determined by fMRI blood oxygen level-dependent activity in response to visual sexual stimuli during kisspeptin administration compared with placebo, (2) physiological sexual arousal (penile tumescence), and (3) behavioral measures of sexual desire and arousal. Results: Of the 37 men randomized, 32 completed the trial. Participants had a mean (SD) age of 37.9 (8.6) years and a mean (SD) body mass index of 24.9 (5.4). On viewing sexual videos, kisspeptin significantly modulated brain activity in key structures of the sexual-processing network on whole-brain analysis compared with placebo (mean absolute change [Cohen d] = 0.81 [95% CI, 0.41-1.21]; P = .003). Furthermore, improvements in several secondary analyses were observed, including significant increases in penile tumescence in response to sexual stimuli (by up to 56% more than placebo; mean difference = 0.28 units [95% CI, 0.04-0.52 units]; P = .02) and behavioral measures of sexual desire-most notably, increased happiness about sex (mean difference = 0.63 points [95% CI, 0.10-1.15 points]; P = .02). Conclusions and Relevance: Collectively, this randomized clinical trial provides the first evidence to date showing that kisspeptin administration substantially modulates sexual brain processing in men with HSDD, with associated increases in penile tumescence and behavioral measures of sexual desire and arousal. These data suggest that kisspeptin has potential as the first pharmacological treatment for men with low sexual desire. Trial Registration: isrctn.org Identifier: ISRCTN17271094.
Subject(s)
Penile Erection , Sexual Dysfunctions, Psychological , Male , Humans , Adult , Kisspeptins/pharmacology , Kisspeptins/therapeutic use , Sexual Behavior , Sexual Dysfunctions, Psychological/drug therapy , Brain/diagnostic imagingABSTRACT
BACKGROUND: Kisspeptin has recently emerged as a key regulator of the reproductive axis in women. Kisspeptin, acting centrally via the kisspeptin receptor, stimulates the secretion of the gonadotrophin-releasing hormone (GnRH). AIMS: To investigate serum kisspeptin levels in infertility patients for its clinical utilisation in management and understanding of the pathophysiology of infertility in a wide array of patients. METHODS: This prospective case-control study analysis involved 92 primary infertile women with PCOS, diminished ovarian reserve (DOR), unexplained infertility (UEI), and male factor infertility between 20 and 42 years of age. Serum samples were collected between the second and fifth day of the menstrual cycle. The kisspeptin level was determined using a human kisspeptin ELISA kit according to the manufacturer's procedure. RESULTS: The median value of serum kisspeptin in the PCOS infertility group was significantly higher than that in the UEI group (p = 0.011). There was a statistically significant (p = 0.015, r = -0.182) negative weak correlation found between serum kisspeptin levels and age. The optimal cutoff value obtained to differentiate the UEI from others (PCOS infertility + DOR + male factor infertility) according to the serum kisspeptin level was 214.3 ng/L with a sensitivity of 55% and specificity of 80.9%. CONCLUSIONS: Understanding the role of kisspeptin may lead to its use as a biomarker in infertility diagnosis in UEI patients and might guide the use of kisspeptin analogues in selected patients for infertility management.
Subject(s)
Infertility, Female , Infertility, Male , Polycystic Ovary Syndrome , Humans , Female , Male , Infertility, Female/drug therapy , Polycystic Ovary Syndrome/drug therapy , Kisspeptins/therapeutic use , Case-Control Studies , Gonadotropin-Releasing Hormone , Infertility, Male/drug therapyABSTRACT
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) adversely affects reproduction. We aimed to study the effect of a high-fat diet (HFD), supplemented with apple vinegar, on folliculogenesis in a rat model of NAFLD. METHODS: Female rats were randomly divided into four groups (N = 28): Standard diet (SD), SD + vinegar, HFD, and HFD + vinegar groups. At the end of the study, biochemical tests were assessed in serum. HOMA-IR (Homeostatic model assessment-Insulin resistance) was calculated. Sex hormones were determined using an ELISA kit; ovary follicle counts were studied using histological methods. The proliferation index of granulosa cells was determined using immunohistochemistry. Kisspeptin expression in the ovary was detected using RT-PCR. RESULTS: The HFD induced steatohepatitis and NAFLD. The ovaries in the rat model of NAFLD were atrophied. The ovaries had less count of developing follicles and corpus luteum, and more degenerated and cystic follicles in comparison with the SD group. Vinegar + HFD consumption decreased ALT, compared to the HFD group (P = 0.004). Steatohepatitis was reduced in the Vinegar + HFD group (P = 0.001). Vinegar + HFD considerably reduced HOMA-IR (p = 0.01). The HFD + vinegar diet could increase estradiol (P = 0.001), without significantly affecting progesterone or testosterone. In addition, an increase of primordial follicles as an ovarian reserve and also primary follicles were determined in the HFD + vinegar group. There were no statistical differences in the granulosa cell proliferation index in various follicle types between groups. HFD + vinegar significantly enhanced ovarian kisspeptin expression (p = 0.04). CONCLUSIONS: The vinegar diet in a rat model of NAFLD raises estradiol, primordial, and small primary follicles, and increases ovarian kisspeptin expression indirectly. Insulin resistance and obesity were improved by apple vinegar, and anti-glycemic and anti-lipidemic effects were also determined. The supplementation of apple vinegar in NAFLD might be useful for ovary. However, it requires further investigation.
Subject(s)
Insulin Resistance , Malus , Non-alcoholic Fatty Liver Disease , Rats , Animals , Female , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/etiology , Ovary/metabolism , Acetic Acid/pharmacology , Acetic Acid/metabolism , Kisspeptins/pharmacology , Kisspeptins/therapeutic use , Kisspeptins/metabolism , Malus/metabolism , Diet, High-Fat/adverse effects , Estradiol , LiverABSTRACT
Kisspeptin is a hypothalamic neuropeptide that acts via the hypothalamus to stimulate hypothalamic gonadotrophin-releasing hormone secretion and downstream gonadotrophin release. In health, kisspeptin induces normal puberty and modulates ovulation in healthy women. Hypothalamic kisspeptin expression is reduced in several functional reproductive disorders; thus, treating such conditions with kisspeptin is conceptually attractive. Recent studies have demonstrated that kisspeptin can induce a more physiological degree of oocyte maturation during in vitro fertilisation treatment that can reduce the risk of potentially life-threatening complications such as ovarian hyperstimulation syndrome seen with human chorionic gonadotrophin. Furthermore, chronic use of kisspeptin could potentially restore reproductive health in females with hypothalamic amenorrhoea, treat hyposexual drive disorder in otherwise healthy males and has potential indications in polycystic ovary syndrome, osteoporosis and metabolic dysfunction-associated fatty liver disease. Finally, kisspeptin analogues could potentially overcome some of the pharmacological challenges associated with the natural forms of kisspeptin such as short duration of action and development of tachyphylaxis.
Subject(s)
Kisspeptins , Ovarian Hyperstimulation Syndrome , Male , Female , Humans , Kisspeptins/therapeutic use , Kisspeptins/metabolism , Kisspeptins/pharmacology , Ovarian Hyperstimulation Syndrome/drug therapy , Ovarian Hyperstimulation Syndrome/etiology , Ovarian Hyperstimulation Syndrome/metabolism , Gonadotropin-Releasing Hormone/metabolism , Fertilization in Vitro/adverse effects , Hypothalamus/metabolismABSTRACT
Importance: Despite being the most common female sexual health complaint worldwide, current treatment options for hypoactive sexual desire disorder (HSDD) are limited in their safety and effectiveness. The hormone kisspeptin is a key endogenous activator of the reproductive hormonal axis with additional emerging roles in sexual and emotional behavior; however, its effects in women with HSDD are unknown. Objective: To test the hypothesis that kisspeptin enhances sexual and attraction brain processing in women with HSDD. Design, Setting, and Participants: This randomized clinical trial was double-masked and placebo controlled with a 2-way crossover. The trial was conducted in a university research setting in the UK from October 2020 to April 2021. Eligible participants were premenopausal women with HSDD. Functional neuroimaging, psychometric, and hormonal analyses were employed to investigate the effects of kisspeptin administration on brain processing, in response to erotic stimuli (erotic videos) and facial attraction (face images of varying attractiveness). Data were analyzed from May to December 2021. Interventions: A 75-minute intravenous infusion of kisspeptin-54 (1 nmol/kg/h) vs equivalent-rate placebo infusion. Main Outcomes and Measures: Blood oxygen level-dependent responses across the whole brain and regions of interest during kisspeptin vs placebo administration in response to erotic and facial attraction stimuli. Results: Of the 40 participants who were randomized, 32 women completed both kisspeptin and placebo visits, with a mean (SE) age of 29.2 (1.2) years. Kisspeptin administration resulted in modulations in sexual and facial attraction brain processing (deactivation of the left inferior frontal gyrus: Z max, 3.76; P = .01; activation of the right postcentral and supramarginal gyrus: Z max, 3.73; P < .001; deactivation of the right temporoparietal junction: Z max 4.08; P = .02). Furthermore, positive correlations were observed between kisspeptin-enhanced hippocampal activity in response to erotic videos, and baseline distress relating to sexual function (r = 0.469; P = .007). Kisspeptin's enhancement of posterior cingulate cortex activity in response to attractive male faces also correlated with reduced sexual aversion, providing additional functional significance (r = 0.476, P = .005). Kisspeptin was well-tolerated with no reported adverse effects. Conclusions and Relevance: These findings lay the foundations for clinical applications for kisspeptin in women with HSDD. Trial Registration: ISRCTN trial registry identifier: ISRCTN17271094.
Subject(s)
Libido , Sexual Dysfunctions, Psychological , Female , Male , Humans , Adult , Kisspeptins/pharmacology , Kisspeptins/therapeutic use , Phentolamine/pharmacology , Phentolamine/therapeutic use , Sexual Dysfunctions, Psychological/drug therapy , Hormones/pharmacology , Hormones/therapeutic useABSTRACT
Rheumatoid arthritis (RA) is an autoimmune disease mainly characterized as chronic inflammation of joint. Both genetic and environmental factors play important roles in RA progression. G protein-coupled receptor 54 (GPR54) and Kisspeptins (KPs), the natural GRP54 ligands encoded by Kiss-1 gene are known to play important roles in immune regulation but the precise role of KP-10/GPR54 in RA remains elusive. Kiss1/Gpr54 expression was determined by immunohistochemistry on protein and real-time PCR on RNA from isolated RA-patient synovial tissue and PBMC. Collagen-induced arthritis (CIA) mouse models were used to investigate the effect of KP-10/Gpr54 on the rheumatic arthritis severity in the mice. The signaling pathway involved in KP-10/GPR54 was assessed by western blot and immunofluorescence.In the present study, we demonstrated that GPR54 upregulation in bone marrow-derived macrophages (BMDM) was associated with the severity of RA. In addition, Gpr54-/- increased the inflammatory cytokines induced by lipopolysaccharide (LPS) in BMDM and diseased severity of CIA (n = 10), while KP-10 reduced the LPS-induced inflammatory cytokines in vitro and ameliorated the CIA symptoms in vivo. Furthermore, we demonstrated that KP-10/GPR54 binds to PP2A-C to suppressed LPS induced NF-κB and MAPK signaling in BMDM. All these findings suggest that KP-10/GPR54 may be a novel therapeutic target for the diagnosis and treatment of RA.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Arthritis, Experimental/drug therapy , Kisspeptins/therapeutic use , Osteoarthritis/genetics , Receptors, Kisspeptin-1/genetics , Rheumatic Fever/genetics , Animals , Ankle Joint/diagnostic imaging , Ankle Joint/drug effects , Ankle Joint/pathology , Anti-Inflammatory Agents/pharmacology , Arthritis, Experimental/diagnostic imaging , Arthritis, Experimental/immunology , Arthritis, Experimental/pathology , Cells, Cultured , Cytokines/genetics , Humans , Kisspeptins/pharmacology , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/immunology , Mice, Inbred DBA , Mice, Knockout , Mitogen-Activated Protein Kinases/immunology , NF-kappa B/immunology , Osteoarthritis/immunology , Receptors, Kisspeptin-1/immunology , Rheumatic Fever/immunology , Signal Transduction/drug effects , Synovial Membrane/drug effects , Synovial Membrane/immunology , Up-Regulation/drug effectsABSTRACT
The aim of the study was to examine possible impacts of paroxetine and agomelatine on the levels of some components that constitute the seminal vesicle fluid. As a second purpose, it was also aimed to examine how possible negative effects induced by paroxetine on seminal vesicle fluid components were affected by kisspeptin and RF9 (an RFamide-related peptide antagonist, RFRP). Forty-two male rats, aged 21 days, divided into six groups; control, sham, paroxetine, agomelatine, paroxetine + kisspeptin and paroxetine + RF9. Paroxetine (3.6 mg/kg) and agomelatine (10 mg/kg) were administrated by oral gavage. Kisspeptin (1 nmol) and RF9 (20 nmol) were administered intracerebroventricular (i.c.v). The experiments were ended on post-natal 120 days; fructose, vitamin E, sodium, potassium and magnesium levels were measured in seminal vesicle fluid. Fructose, vitamin E, magnesium and potassium levels were significantly decreased in seminal vesicle fluid from the rats treated with paroxetine but did not show significant differences following agomelatine administration. The co-administration of kisspeptin or RF9 with paroxetine prevented the paroxetine-induced negative effects on seminal vesicle fluid components. These results suggest that reduction in sperm fertilising ability caused by changes in seminal vesicle fluid can be seen in long-term antidepressant use. RF-9 and kisspeptin might have positive effects on long-term antidepressant use-induced infertility.
Subject(s)
Acetamides/adverse effects , Paroxetine/adverse effects , Selective Serotonin Reuptake Inhibitors/adverse effects , Semen/drug effects , Adamantane/analogs & derivatives , Adamantane/pharmacology , Adamantane/therapeutic use , Animals , Dipeptides/pharmacology , Dipeptides/therapeutic use , Drug Evaluation, Preclinical , Kisspeptins/pharmacology , Kisspeptins/therapeutic use , Male , Random Allocation , Rats , Rats, Sprague-DawleySubject(s)
Endocrinology , Faculty, Medical , Laboratory Personnel , Reproductive Techniques, Assisted , Endocrinology/history , Faculty, Medical/history , Female , History, 20th Century , History, 21st Century , Humans , Infertility/drug therapy , Kisspeptins/therapeutic use , Laboratory Personnel/history , Male , Pregnancy , Reproductive Techniques, Assisted/history , Reproductive Techniques, Assisted/trends , United KingdomABSTRACT
Kisspeptin has well-established critical roles in the control of reproduction and fertility. Recently, evidence has emerged that suggests kisspeptin may have additional roles in the regulation of glucose homeostasis. Conflicting reports on the effects of kisspeptin on insulin secretion in animal models have been published, which cannot be fully accounted for by the different kisspeptin isoforms and range of kisspeptin doses used in these studies. Human studies have demonstrated associations between circulating kisspeptin levels and measures of insulin secretion and insulin resistance; and the only published interventional study has confirmed kisspeptin enhances glucose-stimulated insulin secretion in humans. Further studies are required to elucidate the mechanisms underlying the effects of kisspeptin on the pancreatic ß-cell and to determine the therapeutic potential of kisspeptin receptor agonist in the treatment of disorders of glucose homeostasis.
Subject(s)
Glucose Metabolism Disorders/etiology , Glucose/metabolism , Kisspeptins/physiology , Animals , Fertility/drug effects , Fertility/genetics , Glucose Metabolism Disorders/drug therapy , Glucose Metabolism Disorders/genetics , Homeostasis/drug effects , Homeostasis/genetics , Humans , Insulin/metabolism , Insulin Secretion/drug effects , Insulin Secretion/genetics , Kisspeptins/pharmacology , Kisspeptins/therapeutic use , Receptors, Kisspeptin-1/agonists , Reproduction/drug effects , Reproduction/geneticsABSTRACT
STUDY QUESTION: Can kisspeptin treatment induce gonadotrophin responses and ovulation in preclinical models and anovulatory women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Kisspeptin administration in some anovulatory preclinical models and women with PCOS can stimulate reproductive hormone secretion and ovulation, albeit with incomplete efficacy. WHAT IS KNOWN ALREADY: PCOS is a prevalent, heterogeneous endocrine disorder, characterized by ovulatory dysfunction, hyperandrogenism and deregulated gonadotrophin secretion, in need of improved therapeutic options. Kisspeptins (encoded by Kiss1) are master regulators of the reproductive axis, acting mainly at GnRH neurons, with kisspeptins being an essential drive for gonadotrophin-driven ovarian follicular maturation and ovulation. Altered Kiss1 expression has been found in rodent models of PCOS, although the eventual pathophysiological role of kisspeptins in PCOS remains unknown. STUDY DESIGN, SIZE, DURATION: Gonadotrophin and ovarian/ovulatory responses to kisspeptin-54 (KP-54) were evaluated in three preclinical models of PCOS, generated by androgen exposures at different developmental windows, and a pilot exploratory cohort of anovulatory women with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three models of PCOS were generated by exposure of female rats to androgens at different periods of development: PNA (prenatal androgenization; N = 20), NeNA (neonatal androgenization; N = 20) and PWA (post-weaning androgenization; N = 20). At adulthood (postnatal day 100), rats were subjected to daily treatments with a bolus of KP-54 (100 µg/kg, s.c.) or vehicle for 11 days (N = 10 per model and treatment). On Days 1, 4, 7 and 11, LH and FSH responses were assessed at different time-points within 4 h after KP-54 injection, while ovarian responses, in terms of follicular maturation and ovulation, were measured at the end of the treatment. In addition, hormonal (gonadotrophin, estrogen and inhibin B) and ovulatory responses to repeated KP-54 administration, at doses of 6.4-12.8 nmol/kg, s.c. bd for 21 days, were evaluated in a pilot cohort of anovulatory women (N = 12) diagnosed with PCOS, according to the Rotterdam criteria. MAIN RESULTS AND THE ROLE OF CHANCE: Deregulated reproductive indices were detected in all PCOS models: PNA, NeNA and PWA. Yet, anovulation was observed only in NeNA and PWA rats. However, while anovulatory NeNA rats displayed significant LH and FSH responses to KP-54 (P < 0.05), which rescued ovulation, PWA rats showed blunted LH secretion after repeated KP-54 injection and failed to ovulate. In women with PCOS, KP-54 resulted in a small rise in LH (P < 0.05), with an equivalent elevation in serum estradiol levels (P < 0.05). Two women showed growth of a dominant follicle with subsequent ovulation, one woman displayed follicle growth but not ovulation and desensitization was observed in another patient. No follicular response was detected in the other women. LIMITATIONS, REASONS FOR CAUTION: While three different preclinical PCOS models were used in order to capture the heterogeneity of clinical presentations of the syndrome, it must be noted that rat models recapitulate many but not all the features of this condition. Additionally, our pilot study was intended as proof of principle, and the number of participants is low, but the convergent findings in preclinical and clinical studies reinforce the validity of our conclusions. WIDER IMPLICATIONS OF THE FINDINGS: Our first-in-rodent and -human studies demonstrate that KP-54 administration in anovulatory preclinical models and women with PCOS can stimulate reproductive hormone secretion and ovulation, albeit with incomplete efficacy. As our rat models likely reflect the diversity of PCOS phenotypes, our results argue for the need of personalized management of anovulatory dysfunction in women with PCOS, some of whom may benefit from kisspeptin-based treatments. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by research agreements between Ferring Research Institute and the Universities of Cordoba and Edinburgh. K.S. was supported by the Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative (STMTI). Some of this work was undertaken in the MRC Centre for Reproductive Health which is funded by the MRC Centre grant MR/N022556/1. M.T.-S. is a member of CIBER Fisiopatología de la Obesidad y Nutrición, which is an initiative of Instituto de Salud Carlos III. Dr Mannaerts is an employee of Ferring International PharmaScience Center (Copenhagen, Denmark), and Drs Qi, van Duin and Kohout are employees of the Ferring Research Institute (San Diego, USA). Dr Anderson and Dr Tena-Sempere were recipients of a grant support from the Ferring Research Institute, and Dr Anderson has undertaken consultancy work and received speaker fees outside this study from Merck, IBSA, Roche Diagnostics, NeRRe Therapeutics and Sojournix Inc. Dr Skorupskaite was supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative 102419/Z/13/A. The other authors have no competing interest.
Subject(s)
Kisspeptins/therapeutic use , Ovulation/drug effects , Polycystic Ovary Syndrome/drug therapy , Adult , Animals , Disease Models, Animal , Female , Follicle Stimulating Hormone/blood , Humans , Kisspeptins/pharmacology , Luteinizing Hormone/blood , Pilot Projects , Polycystic Ovary Syndrome/blood , Rats, Wistar , Young AdultABSTRACT
Kisspeptin (KP) is an amidated neurohormone that is encoded by the KiSS1 metastasis suppressor (KISS1) gene and serves as the endogenous ligand for G proteincoupled receptor 54 (GPR54). KP is involved in the regulation of several biological functions, such as reproduction, cancer and atherogenesis. Recent data suggested that KP may induce atherosclerotic plaque progression and instability, which may be reversed by the GPR54 antagonist KP234. Despite the KISS1 gene being previously reported as a downstream target of the classic transforming growth factor (TGF)/Smad2 signaling pathway, its role in fibrosis remains elusive. The purpose of the present study was to evaluate the role of KP13 (a product of the KISS1 gene) in a bleomycin (BLM)induced idiopathic pulmonary fibrosis model. Lung tissue samples were evaluated by quantitative PCR analysis, western blotting and ELISA. Daily intraperitoneal administration of KP13 significantly ameliorated body weight loss, histopathological lung abnormalities and pulmonary collagen deposition induced by BLM. Furthermore, KP13 downregulated the expression levels of tumor necrosis factorα, TGFß, collagen type I α1, actin α2 and matrix metalloproteinase 2 in BLMtreated lungs compared with BLM group. Notably, the production of αsmooth muscle actin in lung tissues, as well as the pulmonary levels of TGFß1 and phosphorylatedSmad2/3, was reduced following treatment with KP13. The antifibrotic effects of KP13 were reversed by KP234 (an antagonist of GPR54), but not by Cetrorelix (an antagonist of the gonadotropinreleasing hormone receptor). Furthermore, apoptosisrelated proteins, such as Bax and caspase3, were decreased, whereas Bcl2 was markedly increased as determined by western blotting. Collectively, these data suggested that the KP/GPR54 signaling pathway may be a promising target for the treatment of idiopathic pulmonary fibrosis.
Subject(s)
Idiopathic Pulmonary Fibrosis/metabolism , Kisspeptins/metabolism , Signal Transduction , Animals , Apoptosis , Bleomycin/toxicity , Disease Models, Animal , Gene Expression Regulation , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/physiopathology , Idiopathic Pulmonary Fibrosis/prevention & control , Kisspeptins/pharmacology , Kisspeptins/therapeutic use , Male , Matrix Metalloproteinase 2/genetics , Mice , Mice, Inbred C57BL , Receptors, Kisspeptin-1/metabolism , Transforming Growth Factor beta/genetics , Tumor Necrosis Factor-alpha/geneticsABSTRACT
The purpose of this study was to determine the kisspeptin-10 (Kiss) administration on the damages in testicular oxidant-antioxidant system, reproductive organ weights and some spermatological characteristics resulted from methotrexate (MTX) exposure. Group 1 (n:6) received saline only; group 2 (n:6) received 50 nmol/kg kisspeptin-10 for 10 days; group 3 (n:10) received single-dose methotrexate 20 mg/kg; and group 4 (n:10) received MTX 20 mg/kg single dose and, after 3 days, received kisspeptin-10, 50 nmol/kg, lasted for 10 days by intraperitoneal injection. At the end of the study, malondialdehyde levels were found to have increased following the application of MTX while showing a significant reduction in group 4 with Kiss administration. With respect to the spermatological parameters, administering MTX decreased motility and increased the rates of abnormal spermatozoa in group 2, while improvements were observed in group 4 in the form of increased motility in the spermatozoa and fewer abnormal spermatozoa. In addition, Kiss treatment provided statistically significant increases in the absolute weight of the seminal vesicles and the relative weights of the right cauda epididymis and seminal vesicles resulting from MTX administration. MTX administration damaged some spermatological parameters and increased oxidative stress when compared to the control group. However, Kiss treatment was observed to mitigate these adverse effects as demonstrated by the improvements in coadministration of Kiss and MTX when compared to the MTX group. It is concluded that Kiss treatment may reduce MTX-induced reproductive toxicity as a potential antioxidant compound.
Subject(s)
Folic Acid Antagonists/adverse effects , Infertility, Male/prevention & control , Kisspeptins/therapeutic use , Methotrexate/adverse effects , Spermatozoa/drug effects , Animals , Kisspeptins/pharmacology , Lipid Peroxidation/drug effects , Male , Oxidative Stress/drug effects , Rats, Wistar , Testis/drug effectsABSTRACT
BACKGROUND: The neuropeptide kisspeptin stimulates luteinizing hormone (LH) secretion in healthy adults but not in adults with idiopathic hypogonadotropic hypogonadism. We hypothesized that, in children presenting with delayed or stalled puberty, kisspeptin would elicit LH secretion in those children found on detailed nighttime neuroendocrine profiling to have evidence of emerging reproductive endocrine function. METHODS: Eleven boys and four girls were admitted overnight to assess LH secretion at baseline, after a single intravenous bolus of kisspeptin, and after a single intravenous bolus of gonadotropin-releasing hormone (GnRH). Subjects then received exogenous pulsatile GnRH for 6 days and returned for a second visit to measure responses to kisspeptin and GnRH after this pituitary "priming." Responses to kisspeptin and GnRH were also measured in 5 healthy men. RESULTS: Of the 15 children with delayed/stalled puberty, 6 exhibited at least one spontaneous LH pulse overnight; all of these subjects had clear responses to kisspeptin, as did one additional subject. Seven subjects had no response to kisspeptin, and one subject exhibited an intermediate response. In the children who responded to kisspeptin, the responses had features comparable to those of adult men. CONCLUSION: In this first report of kisspeptin administration to pediatric subjects to our knowledge, children with delayed/stalled puberty showed a wide range of responses, with some showing a robust response and others showing little to no response. Further follow-up will determine whether responses to kisspeptin predict future pubertal entry for children with delayed puberty. TRIAL REGISTRATION: ClinicalTrials.gov NCT01438034 and NCT01952782. FUNDING: NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD043341, R01 HD090071, P50 HD028138), NIH National Center for Advancing Translational (UL1 TR001102), NIH National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK007028), the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery, Harvard Catalyst, Doris Duke Charitable Foundation (award 2013110), Charles H. Hood Foundation, Robert and Laura Reynolds MGH Research Scholar Program, and Harvard University. These funding sources had no role in the design of this study and did not have any role in conducting the study, analyses, interpretation of the data, or the decision to submit results.
Subject(s)
Gonadotropin-Releasing Hormone/administration & dosage , Kisspeptins/administration & dosage , Luteinizing Hormone/blood , Puberty, Delayed/drug therapy , Administration, Intravenous , Adolescent , Adult , Female , Humans , Intercellular Signaling Peptides and Proteins/administration & dosage , Intercellular Signaling Peptides and Proteins/therapeutic use , Kisspeptins/therapeutic use , Luteinizing Hormone/drug effects , Male , Outcome Assessment, Health Care , Peptide Hormones/administration & dosage , Puberty, Delayed/diagnosisABSTRACT
TAK-448 and TAK-683 are kisspeptin agonist analogs with improved in vivo stability and activity. Previous studies showed that continuous subcutaneous administration of TAK-448 or TAK-683 caused rapid and profound reductions in plasma testosterone levels in various species, including male healthy volunteers, suggesting their therapeutic potential as anti-prostate cancer agents. For clinical drug development, one-month sustained-release depots of TAK-448 and TAK-683, TAK-448-SR(1M) and TAK-683-SR(1M), were designed to improve usability in clinical practice. In this study, the pharmacokinetics/pharmacodynamics (PK/PD) profiles of TAK-448-SR(1M) and TAK-683-SR(1M) were initially tested in male rats to ensure their eligibility as one-month depots. The therapeutic advantages of TAK-448-SR(1M) and TAK-683-SR(1M) over TAP-144-SR(1M) were then investigated in a JDCaP xenograft rat model. TAK-448-SR(1M) and TAK-683-SR(1M) maintained certain levels of plasma TAK-448 free form (TAK-448F) and plasma TAK-683 free form (TAK-683F) for at least 4 weeks, before clearance from the circulation. Accompanying their desirable PK profiles, TAK-448-SR(1M) and TAK-683-SR(1M) showed favorable PD responses as one-month depots and demonstrated better testosterone control than TAP-144-SR(1M). Both depots exerted rapid and profound suppression of plasma testosterone levels in male rats. These profound suppressive effects were maintained in dose-dependent manners, before recovery toward normal levels. In the JDCaP xenograft model, TAK-448-SR(1M) and TAK-683-SR(1M) both showed better prostate-specific antigen (PSA) control than TAP-144-SR(1M), although all treatment groups eventually experienced PSA recurrence and tumor regrowth. In conclusion, this study demonstrates that both TAK-448-SR(1M) and TAK-683-SR(1M) have desirable and better PK/PD profiles than TAP-144-SR(1M) in rats, which could potentially provide better clinical outcomes in androgen-dependent prostate cancer.
Subject(s)
Androgens/metabolism , Kisspeptins/pharmacology , Kisspeptins/pharmacokinetics , Prostatic Neoplasms/drug therapy , Animals , Disease Models, Animal , Kisspeptins/therapeutic use , Male , Prostatic Neoplasms/metabolism , Rats , Rats, Sprague-Dawley , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVES: Neurokinin B (NKB) and kisspeptin are obligate for normal gonadotropin secretion, and links between gonadotropin-releasing hormone (GnRH) pulsatility and vasomotor symptoms have been proposed. Using a selective NKB receptor (NK3R) antagonist, the role of NKB in the hypergonadotropic state in menopausal women was explored. METHODS: Eleven postmenopausal women were administered the NK3R antagonist MLE4901 at 40 mg twice daily orally for 7 days. Ten-minute blood sampling for 8 h was performed before and on the last day of NK3R antagonist treatment for luteinising hormone (LH) pulsatility analysis with kisspeptin-10 (0.3 µg/kg i.v. bolus) administered at 6 h on both days. Hot flash frequency and severity were self-reported for 7 days before and during NK3R antagonist administration. RESULTS: LH fell from 29.3 ± 4.1 to 24.4 ± 3.8 IU/L (p < 0.05) after 7 days of NK3R antagonist treatment, with no change in follicle-stimulating hormone (FSH). Basal (non-pulsatile) LH secretion was reduced (549.0 ± 70.8 vs. 366.1 ± 92.1 IU/L/6 h, p = 0.006), and while the LH pulse frequency did not change in the group as a whole (from 0.8 ± 0.1 to 0.7 ± 0.1 pulses/h, ns), it did fall in the 8 women with hot flashes (from 1.0 ± 0.1 to 0.7 ± 0.1 pulses/h, p < 0.05). These women also reported a reduction in hot flash frequency (from 3.4 ± 1.2 to 1.0 ± 0.6 hot flashes/day, p = 0.008) whilst taking the NK3R antagonist. Kisspeptin-10 did not affect LH secretion with or without the NK3R antagonist. CONCLUSIONS: The administration of an NK3R antagonist indicates a role for NKB in the regulation of LH/GnRH in postmenopausal women, whereas the lack of response to kisspeptin may reflect the hypo-oestrogenic state. These data support a link of LH/GnRH pulsatility and vasomotor symptoms with NK3R antagonism as a potential therapeutic approach.
Subject(s)
Gonadotropins/metabolism , Hot Flashes/drug therapy , Neurokinin B/metabolism , Postmenopause/drug effects , Receptors, Neurokinin-3/antagonists & inhibitors , Administration, Oral , Female , Follicle Stimulating Hormone/blood , Gonadotropin-Releasing Hormone/metabolism , Hot Flashes/metabolism , Humans , Kisspeptins/metabolism , Kisspeptins/therapeutic use , Luteinizing Hormone/blood , Middle Aged , Periodicity , Postmenopause/metabolism , Receptors, Neurokinin-3/metabolism , Treatment OutcomeABSTRACT
STUDY QUESTION: What are the in vivo and in vitro actions of kisspeptin-54 on the expression of genes involved in ovarian reproductive function, steroidogenesis and ovarian hyperstimulation syndrome (OHSS) in granulosa lutein (GL) cells when compared with traditional triggers of oocyte maturation? SUMMARY ANSWER: The use of kisspeptin-54 as an oocyte maturation trigger augmented expression of genes involved in ovarian steroidogenesis in human GL cells including, FSH receptor (FSHR), LH/hCG receptor (LHCGR), steroid acute regulatory protein (STAR), aromatase, estrogen receptors alpha and beta (ESR1, ESR2), 3-beta-hydroxysteroid dehydrogenase type 2 (3BHSD2) and inhibin A (INHBA), when compared to traditional maturation triggers, but did not alter markers of OHSS. WHAT IS KNOWN ALREADY: hCG is the most widely used trigger of oocyte maturation, but is associated with an increased risk of OHSS. The use of GnRH agonists to trigger oocyte maturation is a safer alternative to hCG. More recently, kisspeptin-54 has emerged as a novel therapeutic option that safely triggers oocyte maturation even in women at high risk of OHSS. Kisspeptin indirectly stimulates gonadotropin secretion by acting on hypothalamic GnRH neurons. Kisspeptin and its receptor are also expressed in the human ovary, but there is limited data on the direct action of kisspeptin on the ovary. STUDY DESIGN SIZE, DURATION: Forty-eight women undergoing IVF treatment for infertility consented to kisspeptin-54 triggering and/or granulosa cell collection and were included in the study. Twelve women received hCG, 12 received GnRH agonist and 24 received kisspeptin-54 to trigger oocyte maturation. In the kisspeptin-54 group, 12 received one injection of kisseptin-54 (9.6 nmol/kg) and 12 received two injections of kisspeptin-54 at a 10 h interval (9.6 nmol/kg × 2). PARTICIPANTS/MATERIALS, SETTING, METHODS: Follicular fluid was aspirated and pooled from follicles during the retrieval of oocytes for IVF/ICSI. GL cells were isolated and either RNA extracted immediately or cultured in vitro ± kisspeptin or hCG. MAIN RESULTS AND THE ROLE OF CHANCE: GL cells from women who had received kisspeptin-54 had a 14-fold and 8-fold higher gene expression of FSHR and a 2-fold (ns) and 2.5-fold (P < 0.05) higher expression of LHCGR than GL cells from women who had received hCG or GnRH agonist, respectively. CYP19A1 expression was 3.6-fold (P < 0.05) and 4.5-fold (P < 0.05) higher, STAR expression was 3.4-fold (P < 0.01) and 1.8-fold (P < 0.05) higher, HSD3B2 expression was 7.5- (P < 0.01) and 2.5-fold higher (P < 0.05), INHBA was 2.5-fold (P < 0.01) and 2.5-fold (P < 0.01) higher in GL cells from women who had received kisspeptin-54 than hCG or GnRHa, respectively. ESR1 (P < 0.05) and ESR2 (P < 0.05) both showed 3-fold higher expression in cells from kisspeptin treated than GnRHa treated women. Markers of vascular permeability and oocyte growth factors were unchanged (VEGFA, SERPINF1, CDH5, amphiregulin, epiregulin). Gene expression of kisspeptin receptor was unchanged. Whereas treating GL cells in vitro with hCG induced steroidogenic gene expression, kisspeptin-54 had no significant direct effects on either OHSS genes or steroidogenic genes. LIMITATIONS REASONS FOR CAUTION: Most women in the study had PCOS, which may limit applicability to other patient groups. For the analysis of the in vitro effects of kisspeptin-54, it is important to note that GL cells had already been exposed in vivo to an alternate maturation trigger. WIDER IMPLICATIONS OF THE FINDINGS: The profile of serum gonadotropins seen with kisspeptin administration compared to other triggers more closely resemble that of the natural cycle as compared with hCG. Thus, kisspeptin could potentially permit an ovarian environment augmented for steroidogenesis, in particular progesterone synthesis, which is required for embryo implantation. STUDY FUNDING/COMPETING INTEREST(S): Dr Owens is supported by an Imperial College London PhD Scholarship. Dr Abbara is supported by an National Institute of Health Research Academic Clinical Lectureship. The authors do not have any conflict of interest to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01667406.
Subject(s)
Kisspeptins/therapeutic use , Luteal Cells/drug effects , Luteal Cells/physiology , Ovulation Induction/methods , Adult , Cells, Cultured , Chorionic Gonadotropin/therapeutic use , Female , Gene Expression/drug effects , Gonadotropin-Releasing Hormone/agonists , Humans , In Vitro Oocyte Maturation Techniques/methods , Infertility/therapy , Kisspeptins/administration & dosage , Kisspeptins/adverse effects , Ovarian Hyperstimulation Syndrome/etiology , Ovarian Hyperstimulation Syndrome/genetics , Ovulation Induction/adverse effects , Pregnancy , Receptors, Gonadotropin/genetics , Receptors, Kisspeptin-1/geneticsABSTRACT
Gonadotropin-releasing hormone (GnRH) plays an important role in the process of reproduction. Studies have shown that a family of peptides Kisspeptin can act on GnRH-related neurons, stimulating the secretion of GnRH, and activating the hypothalamic-pituitary-gonadal axis. Both animal experiments and clinical studies have shown that exogenous administration of Kisspeptin is able to induce physiological GnRH release in healthy individuals and those with endocrine-disorders, which brings great hope for treatment of reproductive endocrine diseases. The effect of Kisspeptin is similar to the physiological process in induction of ovulation and ovum maturation, leading to high security and efficiency for women receiving in vitro fertilization. Kisspeptin is involved in trophoblast invasion, so it may be useful for predicting pregnancy outcomes. In addition, Kisspeptin is the key hormone in the onset of puberty acting as a signal transducer in metabolism and reproduction, so it provides some directions for studies of polycystic ovary syndrome, hyperprolactinemia, and other metabolic-related reproductive endocrine diseases. This article reviews the character of Kisspeptin and the prospect of its application in treatment of reproductive endocrine diseases.
Subject(s)
Endocrinology , Infertility , Kisspeptins , Animals , Female , Gonadotropin-Releasing Hormone/metabolism , Humans , Infertility/therapy , Kisspeptins/metabolism , Kisspeptins/therapeutic use , PregnancyABSTRACT
Kissorphin (KSO) is a new peptide derived from kisspeptin-10. This peptide possesses neuropeptide FF (NPFF)-like biological activity in vitro; NPFF, in many cases, inhibits opioid and ethanol effects in rodents. Therefore, the current study explored the influence of KSO on acute ethanol- and morphine-induced hyperactivity, and on the development and expression of locomotor sensitization induced by these drugs. In the present study, sensitization to locomotor effects was induced by repeated exposure to ethanol (2.4 g/kg, intraperitoneally [i.p.], 1 × 4 days) or morphine (10 mg/kg, subcutaneously [s.c.], 1 × 7 days). We found that KSO (1-10 nmol/300 µL, intravenously [i.v.]) did not have an impact on locomotor activity of naïve mice. However, it reduced both acute ethanol- (10 nmol/300 µL) and morphine-induced hyperactivity (3 and 10 nmol/300 µL). Pretreatment of animals with KSO (10 nmol/300 µL), before every ethanol or morphine injection during development of sensitization or before the ethanol or morphine challenge, attenuated the development, as well as the expression of locomotor sensitization to both substances. Moreover, prior administration of the NPFF receptor antagonist RF9 (10 nmol/300 µL, i.v.) inhibited the ability of KSO (10 nmol/300 µL) to reduce the expression of ethanol and morphine sensitization. KSO given alone, at all used doses, did not influence the motor coordination measured via the rotarod test. The results from this study show that KSO effectively attenuated acute and repeated effects of ethanol and morphine. Thus, KSO possesses NPFF-like anti-opioid activity in these behavioral studies.