Research progress of manganese exposure on abnormal GnRH release in hypothalamus affecting reproductive function / 环境与职业医学

Manganese plays an important physiological role in the organism, and excessive manganese exposure can cause impairment of neurological and reproductive functions. Gonadotropin-releasing hormone secreted by the hypothalamus acts as an initiator to regulate reproductive functions, such as gonadal development, onset of puberty, and gonadal hormone release. But the mechanism by which manganese damages the hypothalamus leading to abnormal gonadotropin-releasing hormone release is still unclear yet. Kisspeptin, prostaglandin E2, and nitric oxide may act as stimulators to increase the release of gonadotropin-releasing hormone, while the stimulatory or inhibitory effect of γ-aminobutyric acid on the release of gonadotropin-releasing hormone is controversial. Based on current research, manganese has been less studied with Kisspeptin, and studies with prostaglandin E2, nitric oxide, and γ-aminobutyric acid mainly focused on inflammation, oxidative stress, and neurotransmitter transmission. Therefore, taking Kisspeptin, prostaglandin E2, γ-aminobutyric acid, and nitric oxide as the breakthrough points, this paper introduced the mechanism of manganese affecting the release of gonadotropin-releasing hormone in the hypothalamus through the above four pathways, and proposed that the abnormal release of gonadotropin-releasing hormone in the hypothalamus may be one of the mechanisms by which manganese regulates reproductive function, providing a new direction for the prevention and treatment of manganese-induced reproductive damage in the future.

Role of Kisspeptin in Puberty in Humans

Kisspeptin or GPR-54 is a product of KISS 1 gene regulating the production of gonadotropin releasing hormone (GnRH), luteinizing (LH) as well follicle stimulating hormone (FSH). Both LH and FSH are important hormones for reproduction in animals as well in humans. The recognition of Kisspeptin has a landmark bearing in reproductive biology. Few recent pilot studies have convincingly proven it to be a promising molecule in treating infertile couples especially those having hypogonadotropic hypogonadism not responding to conventional treatment

Clinical significance of serum Kisspeptin-1 in diagnosis and prognosis prediction in pancreatic cancer / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the value of pre-treatment kisspeptin (KISS-1) expression for diagnosis and prognosis prediction of pancreatic cancer. Methods: The clinical data of 90 patients with pancreatic cancer (pancreatic cancer group) in Cancer Hospital of Hubei Province from April 2015 to December 2018 were retrospectively analyzed; in addition, 40 patients with benign pancreatic lesions were selected as the benign pancreatic lesion group and 30 healthy people were chosen as control group. The serum levels of KISS-1 and CA19-9 in each group were detected by ELISA. The diagnostic efficacies of CA19-9 and KISS-1 in pancreatic cancer and their relationship with the prognosis of pancreatic cancer were analyzed. Results: The serum KISS-1 level in the pancreatic cancer group was significantly higher than that in the benign pancreatic lesion group and the control group (both P<0.01); the area under the curve (AUC) of serum KISS-1, CA19-9 and their combination for pancreatic cancer detection was 0.757 (95% CI: 0.684-0.831, P=0.000), 0.900 (95% CI: 0.854-0.946, P=0.000), and 0.906 (95% CI: 0.861-0.950, P=0.000), respectively. The AUC value of the combined detection was statistically different from that of KISS-1 (Z=3.124, P=0.024), and the AUC value of CA19-9 was also statistically differently from KISS-1 (Z=3.253, P=0.025). Correlation analysis showed that there was a significant negative correlation between KISS-1 and CA19-9 (r=-0.358, P=0.002). The results of survival curve analysis showed that the survival time of patients with serum KISS-1≥73.6 pg/ml was significantly better than that of patients with KISS-1<73.6 pg/ml (χ2=4.520, P=0.036); KISS-1<73.6 pg/ml was independently related to the patient's prognosis with an OR of 2.37 (1.08-4.75). Conclusion: Serum KISS-1 is helpful for the early diagnosis of pancreatic cancer, and the combined detection of KISS-1 and CAI9-9 can improve the sensitivity and specificity of pancreatic cancer diagnosis, and also is beneficial for prognosis evaluation.

Kisspeptin: new biomarker of pregnancy

Background: The recently identified hormone kisspeptin has been suggested to play an important regulatory role in placentation. The aim and objective of the study is the measurement of serum kisspeptin level in asymptomatic pregnant women and to find out the association of serum kisspeptin with gestational age in women with early pregnancy.Methods: This was a longitudinal study to the evaluation of 178 asymptomatic pregnant women with a gestation of 6 to 16 weeks attending routine antenatal booking visit recruited as study participants from the Antenatal Clinical of Obstetrics and Gynaecology Department, S.M.S. Medical College and Attached Hospitals, Jaipur, Rajasthan, India.Results: After initial clinical examination of every participant, a single blood sample was taken for the measurement of serum kisspeptin. Serum kisspeptin measurement test was performed by ELISA method and results were expressed as ng/ml. Pregnancy outcome was recorded prospectively. Mean serum kisspeptin level of study participants was 2.80±1.87ng/ml and median were 2.41 (Range 0.244-14.06ng/ml). Our result showed the relationship of serum kisspeptin with gestational age (GA) (p<0.000).Conclusions: serum kisspeptin level increases in pregnancy and showed positive relationship with gestational age significantly (p<0.000).

Hypothalamic transcriptional expression of the kisspeptin system and sex steroid receptors differs among polycystic ovary syndrome rat models with different endocrine phenotypes

OBJECTIVES: Polycystic ovary syndrome is a heterogeneous endocrine disorder that affects reproductive-age women. The mechanisms underlying the endocrine heterogeneity and neuroendocrinology of polycystic ovary syndrome are still unclear. In this study, we investigated the expression of the kisspeptin system and gonadotropin-releasing hormone pulse regulators in the hypothalamus as well as factors related to luteinizing hormone secretion in the pituitary of polycystic ovary syndrome rat models induced by testosterone or estradiol. METHODS: A single injection of testosterone propionate (1.25 mg) (n=10) or estradiol benzoate (0.5 mg) (n=10) was administered to female rats at 2 days of age to induce experimental polycystic ovary syndrome. Controls were injected with a vehicle (n=10). Animals were euthanized at 90-94 days of age, and the hypothalamus and pituitary gland were used for gene expression analysis. RESULTS: Rats exposed to testosterone exhibited increased transcriptional expression of the androgen receptor and estrogen receptor-β and reduced expression of kisspeptin in the hypothalamus. However, rats exposed to estradiol did not show any significant changes in hormone levels relative to controls but exhibited hypothalamic downregulation of kisspeptin, tachykinin 3 and estrogen receptor-α genes and upregulation of the gene that encodes the kisspeptin receptor. CONCLUSIONS: Testosterone- and estradiol-exposed rats with different endocrine phenotypes showed differential transcriptional expression of members of the kisspeptin system and sex steroid receptors in the hypothalamus. These differences might account for the different endocrine phenotypes found in testosterone- and estradiol-induced polycystic ovary syndrome rats.

Progress in research of KISS1/KISS1R system and reproductive function / 中华内分泌代谢杂志

Kiss1 gene encodes Kisspeptins,an intercellular signal peptide whose corresponding receptor is Kiss1R. The initial study found that the Kiss1/Kiss1R system has the effect on inhibiting tumor metastasis. More and more evidence suggests that it can act on the hypothalamic-pituitary-gonadal(HPG) axis and is the key to puberty initiation and progression. It plays an important role in the neuroendocrine regulation of reproduction. In this paper, we reviewed the studies on Kiss1/Kiss1R system,its intracellular signal transduction pathway,role on HPG axis,and clinical application.

The clinical detection significance of serum miR-137 in central precocious puberty girls / 实用医学杂志

Objective To investigate the clinical significance of testing serum kisspeptin in central precocious puberty (CPP) girls. Methods Sixty eight CPP girls and 68 healthy girls was studied from December 2012 to December 2014. HEK293 cells were cultured. Luciferase reporter assay was performed to verify the binding of miR-137 to the 3′UTR of KISS1. Serum miR-137 level was levaluated by qRT-PCR. Level of serum luteinizing hormone , prolactin , follicle stimulating hormone , thyrotropin , free thyroxine and estradiol was evaluated by chemi-luminescence immunoassay. The level of serum kisspeptin was detected by ELISA. Results MiR-137 was confirmed to bind to the 3′UTR of KISS1. The level of serum miR-137 was downregulated and kisspeptin was enhanced in CPP girls. The expression of miR-137 and kisspeptin was negatively correlated. Serum miR-137 level was negatively related to bone age and bone age advancement. According to the results of GnRH stimulating test, serum miR-137 was related to peak LH and peak/basal LH ratio. Conclusions MiR-137 could bind to the 3′UTR of KISS1. MiR-137 may be a potential biomarker for CPP assisted diagnosis.

Kisspeptin-A new link bridging energy homeostasis and reproduction / 中华内分泌代谢杂志

[Summary] Kisspeptin is vital for the neuroendocrine regulation of GnRH secretion. Kisspeptin neurons are now recognized as a central pathway responsible for conveying key homeostatic information to GnRH neurons. A number of metabolic modulators have been proposed as regulators of kisspeptin including leptin, adiponectin, insulin, ghrelin, POMC, and neuropeptide Y. Recent data indicate that kisspeptin may have a direct role in regulating energy balance by its regulation of food intake and glucose homeostasis. Thus, kisspeptin may serve as a new connection between reproductive function and energy metabolism.

Kisspeptin Regulation of Neuronal Activity throughout the Central Nervous System

Kisspeptin signaling at the gonadotropin-releasing hormone (GnRH) neuron is now relatively well characterized and established as being critical for the neural control of fertility. However, kisspeptin fibers and the kisspeptin receptor (KISS1R) are detected throughout the brain suggesting that kisspeptin is involved in regulating the activity of multiple neuronal circuits. We provide here a review of kisspeptin actions on neuronal populations throughout the brain including the magnocellular oxytocin and vasopressin neurons, and cells within the arcuate nucleus, hippocampus, and amygdala. The actions of kisspeptin in these brain regions are compared to its effects upon GnRH neurons. Two major themes arise from this analysis. First, it is apparent that kisspeptin signaling through KISS1R at the GnRH neuron is a unique, extremely potent form or neurotransmission whereas kisspeptin actions through KISS1R in other brain regions exhibit neuromodulatory actions typical of other neuropeptides. Second, it is becoming increasingly likely that kisspeptin acts as a neuromodulator not only through KISS1R but also through other RFamide receptors such as the neuropeptide FF receptors (NPFFRs). We suggest likely locations of kisspeptin signaling through NPFFRs but note that only limited tools are presently available for examining kisspeptin cross-signaling within the RFamide family of neuropeptides.

Expression and clinical significance of kisspeptin-1, matrix metalloproteinase-2 and vascular endothelial growth factor in tissue of colon cancer / 中华流行病学杂志

Objective To detect the expression of kisspeptin-1 (KISS-1),matrix metallopmteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in the tissue of colon cancer,and analyze the relativity between KISS-1,MMP-2,VEGF and pathological characteristics of colon cancer.Methods A total of 60 colon cancer patients and 60 patients with benign colorectal disease who received surgical treatment in our hospital from January 2009 to June 2010 were selected as observation group and control group respectively.The cancer tissue samples and excision samples collected from them were used to detect KISS-1,MMP-2 and VEGF with immunohistochemistry.Results The positive rates of KISS-l,MMP-2 and VEGF were 31.7％,58.3％ and 78.3％ in observation group,and 73.3％,16.7％ and 33.3％ in control group.The positive rate of KISS-1 in observation group was lower than that in control group (x2=23.489,P＜0.001),and the positive rates of MMP-2 and VEGF in observation group were higher than those in control group (x2=27.469,P＜ 0.001;x2=25.817,P＜0.001).The expressions of KISS-1,MMP-2 and VEGF were significantly related with the histological grade and TNM stage of colon cancer (x2=8.997,P=0.011;x2=6.163,P=0.013;x2=8.519,P=0.014;x2=9.160,P=0.002;x2=16.577,P＜0.001;x2=10.523,P=0.001).Conclusion It is helpful to understand the differentiation and clinical stage of colon cancer and provide evidence for clinical diagnosis and prognosis prediction by detecting KISS-1,MMP-2 and VEGE

Role of kisspeptin/GPR54 signaling pathways in prompting formation of precocious puberty / 中国病理生理杂志

[ABSTRACT]AIM:Toexploretheroleofkisspeptin/GPR54signalingpathwayinthepathogenesisofprecocious puberty based on female precocious puberty rat model induced by the single dose of danazol .METHODS:Female SD rats aged 3 d were randomly divided into normal group , vehicle group and model group .On the 5th day, the model rats were given a single subcutaneous injection of danazol with ethanol and ethylene glycol mixture .All rats were executed on 15 d, 25 d, 30 d, 35 d and 40 d, and the samples were collected to observe the sexual organ development .The levels of E2 , FSH and LH in peripheral blood were measured by ELISA .The Kiss-1 mRNA expression of Kiss-1, GPR54 and GnRH in hypothalamus was detected by real-time PCR.The kisspeptin expression in rat hypothalamus was observed by immunofluo-rescence .RESULTS:The time for puberty onset and sexual maturation in the model rats was significantly earlier than that in normal group and vehicle group .On days 25 and 30, the levels of peripheral sex hormones and uterine coefficients in model group were significantly higher than those in normal group and vehicle group .On days 25 and 30, the ovarian mor-phological development in the model rats was significantly earlier than that in normal group .On day 25, the mRNA expres-sion of hypothalamic Kiss-1 and GnRH, and kisspeptin expression of hypothalamic arcuate nucleus in the model rats signifi -cantly increased compared with normal group and vehicle group .On day 30, kisspeptin expression of hypothalamic arcuate nucleus in the model rats decreased compared with normal group and vehicle group .On day 35, the mRNA expression of Kiss-1 and GnRH in the model rats decreased compared with normal group and vehicle group .The mRNA expression of GPR54 had no obvious difference among all groups .CONCLUSION:The Kiss-1 mRNA and kisspeptin expression in the model rats with precocious puberty is significantly increased in the hypothalamus during onset of puberty , suggesting that kisspeptin is an initiating factor for precocious puberty .Kisspeptin/GPR54 signaling pathway may play an important role in the occurrence of precocious puberty .

A study of bisphenol A and precocious puberty in 6-8 years old girls / 临床儿科杂志

Objective To study the relationship between bisphenol A and precocious puberty in 6-8 years girls. Meth-ods Atotal of 103 girls aged 6-8 years with precocious puberty in our Endocrine clinic from August to December 2012 were se-lected. According to the classiifcation standard of precocious puberty, girls are divided into idiopathic central precocious puberty (ICPP) group (n=47) and permature thelarche (PT) group (n=56), 53 girls with no puberty development were chosen as control group. BPA concentrations were determined with HPLC-MS-MS, sex hormones were determined with chemiluminescence meth-od and Kisspeptin concentrations were determined with ELISA, then the differences among the three groups were compared and the relationships between bisphenol A and sex hormones and Kisspeptin were analyzed. Results The BPA relevance ratio and concentration in ICPP group were higher than those of PT group and control group (P0.05). There were correlations between the concentrations of BPA and E2 and LH peak concentration and LH/FSH (P<0.05). Conclusions There is a certain correlation between the concentrations of BPA and ICPP.

Influence and mechanism of obesity on the onset of pubertal development in obese children / 中华实用儿科临床杂志

Timing of puberty showed a dramatic decrease in the past decades,and it depends on the gene,nutrition,environment,social economics,and so on.Childhood obesity affects both the timing of puberty and sex hormone levels.However,the influence of obesity on the timing of puberty has gender differences.Current studies show that childhood obesity accelerates the onset of puberty in girls,but it still has controversy in boys.Mechanisms of concrete have not clear,may be related to the subjectivity of standard of male sexual development and the correlation of body mass index as a substitute for male obesity is poor.Through literature review at home and abroad,this article will explain the influence of obesity on the timing of puberty,sex hormone levels and its gender differences,further explore the possible mechanisms of body fat participate in starting the gonad axis,and provide new research direction on the switch for the gonad axis.

Environmental endocrine disruptors and kisspeptin system / 国际儿科学杂志

Environmental endocrine disruptors have garnered considerable attention in recent years be-cause of their endocrine disruption on sex development disorders. Kisspeptin system might be a novel target for endocrine disruption at the hypothalamic-pituitary-gonad axis. Environmental endocrine disruptors′estrogenic properties make them capable of interacting with the kisspeptin system,and then confer lifelong consequences in-cluding altered pubertal timing, infertility, and metabolic disorders. To date, three compounds have been well studied for their capacity to interfere with kisspeptin signaling pathways:BPA,PCB mixtures,and the phytoestro-gen GEN.

GnIH/GPR147 and Kisspeptin/GPR54 in puberty onset / 国际儿科学杂志

The initiation of puberty is associated with the hypothalamus-pituitary-gonadal( HPG) axis. The activation of gonadotropin-releasing hormone( GnRH) is the key factor in the initiation of puberty. The initi-ation of puberty is a complicated process,GnRH is under the influence of many associated neuropeptides. Re-cently,the studies have found that GnIH and Kisspeptin can respectively inhibit and promote the hypothalamus GnRH secretion of mammals,indicating that GnIH and Kisspeptin on regulation of reproductive endocrine axis play very important roles. Therefore,GnIH/GPR147 and Kisspeptin/GPR54 pathways may be closely associated with the initiation of puberty.

Significance of Kisspeptin levels in diagnosis and therapeutic evaluation of idiopathic central precocious puberty in girls / 中华实用儿科临床杂志

Objective To explore the significance and value of Kisspeptin in the diagnosis and therapeutic evaluation for idiopathic central precocious puberty(ICPP) in girls.Methods Twenty-four girls with ICPP and 21 girls with premature thelarche(PT) who were hospitalized in the Children's Hospital of Jiangxi Province from Jun.2012 to Jan.2013 were selected as ICPP group and PT group,and 25 healthy girls were selected as healthy control group.The coagulation vein blood in ICPP girls before treatment and after 6 months treatment and PT girls and healthy girls were collected,and enzyme linked immunosorbent assay was used to detect the plasma Kisspeptin level,and t test was used to analyze the differences among the 4 groups.Results The Kisspeptin level of girls with ICPP [(1.80 ± 0.13) μg/L]was apparently higher than that of PT groups [(1.41 ± 0.10) μg/L] and healthy control group[(1.39 ± 0.13) μg/L],and the differences were statistically significant (t =10.974,14.787,all P =0.000).However,the difference of Kisspeptin between PT group and healthy control group was not statistically significant(t =10.970,P =0.095).In addition,the Kisspeptin level of ICPP girls who undewent 6-month treatment [(1.49 ± 0.15) μg/L] was significantly lower than that before treatment,and the difference was statistically significant (t =10.80,P ＜ 0.05) ;but,compared with PT group and healthy control group,there was no significant difference (t =6.32,P =0.060 ; t =7.44,P =0.214).Conclusions Kisspeptin level is related with pubertal development,and it can be used as an important evidence in ICPP diagnosis and an important parameter in ICPP therapeutic evaluation.

Kisspeptin/G protein-coupled receptor-54 system as an essential gatekeeper of pubertal development

Puberty is the end-point of a complex series of developmental events, defined by the dynamic interaction between genetic factors and environmental cues, ultimately leading to the attainment of reproductive capacity. Kisspeptins, products of the KISS1 gene, were originally identified as metastasis suppressor peptides with the ability to bind G protein-coupled receptors (GPR54). In 2003, loss-of-function mutations of the GPR54 gene were found in patients with hypogonadotropic hypogonadism. This finding triggered study of the role of the kisspeptin/GPR54 system as an essential gatekeeper of control of reproduction and pubertal development. Kisspeptins are very potent elicitors of gonadotropin secretion, primarily through stimulation of gonadotropin-releasing hormone release. KISS1 also functions as an essential integrator for peripheral inputs, including gonadal steroids and nutritional signals, and for controlling GnRH and gonadotropin secretion. Whether the kisspeptin/GPR54 system is the trigger for puberty onset and/or it operates as integrator and effector of up-stream regulatory factors warrants further investigation.

Kisspeptin/G protein-coupled receptor-54 system as an essential gatekeeper of pubertal development

Puberty is the end-point of a complex series of developmental events, defined by the dynamic interaction between genetic factors and environmental cues, ultimately leading to the attainment of reproductive capacity. Kisspeptins, products of the KISS1 gene, were originally identified as metastasis suppressor peptides with the ability to bind G protein-coupled receptors (GPR54). In 2003, loss-of-function mutations of the GPR54 gene were found in patients with hypogonadotropic hypogonadism. This finding triggered study of the role of the kisspeptin/GPR54 system as an essential gatekeeper of control of reproduction and pubertal development. Kisspeptins are very potent elicitors of gonadotropin secretion, primarily through stimulation of gonadotropin-releasing hormone release. KISS1 also functions as an essential integrator for peripheral inputs, including gonadal steroids and nutritional signals, and for controlling GnRH and gonadotropin secretion. Whether the kisspeptin/GPR54 system is the trigger for puberty onset and/or it operates as integrator and effector of up-stream regulatory factors warrants further investigation.

The role of neurokinin B and its receptor in hypothalamic-pituitary-gonad axis / 国际儿科学杂志

Kisspoptin signaling plays an essential role in the onset of puberty and reproductive development.Recently studies implicate that steroid-responsive NKB,kisspeptin,NK3 R,and estrogen receptor α (ERα) coexpress in arcuate nucleus of hypothalamus of variety of mammalian species and regulate the secretion of gonadotrophic hormone.The function of neurons in the hypothalamus is to regulate the estrogen negative feedback on gonadotropin-releasing hormone (GnRH) secretion.Loss of function of neurokinin B (NKB) or its receptor,the neurokinin-3 receptor produces idiopathic hypogonadotropic hypogonadism.These studies demonstrate NKB and neurokinin-3 receptor as the essential elements of the human reproductive axis.

The role of Kisspeptin in sexual development / 国际儿科学杂志

Activation of gonadotrophic hormone neuronstion and downstream reproductive hormones (luteinizing hormone and follicle stimulating hormone) secretion is the key event representing the onset of puberty.Hypothalamic pituitary gonad axis varies among gender,season and the stage of development.A number of hormones are involved in the control of hypothalamic pituitary gonad axis.Kisspeptins are potent secretagogues for gonadotrophic hormone,and the KISS1 gene is a target for regulation by gonadal steroids,metabolic factors,photoperiod,and season.This review focuses on Kisspeptin in the regulation of sexual development.