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Reviews in Endocrine & Metabolic... Mar 2007Estrous cyclicity is controlled by a cascade of neuroendocrine events, involving the activation of the hypothalamo-pituitary-gonadal axis. Two modes of... (Review)
Review
Estrous cyclicity is controlled by a cascade of neuroendocrine events, involving the activation of the hypothalamo-pituitary-gonadal axis. Two modes of gonadotropin-releasing hormone (GnRH) are well established to regulate the estrous cycle: one is a tonic or pulse mode of secretion which is responsible for the stimulation of follicular development and steroidogenesis; the other is a surge mode, which is solely responsible for the induction of luteinizing hormone (LH) surges, eventually leading to ovulation. Metastin/kisspeptin-GPR54 signaling has been suggested to control ovarian cyclicity through regulating the two modes of GnRH release. A population of metastin/kisspeptin neurons located in the anteroventral periventricular nucleus (AVPV) is considered to trigger GnRH surge and thus to mediate the estrogen positive feedback action on GnRH release. The other hypothalamic population of metastin/kisspeptin neurons is located in the arcuate nucleus (ARC) and could be involved in generating GnRH pulses and mediating negative feedback action of estrogen on GnRH release. GnRH neurons express mRNA for GPR54, a metastin/kisspeptin receptor, and have a close association with metastin/kisspeptin neurons at the cell body and terminal level, but the precise mechanism by which this peptide regulates the two modes of GnRH release needs to be determined. Metastin/kisspeptin, therefore, is a key hypothalamic neuropeptide, which is placed immediately upstream of GnRH neurons and relays the peripheral steroidal information to GnRH neurons to control estrous cyclicity.
Topics: Animals; Brain; Estrogens; Estrous Cycle; Feedback, Physiological; Female; Gonadotropin-Releasing Hormone; Kisspeptins; Models, Biological; Proteins; Pulsatile Flow; Rats
PubMed: 17377846
DOI: 10.1007/s11154-007-9032-6 -
Current Opinion in Pharmacology Dec 2022Functional hypothalamic amenorrhea (FHA) is the most common cause of secondary amenorrhea in women of reproductive age. FHA is predominantly caused by stress, decreased... (Review)
Review
Functional hypothalamic amenorrhea (FHA) is the most common cause of secondary amenorrhea in women of reproductive age. FHA is predominantly caused by stress, decreased caloric intake, excessive exercise, or a combination thereof. These physical, psychological, and metabolic stressors cause aberration in the pulsatile release of gonadotropin-releasing hormone (GnRH) and subsequently impair function of the hypothalamic-pituitary-ovarian (HPO) axis. Various neurotransmitters acting in the central nervous system are involved in control of the HPO axis and of these, kisspeptin is one of the most important. Corticotropin-releasing hormone (CRH), also inhibits the pulsatile secretion of GnRH and also acts as an intermediary between stress factors and the reproductive system. One of the main ongoing concerns in patients with FHA is chronic hypoestrogenism, a condition, which is associated with sexual dysfunction and infertility. It may also lead to osteoporosis, and predispose to neurodegenerative and cardiovascular diseases. Treatment of FHA requires the elimination of causative factors, however, making the necessary lifestyle changes is not always easy to initiate and maintain. Broadening our knowledge of the complex neural mechanisms regulating reproductive function in which kisspeptin plays a key role can help in the development of new treatment options such as the potential of kisspeptin receptor agonists for patients with FHA.
Topics: Female; Humans; Kisspeptins; Amenorrhea; Luteinizing Hormone; Gonadotropin-Releasing Hormone; Reproduction
PubMed: 36103784
DOI: 10.1016/j.coph.2022.102288 -
Nature Reviews. Endocrinology Aug 2020Hypothalamic kisspeptin neurons serve as the nodal regulatory centre of reproductive function. These neurons are subjected to a plethora of regulatory factors that... (Review)
Review
Hypothalamic kisspeptin neurons serve as the nodal regulatory centre of reproductive function. These neurons are subjected to a plethora of regulatory factors that ultimately affect the release of kisspeptin, which modulates gonadotropin-releasing hormone (GnRH) release from GnRH neurons to control the reproductive axis. The presence of sufficient energy reserves is critical to achieve successful reproduction. Consequently, metabolic factors impose a very tight control over kisspeptin synthesis and release. This Review offers a synoptic overview of the different steps in which kisspeptin neurons are subjected to metabolic regulation, from early developmental stages to adulthood. We cover an ample array of known mechanisms that underlie the metabolic regulation of KISS1 expression and kisspeptin release. Furthermore, the novel role of kisspeptin neurons as active players within the neuronal circuits that govern energy balance is discussed, offering evidence of a bidirectional role of these neurons as a nexus between metabolism and reproduction.
Topics: Animals; Dynorphins; Energy Metabolism; Female; Gonadotropin-Releasing Hormone; Homeostasis; Humans; Hypothalamo-Hypophyseal System; Hypothalamus; Kisspeptins; Luteinizing Hormone; Neurokinin B; Neurons; Ovary; Puberty; Reproduction
PubMed: 32427949
DOI: 10.1038/s41574-020-0363-7 -
The Lancet. Diabetes & Endocrinology Mar 2023Puberty is a major maturational event; its mechanisms and timing are driven by genetic determinants, but also controlled by endogenous and environmental cues.... (Review)
Review
Puberty is a major maturational event; its mechanisms and timing are driven by genetic determinants, but also controlled by endogenous and environmental cues. Substantial progress towards elucidation of the neuroendocrine networks governing puberty has taken place. However, key aspects of the mechanisms responsible for the precise timing of puberty and its alterations have only recently begun to be deciphered, propelled by epidemiological data suggesting that pubertal timing is changing in humans, via mechanisms that are not yet understood. By integrating basic and clinical data, we provide a comprehensive overview of current advances on the physiological basis of puberty, with a particular focus on the roles of kisspeptins and other central transmitters, the underlying molecular and endocrine mechanisms, and the pathways involved in pubertal modulation by nutritional and metabolic cues. Additionally, we have summarised molecular features of precocious and delayed puberty in both sexes, as revealed by clinical and genetic studies. This Review is a synoptic up-to-date view of how puberty is controlled and of the pathogenesis of major pubertal alterations, from both a clinical and translational perspective. We also highlight unsolved challenges that will seemingly concentrate future research efforts in this active domain of endocrinology.
Topics: Male; Female; Humans; Puberty; Kisspeptins; Puberty, Precocious
PubMed: 36620967
DOI: 10.1016/S2213-8587(22)00339-4 -
The Journal of Maternal-fetal &... Dec 2012To evaluate the role of metastin levels in the pathophysiology of pre-eclampsia and to determine whether there is a relationship between the severity of the disease and...
AIMS
To evaluate the role of metastin levels in the pathophysiology of pre-eclampsia and to determine whether there is a relationship between the severity of the disease and Doppler velocimetry measurements.
METHODS
This cross-sectional study included 89 pregnant women (50 healthy normotensive pregnant women, 15 patients with mild pre-eclampsia, and 24 patients with severe pre-eclampsia) at the third trimester of pregnancy. The maternal levels of plasma metastin were determined by enzyme-linked immunosorbent assay. The umbilical artery and uterine artery blood flow velocities were measured by transabdominal color and pulsed Doppler ultrasound.
RESULTS
Plasma metastin levels were lower in patients with pre-eclampsia than those in the normotensive pregnant women. Four patients with mild pre-eclampsia and seven patients with severe pre-eclampsia had abnormal Doppler velocimetry findings. Metastin levels of pre-eclamptic patients with abnormal Doppler velocimetry findings were significantly lower than those in patients with normal Doppler velocimetry findings. Plasma metastin levels negatively correlated with proteinuria in 24 hours and with mean arterial pressure in the cases of pre-eclampsia.
CONCLUSIONS
The findings suggest that decreased maternal concentrations of plasma metastin may be involved in the pathogenesis of pre-eclampsia. Plasma metastin levels may be useful in the assessment of the severity of pre-eclampsia. However, further trials are needed to clarify the role of metastin in pre-eclampsia.
Topics: Adult; Blood Flow Velocity; Cross-Sectional Studies; Female; Humans; Kisspeptins; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Proteinuria; Severity of Illness Index; Ultrasonography, Doppler; Ultrasonography, Prenatal; Umbilical Arteries; Uterine Artery
PubMed: 22769053
DOI: 10.3109/14767058.2012.708369 -
Medical Molecular Morphology Jun 2015Metastin/kisspeptin is encoded by KISS1 and functions as an endogenous ligand of GPR54. Interaction of metastin with GPR54 suppresses metastasis and also regulates...
Metastin/kisspeptin is encoded by KISS1 and functions as an endogenous ligand of GPR54. Interaction of metastin with GPR54 suppresses metastasis and also regulates release of gonadotropin-releasing hormone, which promotes secretion of estradiol (E2) and progesterone (P4). We have previously demonstrated epigenetic regulation of GPR54 in endometrial cancer and the potent role of metastin peptides in inhibiting metastasis in endometrial cancer. However, little is known about how the metastin-GPR54 axis is regulated in the endometrium, the precursor tissue of endometrial cancer. Endometrial stromal cells (ESCs) and endometrial glandular cells (EGCs) within the endometrium show morphological changes when exposed to E2 and P4. In this study, we show that metastin expression is induced in ESCs through decidualization, but is repressed in glandular components of atypical endometrial hyperplasia (AEH) and endometrial cancer relative to EGCs. The promoter of GPR54 is unmethylated in normal endometrium and in AEH. These results indicate metastin may function in decidualized endometrium to prepare for adequate placentation but this autocrine secretion of metastin is deregulated during oncogenesis to enable tumor cells to spread.
Topics: Adult; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Epigenesis, Genetic; Estradiol; Female; Humans; Kisspeptins; Menstrual Cycle; Middle Aged; Progesterone; Promoter Regions, Genetic; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Stromal Cells
PubMed: 24908069
DOI: 10.1007/s00795-014-0081-0 -
Journal of Andrology 2006Recent genetic analysis has suggested that the expression of the orphan receptor GPR54 is essential for the onset of puberty in both rodents and humans. Indirect...
Recent genetic analysis has suggested that the expression of the orphan receptor GPR54 is essential for the onset of puberty in both rodents and humans. Indirect evidence has suggested that this action is via gonadotropin-releasing hormone induction of luteinizing hormone release. The experiments described here were intended to provide direct evidence that metastin, the naturally occurring ligand for GPR54, was capable of stimulating GnRH secretion by examining GnRH release from an immortalized hypothalamic cell line (GT1-7) and from male rat hypothalamic explants. GT1-7 cells were treated for 2(1/2) hours and overnight with the biologically active fragment of metastin, metastin(45-54), in amounts ranging from 0.1 nM to 1 muM. Hypothalamic fragments were obtained from infantile male rats and exposed to progressively increasing concentrations of metastin(45-54) (0.1 nM to 1 muM) for 1-hour periods. In both experiments, GnRH release was measured by radioimmunoassay (RIA). The release of metastin from hypothalami obtained from infantile and adult male rats was also determined. Explants were incubated for 6 hours, and the release of metastin into the media was determined by RIA. The results support the hypothesis that metastin stimulates GnRH secretion from the hypothalamus. The data indicate that an increase in the secretion of metastin, rather than the appearance of the receptor, is required for puberty onset. The results also suggest that metastin influences the GnRH-secreting neurons indirectly via an interneuron rather than acting directly on the GnRH-secreting neurons.
Topics: Animals; Cells, Cultured; Gonadotropin-Releasing Hormone; Hypothalamus; Kisspeptins; Male; Proteins; Rats; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1
PubMed: 16339453
DOI: 10.2164/jandrol.05144 -
ELife Apr 2024Prolactin suppresses the ovarian cycles of lactating mice by directly repressing the activity of a cell population known as kisspeptin neurons.
Prolactin suppresses the ovarian cycles of lactating mice by directly repressing the activity of a cell population known as kisspeptin neurons.
Topics: Female; Mice; Animals; Gonadotropin-Releasing Hormone; Lactation; Fertility; Prolactin; Neurons; Kisspeptins
PubMed: 38591514
DOI: 10.7554/eLife.97432 -
International Journal of Toxicology 2021Kisspeptin-10 (previously referred as metastin 45-54), an active fragment of the endogenous full-length kisspeptin-145, is a potential therapeutic agent for reproductive...
Kisspeptin-10 (previously referred as metastin 45-54), an active fragment of the endogenous full-length kisspeptin-145, is a potential therapeutic agent for reproductive disorders such as infertility, amenorrhea, and pubertal delay. A safety evaluation of KP-10 was conducted in dogs at the doses of 30, 100, and 1,000 μg/kg, given once daily intravenously for 14 days with a 14-day recovery period. There were no overt signs of drug-related toxicity observed in clinical signs, body weights, food consumption, clinical pathology, histopathology, urinalysis, electrocardiogram, or respiratory rate. Due to very rapid clearance of the peptide, luteinizing hormone (LH) levels were measured as a surrogate marker to demonstrate KP-10 exposure. The LH response reached a maximum concentration at 5 minutes post-dose and remained relatively unchanged for at least 30 minutes after dosing with no gender effect. LH concentrations on Day 1 were generally greater than on day 14. Vaginal cytology results indicated all dogs were in anestrous throughout the dosing period. There were also no KP-10-related findings observed in recovery animals on Day 29. In conclusion, KP-10 demonstrated favorable safety profile in dog where 1,000 μg/kg dose was considered as a no-observed-adverse-effect level dose when administered IV once daily for 14 days.
Topics: Administration, Intravenous; Animals; Dogs; Drug Administration Schedule; Kisspeptins; Luteinizing Hormone; No-Observed-Adverse-Effect Level
PubMed: 34126799
DOI: 10.1177/10915818211023459 -
Journal of Immunoassay & Immunochemistry 2016Metastin, also known as kisspeptin-10, is a potent stimulator of gonadotropin-releasing hormone (GnRH) neurons in the central nervous system. Recently, it has been...
Metastin, also known as kisspeptin-10, is a potent stimulator of gonadotropin-releasing hormone (GnRH) neurons in the central nervous system. Recently, it has been emerged as a key player in the regulation of reproduction in mammals. Blood concentrations of metastin during different physiological stages in bovine species in general and mithun (Bos frontalis) in particular are not available. Lacking of such information may probably be due to non-availability of simple assay procedure to measure the peptide. Therefore, the objective of this study was to develop and validate a simple and sufficiently sensitive enzyme immunoassay (EIA) for metastin determination in mithun plasma using the biotin-streptavidin amplification system and second antibody coating technique. Biotin was coupled to metastin and used to bridge between streptavidin-peroxidase and the immobilized metastin antiserum in the competitive assay. The EIA was conducted directly in 150 μ L of unknown mithun plasma. Metastin standards ranging from 0.01-51.2 ng/150 μ L/well were prepared in hormone-free plasma. The lowest detection limit was 0.07 ng/mL plasma. Plasma volumes for the EIA, viz., 75, 150, and 200 μ L did not influence the shape of standard curve even though a drop in OD450 was seen with higher plasma volumes. A parallelism test was carried out to compare the endogenous mithun metastin with metastin standard used. It showed good parallelism with the metastin standard curve. For the biological validation of the assay, metastin was measured in (a) blood samples collected from 12 pregnant mithun cows during different stages of pregnancy, (b) in blood from seven early pregnant and 12 non-pregnant mithuns, and (c) in follicular fluid obtained from different types of follicle. It was found that the plasma metastin concentrations increased (P < 0.001) from first through last trimester of pregnancy. Plasma metastin levels were much higher (P < 0.001) in early pregnant than non-pregnant cows. Follicular fluid metastin concentrations were found to increase (P < 0.001) as the follicles grow and the highest levels were recorded in preovulatory follicles. In conclusion, a simple, sufficiently sensitive and direct EIA procedure has been developed for the first time to determine metastin levels in mithun. A wide range of metastin concentrations can be detected during different physiological stages in mithun using this metastin-EIA procedure.
Topics: Animals; Cattle; Enzyme-Linked Immunosorbent Assay; Female; Kisspeptins; Pregnancy
PubMed: 26599603
DOI: 10.1080/15321819.2015.1120745