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Journal of Neuroendocrinology May 2022Mathematical modelling is an indispensable tool in modern biosciences, enabling quantitative analysis and integration of biological data, transparent formulation of our... (Review)
Review
Mathematical modelling is an indispensable tool in modern biosciences, enabling quantitative analysis and integration of biological data, transparent formulation of our understanding of complex biological systems, and efficient experimental design based on model predictions. This review article provides an overview of the impact that mathematical models had on GnRH research. Indeed, over the last 20 years mathematical modelling has been used to describe and explore the physiology of the GnRH neuron, the mechanisms underlying GnRH pulsatile secretion, and GnRH signalling to the pituitary. Importantly, these models have contributed to GnRH research via novel hypotheses and predictions regarding the bursting behaviour of the GnRH neuron, the role of kisspeptin neurons in the emergence of pulsatile GnRH dynamics, and the decoding of GnRH signals by biochemical signalling networks. We envisage that with the advent of novel experimental technologies, mathematical modelling will have an even greater role to play in our endeavour to understand the complex spatiotemporal dynamics underlying the reproductive neuroendocrine system.
Topics: Gonadotropin-Releasing Hormone; Kisspeptins; Models, Theoretical; Neurons; Reproduction
PubMed: 35080068
DOI: 10.1111/jne.13085 -
Frontiers in Endocrinology 2022Kisspeptin and its receptor are central to reproductive health acting as key regulators of the reproductive endocrine axis in humans. Kisspeptin is most widely... (Review)
Review
Kisspeptin and its receptor are central to reproductive health acting as key regulators of the reproductive endocrine axis in humans. Kisspeptin is most widely recognised as a regulator of gonadotrophin releasing hormone (GnRH) neuronal function. However, recent evidence has demonstrated that kisspeptin and its receptor also play a fundamental role during pregnancy in the regulation of placentation. Kisspeptin is abundantly expressed in syncytiotrophoblasts, and its receptor in both cyto- and syncytio-trophoblasts. Circulating levels of kisspeptin rise dramatically during healthy pregnancy, which have been proposed as having potential as a biomarker of placental function. Indeed, alterations in kisspeptin levels are associated with an increased risk of adverse maternal and foetal complications. This review summarises data evaluating kisspeptin's role as a putative biomarker of pregnancy complications including miscarriage, ectopic pregnancy (EP), preterm birth (PTB), foetal growth restriction (FGR), hypertensive disorders of pregnancy (HDP), pre-eclampsia (PE), gestational diabetes mellitus (GDM), and gestational trophoblastic disease (GTD).
Topics: Biomarkers; Female; Humans; Kisspeptins; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premature Birth
PubMed: 35928889
DOI: 10.3389/fendo.2022.942664 -
Advances in Experimental Medicine and... 2013The hypothalamic hormone GnRH has traditionally been viewed as a central driver of the hypothalamic-pituitary-gonadal axis. Pulsatile GnRH release is required for... (Review)
Review
The hypothalamic hormone GnRH has traditionally been viewed as a central driver of the hypothalamic-pituitary-gonadal axis. Pulsatile GnRH release is required for pulsatile gonadotropin secretion, which then modulates gonadal steroid feedback and brings about full fertility in the adult. Pathways governing GnRH ontogeny and physiology have been discovered by studying humans with disorders of GnRH secretion. In this chapter, the human genetics of the kisspeptin signaling pathway in patients with diverse reproductive phenotypes will be explored. The discovery of defects in the kisspeptin system in several reproductive disorders has shed light on the mechanisms involved in regulating GnRH secretion, revealing the critical role played by the kisspeptin signaling pathway in pubertal initiation and reproductive function.
Topics: Adult; Female; Fertility; Humans; Hypothalamo-Hypophyseal System; Infertility; Kisspeptins; Male; Signal Transduction
PubMed: 23550007
DOI: 10.1007/978-1-4614-6199-9_9 -
Seminars in Reproductive Medicine Jul 2019Kisspeptins (KPs), peptide products of the kisspeptin-1 () gene, are the endogenous ligands for the KISS1 receptor, KISS1R, which is a G protein-coupled receptor. In... (Review)
Review
Kisspeptins (KPs), peptide products of the kisspeptin-1 () gene, are the endogenous ligands for the KISS1 receptor, KISS1R, which is a G protein-coupled receptor. In many human tumors, functions as a metastasis-suppressor gene and KISS1/KISS1R signaling has antimetastatic and tumor-suppressor roles. On the contrary, emerging evidence indicates that the KP/KISS1R pathway plays detrimental roles in triple negative breast cancer (TNBC), the most difficult type of breast cancer to treat. TNBC patients initially respond to chemotherapy, but tumors acquire drug resistance and many patients relapse and die of metastases within a few years. In this review, we summarize recent developments in the understanding of the mechanisms by which KP/KISS1R signaling plays an adverse role in TNBC. This includes focusing on how KISS1R signaling regulates the cell cytoskeleton to induce tumor invadopodia formation and how KISS1R communicates with growth factor receptors such as the epidermal growth factor receptor, the receptor tyrosine kinase AXL, and transforming growth factor-β to promote cell invasion, metastasis, and drug resistance.
Topics: Animals; Breast Neoplasms; Female; Humans; Kisspeptins; Neoplasm Metastasis; Neoplasm Recurrence, Local; Receptors, Kisspeptin-1; Signal Transduction
PubMed: 31972865
DOI: 10.1055/s-0039-3400968 -
Journal of Neuroendocrinology May 2022For about two decades, recordings of identified gonadotropin-releasing hormone (GnRH) neurons have provided a wealth of information on their properties. We describe... (Review)
Review
For about two decades, recordings of identified gonadotropin-releasing hormone (GnRH) neurons have provided a wealth of information on their properties. We describe areas of consensus and debate the intrinsic electrophysiologic properties of these cells, their response to fast synaptic and neuromodulatory input, Ca imaging correlates of action potential firing, and signaling pathways regulating these aspects. How steroid feedback and development change these properties, functions of GnRH neuron subcompartments and local networks, as revealed by chemo- and optogenetic approaches, are also considered.
Topics: Action Potentials; Estradiol; Gonadotropin-Releasing Hormone; Kisspeptins; Neurons; Signal Transduction
PubMed: 34939256
DOI: 10.1111/jne.13073 -
Experimental Physiology Nov 2013Kisspeptin (Kiss1) neurons are vital for reproduction. Gonatotrophin-releasing hormone (GnRH) neurons express the kisspeptin receptor (GPR54), and kisspeptins potently... (Review)
Review
Kisspeptin (Kiss1) neurons are vital for reproduction. Gonatotrophin-releasing hormone (GnRH) neurons express the kisspeptin receptor (GPR54), and kisspeptins potently stimulate the release of GnRH by depolarizing and inducing sustained action potential firing in GnRH neurons. As such, Kiss1 neurons may be the presynaptic pacemaker neurons in the hypothalamic circuitry that controls reproduction. There are at least two different populations of Kiss1 neurons; one in the rostral periventricular area (RP3V) that is stimulated by oestrogens and the other in the arcuate nucleus that is inhibited by oestrogens. How each of these Kiss1 neuronal populations participates in the regulation of the reproductive cycle is currently under intense investigation. Based on electrophysiological studies in the guinea-pig and mouse, Kiss1 neurons in general are capable of generating burst-firing behaviour. Essentially, all Kiss1 neurons, which have been studied thus far in the arcuate nucleus, express the ion channels necessary for burst firing, which include hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels and the T-type calcium (Cav3.1) channels. In voltage-clamp conditions, these channels produce distinct currents that can generate burst-firing behaviour in current-clamp conditions. The future challenge is to identify other key channels and synaptic inputs involved in the regulation of the firing properties of Kiss1 neurons and the physiological regulation of the expression of these channels and receptors by oestrogens and other hormones. The ultimate goal is to understand how Kiss1 neurons control the different phases of GnRH neurosecretion, hence reproduction.
Topics: Action Potentials; Animals; Arcuate Nucleus of Hypothalamus; Estradiol; Estrogens; Female; Guinea Pigs; Hypothalamus; Kisspeptins; Mice; Neurons; TRPC Cation Channels
PubMed: 23884368
DOI: 10.1113/expphysiol.2013.074559 -
Journal of Experimental & Clinical... Jan 2009KiSS-1 was identified as a metastasis-suppressing gene in melanoma cells. The KiSS-1 gene product (metastin) was isolated from human placenta as the ligand of GPR54, a...
BACKGROUND
KiSS-1 was identified as a metastasis-suppressing gene in melanoma cells. The KiSS-1 gene product (metastin) was isolated from human placenta as the ligand of GPR54, a G-protein-coupled receptor. The role of metastin and GPR54 in tumor progression is not fully understood.
METHODS
We investigated the clinical significance of metastin and GPR54 expression in pancreatic cancer. We evaluated immunohistochemical expression of metastin and GPR54 in pancreatic ductal adenocarcinoma tissues obtained from 53 consecutive patients who underwent resection between July 2003 and May 2007 at Kyoto University Hospital. In 23 consecutive patients, the plasma metastin level was measured before surgery by enzyme immunoassay.
RESULTS
Strong immunohistochemical expression of metastin was detected in 13 tumors (24.5%), while strong expression of GPR54 was detected in 30 tumors (56.6%). Tumors that were negative for both metastin and GPR54 expression were significantly larger than tumors that were positive for either metastin or GPR54 (p = 0.047). Recurrence was less frequent in patients who had metastin-positive tumors compared with those who had metastin-negative tumors (38.5% versus 70.0%, p = 0.04). Strong expression of metastin and GPR54 was significantly correlated with longer survival (p = 0.02). Metastin expression by pancreatic cancer was an independent prognostic factor for longer survival (hazard ratio, 2.1; 95% confidence interval, 1.1-4.7; p = 0.03), and the patients with a high plasma metastin level (n = 6) did not die after surgical resection.
CONCLUSION
Strong expression of metastin and GPR54 by pancreatic cancer is associated with longer survival. Metastin expression is an independent prognostic factor for the survival of pancreatic cancer patients. The plasma metastin level could become a noninvasive prognostic factor for the assessment of pancreatic cancer.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Female; Health; Humans; Immunohistochemistry; Kisspeptins; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Prognosis; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Recurrence; Survival Rate; Tumor Suppressor Proteins
PubMed: 19154616
DOI: 10.1186/1756-9966-28-9 -
Trends in Endocrinology and Metabolism:... Oct 2015While kisspeptin was initially found to function as a metastasis suppressor, after identification of its receptor KISS1R and their expression profiles in tissues such as... (Review)
Review
While kisspeptin was initially found to function as a metastasis suppressor, after identification of its receptor KISS1R and their expression profiles in tissues such as the hypothalamus and adrenals, kisspeptin and KISS1R were predominantly assigned endocrine functions, including regulating puberty and fertility through their actions on hypothalamic gonadotropin releasing hormone production. More recently, an alter ego for kisspeptin has emerged, with a significant role in regulating glucose homeostasis, insulin secretion, as well as food intake and body composition, and deficient kisspeptin signaling results in reduced locomotor activity and increased adiposity. This review highlights these recent observations on the role of kisspeptin in metabolism as well as several key questions that need to be addressed in the future.
Topics: Animals; Female; Glucagon; Humans; Kisspeptins; Male; Receptors, G-Protein-Coupled; Satiety Response
PubMed: 26412157
DOI: 10.1016/j.tem.2015.07.008 -
Journal of Neuroendocrinology May 2022The effect of stress on reproduction and gonadal function has captivated investigators for almost 100 years. Following the identification of gonadotropin-releasing... (Review)
Review
The effect of stress on reproduction and gonadal function has captivated investigators for almost 100 years. Following the identification of gonadotropin-releasing hormone (GnRH) 50 years ago, a niche research field emerged fixated on how stress impairs this central node controlling downstream pituitary and gonadal function. It is now clear that both episodic GnRH secretion in males and females and surge GnRH secretion in females are inhibited during a variety of stress types. There has been considerable advancement in our understanding of numerous stress-related signaling molecules and their ability to impair reproductive neuroendocrine activity during stress. Recently, much attention has turned to the effects of stress on two populations of kisspeptin neurons: the stimulatory afferents to GnRH neurons that regulate pulsatile and surge-type gonadotropin secretion. Indeed, future work is still required to fully construct the neuroanatomical framework underlying stress effects, directly or indirectly, on GnRH neuron function. The present review evaluates and synthesizes evidence related to stress-related signaling molecules acting directly on GnRH neurons. Here, we review the evidence for and against the action of a handful of signaling molecules as inhibitors of GnRH neuron function, including corticotropin-releasing hormone, urocortins, norepinephrine, cortisol/corticosterone, calcitonin gene-related peptide and arginine-phenylalanine-amide-related peptide-3.
Topics: Corticotropin-Releasing Hormone; Female; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Luteinizing Hormone; Male; Neurons
PubMed: 35128742
DOI: 10.1111/jne.13098 -
Endocrinology Feb 2022Hypothalamic kisspeptin (Kiss1) neurons provide indispensable excitatory transmission to gonadotropin-releasing hormone (GnRH) neurons for the coordinated release of... (Review)
Review
Hypothalamic kisspeptin (Kiss1) neurons provide indispensable excitatory transmission to gonadotropin-releasing hormone (GnRH) neurons for the coordinated release of gonadotropins, estrous cyclicity, and ovulation. But maintaining reproductive functions is metabolically demanding so there must be a coordination with multiple homeostatic functions, and it is apparent that Kiss1 neurons play that role. There are 2 distinct populations of hypothalamic Kiss1 neurons, namely arcuate nucleus (Kiss1ARH) neurons and anteroventral periventricular and periventricular nucleus (Kiss1AVPV/PeN) neurons in rodents, both of which excite GnRH neurons via kisspeptin release but are differentially regulated by ovarian steroids. Estradiol (E2) increases the expression of kisspeptin in Kiss1AVPV/PeN neurons but decreases its expression in Kiss1ARH neurons. Also, Kiss1ARH neurons coexpress glutamate and Kiss1AVPV/PeN neurons coexpress gamma aminobutyric acid (GABA), both of which are upregulated by E2 in females. Also, Kiss1ARH neurons express critical metabolic hormone receptors, and these neurons are excited by insulin and leptin during the fed state. Moreover, Kiss1ARH neurons project to and excite the anorexigenic proopiomelanocortin neurons but inhibit the orexigenic neuropeptide Y/Agouti-related peptide neurons, highlighting their role in regulating feeding behavior. Kiss1ARH and Kiss1AVPV/PeN neurons also project to the preautonomic paraventricular nucleus (satiety) neurons and the dorsomedial nucleus (energy expenditure) neurons to differentially regulate their function via glutamate and GABA release, respectively. Therefore, this review will address not only how Kiss1 neurons govern GnRH release, but how they control other homeostatic functions through their peptidergic, glutamatergic and GABAergic synaptic connections, providing further evidence that Kiss1 neurons are the key neurons coordinating energy states with reproduction.
Topics: Animals; Body Temperature Regulation; Brain Chemistry; Energy Metabolism; Female; Gonadotropin-Releasing Hormone; Homeostasis; Humans; Hypothalamus; Kisspeptins; Luteinizing Hormone; Neurons; RNA, Messenger; Reproduction
PubMed: 34953135
DOI: 10.1210/endocr/bqab253