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Scientific Reports May 2024Dysfunction of central serotonergic neurons is known to cause depressive disorders in humans, who often show reproductive and/or glucose metabolism disorders. This study...
Dysfunction of central serotonergic neurons is known to cause depressive disorders in humans, who often show reproductive and/or glucose metabolism disorders. This study examined whether dorsal raphe (DR) serotonergic neurons sense high glucose availability to upregulate reproductive function via activating hypothalamic arcuate (ARC) kisspeptin neurons (= KNDy neurons), a dominant stimulator of gonadotropin-releasing hormone (GnRH)/gonadotropin pulses, using female rats and goats. RNA-seq and histological analysis revealed that stimulatory serotonin-2C receptor (5HT2CR) was mainly expressed in the KNDy neurons in female rats. The serotonergic reuptake inhibitor administration into the mediobasal hypothalamus (MBH), including the ARC, significantly blocked glucoprivic suppression of luteinizing hormone (LH) pulses and hyperglycemia induced by intravenous 2-deoxy-D-glucose (2DG) administration in female rats. A local infusion of glucose into the DR significantly increased in vivo serotonin release in the MBH and partly restored LH pulses and hyperglycemia in the 2DG-treated female rats. Furthermore, central administration of serotonin or a 5HT2CR agonist immediately evoked GnRH pulse generator activity, and central 5HT2CR antagonism blocked the serotonin-induced facilitation of GnRH pulse generator activity in ovariectomized goats. These results suggest that DR serotonergic neurons sense high glucose availability to reduce gluconeogenesis and upregulate reproductive function by activating GnRH/LH pulse generator activity in mammals.
Topics: Animals; Luteinizing Hormone; Female; Receptor, Serotonin, 5-HT2C; Rats; Serotonergic Neurons; Goats; Gonadotropin-Releasing Hormone; Glucose; Serotonin; Kisspeptins; Arcuate Nucleus of Hypothalamus; Dorsal Raphe Nucleus; Rats, Sprague-Dawley
PubMed: 38702366
DOI: 10.1038/s41598-024-58470-4 -
Cellular and Molecular Biology... Mar 2024We attempted to clarify clinical value of KiSS-1 and MMP-2 levels in breast cancer (BC) tissue in evaluating prognosis of elderly BC patients after modified radical...
We attempted to clarify clinical value of KiSS-1 and MMP-2 levels in breast cancer (BC) tissue in evaluating prognosis of elderly BC patients after modified radical mastectomy (MCM). The data of 192 elderly female BC patients receiving MCM in our hospital from January 2018 to December 2022 were collected. According to prognosis, patients received division into poor prognosis group (n = 43) and good prognosis group (n = 149). The serum CEA level and KiSS-1 and MMP-2 levels in BC tissue received measurement in both groups. The predictive value of KiSS-1 and MMP-2 alone and jointly in adverse prognosis of elderly BC patients after MCM received assessment. Results showed that No statistical significance was exhibited between both groups in general data (P > 0.05). The serum CEA level and MMP-2 expression in BC tissue in poor prognosis group exhibited elevation relative to those in good prognosis group, and KiSS-1 expression in BC tissue in poor prognosis group exhibited depletion relative to that in good prognosis group, indicating statistical significance (P < 0.05). The high-level KiSS-1 might be a protective element for adverse prognosis of elderly BC patients after MCM, and high-level CEA and MMP-2 might be an independent risk element for adverse prognosis of elderly BC patients after MCM (P < 0.05). KiSS-1 and MMP-2 alone and jointly predicted AUC of adverse prognosis in elderly BC patients after MCM were 0.93, 0.802 and 0.958, with certain predictive values; when cutoff values of KiSS-1 and MMP-2 were 6.15 and 2.26, the predictive value was the best. In conclusion, KiSS-1 and MMP-2 levels in BC tissue possess relation to adverse prognosis of MCM. KiSS-1 and MMP-2 levels in elderly BC patients before surgery may be detected in the future to assist in prognosis evaluation of elderly BC patients after MCM.
Topics: Humans; Female; Matrix Metalloproteinase 2; Breast Neoplasms; Aged; Prognosis; Kisspeptins; Mastectomy, Modified Radical; ROC Curve; Biomarkers, Tumor; Aged, 80 and over
PubMed: 38650158
DOI: 10.14715/cmb/2024.70.3.38 -
Journal of Receptor and Signal... Feb 2024Kisspeptin is an important hormone involved in the stimulation of the hypothalamo-pituitary gonadal (HPG) axis. The HPG axis can be suppressed in certain conditions such...
Kisspeptin is an important hormone involved in the stimulation of the hypothalamo-pituitary gonadal (HPG) axis. The HPG axis can be suppressed in certain conditions such as stress, which gives rise to the activation of the hypothalamo-pituitary-adrenal (HPA) axis. However, the physiological role of kisspeptin in the interaction of HPG and HPA axis is not fully understood yet. This study was conducted to investigate the possible effects of central kisspeptin injection on HPG axis as well as HPA axis activity. Adult male Wistar rats were randomly divided into seven groups as followed: sham (control), kisspeptin (50 pmol), P234 (1 nmol), kisspeptin + p234, kisspeptin + antalarmin (0.1 μg), kisspeptin + astressin 2B (1 μg), and kisspeptin + atosiban (300 ng/rat) ( = 10 each group). At the end of the experiments, the hypothalamus, pituitary, and serum samples of the rats were collected. There was no significant difference in corticotropic-releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone, and corticosterone levels among all groups. Moreover, no significant difference was detected in pituitary oxytocin level. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin, and kisspeptin + astressin 2B groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin kisspeptin + antalarmin, kisspeptin + astressin 2B, and kisspeptin + atosiban groups compared to the control group. Our findings suggest that central kisspeptin injection causes activation in the HPG axis, but not the HPA axis in male rats.
Topics: Animals; Male; Kisspeptins; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Rats; Rats, Wistar; Peptide Fragments; Luteinizing Hormone; Corticosterone; Vasotocin; Testosterone; Injections, Intraventricular; Gonads; Pituitary Gland; Gonadotropin-Releasing Hormone; Adrenocorticotropic Hormone; Corticotropin-Releasing Hormone; Oligopeptides
PubMed: 38647103
DOI: 10.1080/10799893.2024.2333470 -
General and Comparative Endocrinology Jul 2024Kisspeptin is a peptide that plays an important role through its effects on the hypothalamus-pituitary-gonadal (HPG) axis. It has also been implicated in sexual...
Kisspeptin administration may promote precopulatory behavior in male rats independently or supplementally to testosterone and contribute to proceptive behavior in female partners, reducing mating failure.
Kisspeptin is a peptide that plays an important role through its effects on the hypothalamus-pituitary-gonadal (HPG) axis. It has also been implicated in sexual behavior. The present study investigated whether the relationship between kisspeptin and sexual behavior is independent of the HPG axis, i.e., testosterone. Sexual behavior was examined after the administration of kisspeptin to gonadally intact male rats and gonadectomized male rats that received testosterone supplementation. Other male rats were also observed for sexual behavior once a week from 2 to 5 weeks after gonadectomy and receiving kisspeptin for the sixth postoperative week. Sexual behavior in female rats serving as the partner for each male was also observed. Female rats were not administered kisspeptin in the present study. The results obtained showed that the administration of kisspeptin increased precopulatory behavior in gonadally intact male rats and gonadectomized male rats that received testosterone supplementation and proceptive behavior in their female partners. Precopulatory behavior in males and receptive behavior in females increased, while copulatory behavior in males and receptive behavior in females remained unchanged. Furthermore, the administration of kisspeptin increased precopulatory behavior in gonadectomized males, but did not affect receptive behavior in females. These results suggest that kisspeptin affected males independently and/or supplementally to testosterone, and also that changes in the presence of testosterone in males had an impact on proceptive behavior in their female partners. In conclusion, kisspeptin may involve an as-yet-unidentified neural pathway in sexual desire independently of the HPG axis.
Topics: Animals; Kisspeptins; Male; Testosterone; Female; Rats; Sexual Behavior, Animal; Rats, Wistar; Copulation
PubMed: 38643848
DOI: 10.1016/j.ygcen.2024.114528 -
Domestic Animal Endocrinology Jul 2024Kisspeptins are neuropeptides encoded by the Kiss1 gene that was discovered as a metastasis suppressor gene in melanoma and breast cancer. Kisspeptin has pivotal...
Kisspeptins are neuropeptides encoded by the Kiss1 gene that was discovered as a metastasis suppressor gene in melanoma and breast cancer. Kisspeptin has pivotal functions for gonadotropin-releasing hormone secretion and plays integrated roles in the hypothalamic-pituitary-gonadal axis. However, little is known about the peripheral expression of kisspeptin in ruminants, especially in the female reproductive tract. Here, the objectives of the current study were to investigate the spatial localization of kisspeptin and mRNA expression of Kiss1 and its receptor (Kiss1r) in the fallopian tubes (FT) and uterus of goats at varied reproductive activity (cyclic versus true anoestrous goats, n=6, each). Specimens of the uterus and FT were collected and fixed using paraformaldehyde to investigate the localizations of kisspeptin in the selected tissues by immunohistochemistry. Another set of samples was snape-frozen to identify the expressions of mRNAs encoding Kiss1 and Kiss1r using real-time PCR. Results revealed immunolocalizations of kisspeptin in the uterus and the FT. The staining of kisspeptin was found mainly in the mucosal epithelium of the uterus the FT, and the endometrial glands. Very intense staining of kisspeptin was found in the uterine and FT specimens in the true anoestrous goats compared to that in cyclic ones. The expression of mRNA encoding Kiss1 gene was significantly higher in the uterine specimen of cyclic goats (1.00±0.09) compared to that in the true anoestrous goats (0.62±0.08) (P ˂0.05), while the expression of mRNA encoding Kiss1r was significantly (P ˂0.001) higher in the uterine tissues of true anoestrous goats (1.78±0.17) compared to that in cyclic ones (1.00±0.11). In conclusion, immunohistochemical localization of kisspeptin and the expression of mRNA encoding Kiss1/Kiss1r revealed spatial changes in the uterus and FT of goats according to the reproductive potential of goats (cyclic versus true anoestrous goats). However, the definitive local role of kisspeptin in the uterus and FT need further investigation.
Topics: Animals; Female; Goats; Kisspeptins; Uterus; Fallopian Tubes; RNA, Messenger; Reproduction; Gene Expression Regulation; Receptors, Kisspeptin-1; Anestrus
PubMed: 38640803
DOI: 10.1016/j.domaniend.2024.106850 -
The Science of the Total Environment Jun 2024Exposure to phthalate/DINCH metabolites can induce human reproductive toxicity, however, their endocrine-disrupting mechanisms are not fully elucidated.
BACKGROUND
Exposure to phthalate/DINCH metabolites can induce human reproductive toxicity, however, their endocrine-disrupting mechanisms are not fully elucidated.
OBJECTIVE
To investigate the association between concentrations of phthalate/DINCH metabolites, serum kisspeptin, and reproductive hormones among European teenagers from three of the HBM4EU Aligned Studies.
METHODS
In 733 Belgian (FLEHS IV study), Slovak (PCB cohort follow-up), and Spanish (BEA study) teenagers, ten phthalate and two DINCH metabolites were measured in urine by high-performance liquid chromatography-tandem mass spectrometry. Serum kisspeptin (kiss54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were measured by immunosorbent assays. Free Androgen Index (FAI) was calculated as a proxy of free testosterone. Adjusted sex-stratified linear regression models for individual studies, mixed effect models (LME) accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the phthalate/DINCH mixture were performed.
RESULTS
The LME suggested that each IQR increase in ln-transformed levels of several phthalates was associated with lower kisspeptin [MnBP: %change (95%CI): -2.8 (-4.2;-0.4); MEHP: -1.4 (-3.4,0.2)] and higher FSH [∑DINP: 11.8 (-0.6;25.1)] levels in females from pooled studies. G-computation showed that the phthalates/DINCH mixture was associated with lower kisspeptin [-4.28 (-8.07;-0.34)] and higher FSH [22.13 (0.5;48.4)] also in females; BKMR showed similar although non-significant pattern. In males, higher phthalates metabolites [MEHP: -12.22 (-21.09;-1.18); oxo-MEHP: -12.73 (-22.34;-1.93)] were associated with lower TT and FAI, although higher DINCH [OH-MINCH: 16.31 (6.23;27.35), cx-MINCH: 16.80 (7.03;27.46), ∑DINCH: 17.37 (7.26;29.74)] were associated with higher TT levels. No mixture associations were found in males.
CONCLUSION
We observed sex-specific associations between urinary concentrations of phthalate/DINCH metabolites and the panel of selected effect biomarkers (kisspeptin and reproductive hormones). This suggests that exposure to phthalates would be associated with changes in kisspeptin levels, which would affect the HPG axis and thus influence reproductive health. However, further research is needed, particularly for phthalate replacements such as DINCH.
Topics: Kisspeptins; Phthalic Acids; Humans; Adolescent; Female; Cross-Sectional Studies; Male; Environmental Pollutants; Follicle Stimulating Hormone; Testosterone; Environmental Exposure; Sex Hormone-Binding Globulin; Estradiol; Endocrine Disruptors
PubMed: 38631641
DOI: 10.1016/j.scitotenv.2024.172426 -
Revista Brasileira de Ortopedia Apr 2024To evaluate the effects of estrogen, raloxifene and genistein on the expression of (kisspeptin), (kisspeptin receptor), (androgen receptor) and (insulin...
To evaluate the effects of estrogen, raloxifene and genistein on the expression of (kisspeptin), (kisspeptin receptor), (androgen receptor) and (insulin receptor) in the bones of ovariectomized rats. Forty-eight adult rats were randomly divided into 6 groups, containing 8 animals each: G1-nonovariectomized control; G2-ovariectomized and treated with conjugated equine estrogens (50 µg/Kg/day); G3-ovariectomized and treated with raloxifene (0.75 mg/kg/day); G4-ovariectomized animal that received soy extract with genistein (300 mg/kg/day); G5-ovariectomized animal that received estrogen and genistein; and G6-ovariectomized animal that received estrogen and raloxifene. Three months after surgery, the castrated animals received the drugs orally daily for 120 days. All animals were sacrificed after this period, by deepening the anesthesia. The left tibia was removed for total RNA extraction and analysis of gene expression of , , and , by quantitative real-time polymerase chain reaction (qRT-PCR). was not detected in any of the treated groups. , and showed higher expression in the G3 group ( < 0.001), while lower levels of transcripts for these genes were observed in G4 and G5. G2 animals showed hypoexpression of the evaluated genes. The results indicate that raloxifene, alone or combined with estrogen, was able to induce the expression of genes associated with the recovery of bone tissue homeostasis in ovariectomized rats.
PubMed: 38606141
DOI: 10.1055/s-0044-1779319 -
Journal of Diabetes Apr 2024Kisspeptins (KPs) are proteins that were first recognized to have antimetastatic action. Later, the critical role of this peptide in the regulation of reproduction was... (Review)
Review
Kisspeptins (KPs) are proteins that were first recognized to have antimetastatic action. Later, the critical role of this peptide in the regulation of reproduction was proved. In recent years, evidence has been accumulated supporting a role for KPs in regulating metabolic processes in a sexual dimorphic manner. It has been proposed that KPs regulate metabolism both indirectly via gonadal hormones and/or directly via the kisspeptin receptor in the brain, brown adipose tissue, and pancreas. The aim of the review is to provide both experimental and clinical evidence indicating that KPs are peptides linking metabolism and reproduction. We propose that KPs could be used as a potential target to treat both metabolic and reproductive abnormalities. Thus, we focus on the consequences of disruptions in KPs and their receptors in metabolic conditions such as diabetes, undernutrition, obesity, and reproductive disorders (hypogonadotropic hypogonadism and polycystic ovary syndrome). Data from both animal models and human subjects indicate that alterations in KPs in the case of metabolic imbalance lead also to disruptions in reproductive functions. Changes both in the hypothalamic and peripheral KP systems in animal models of the aforementioned disorders are discussed. Finally, an overview of current clinical studies involving KP in fertility and metabolism show fewer studies on metabolism (15%) and only one to date on both. Presented data indicate a dynamic and emerging field of KP studies as possible therapeutic targets in treatments of both reproductive and metabolic dysfunctions.
Topics: Animals; Female; Humans; Kisspeptins; Reproduction; Hypothalamus; Obesity; Peptides
PubMed: 38599822
DOI: 10.1111/1753-0407.13541 -
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 -
Scientific Reports Apr 2024Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting 5-20% of reproductive-age women. However, the treatment of PCOS is mainly based on...
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting 5-20% of reproductive-age women. However, the treatment of PCOS is mainly based on symptoms and not on its pathophysiology. Neuroendocrine disturbance, as shown by an elevated LH/FSH ratio in PCOS patients, was thought to be the central mechanism of the syndrome, especially in lean PCOS. LH and FSH secretion are influenced by GnRH pulsatility of GnRH neurons in the hypothalamus. Kisspeptin is the main regulator of GnRH secretion, whereas neurokinin B (NKB) and dynorphin regulate kisspeptin secretion in KNDy neurons. This study aims to deepen the understanding of the neuroendocrine disorder in lean PCOS patients and its potential pathophysiology-based therapy. A cross-sectional study was performed at Dr. Cipto Mangunkusumo Kencana Hospital and the IMERI UI HRIFP cluster with 110 lean PCOS patients as subjects. LH, FSH, LH/FSH ratio, kisspeptin, NKB, dynorphin, leptin, adiponectin, AMH, fasting blood glucose, fasting insulin, HOMA-IR, testosterone, and SHBG were measured. Bivariate and path analyses were performed to determine the relationship between variables. There was a negative association between dynorphin and kisspeptin, while NKB levels were not associated with kisspeptin. There was no direct association between kisspeptin and the LH/FSH ratio; interestingly, dynorphin was positively associated with the LH/FSH ratio in both bivariate and pathway analyses. AMH was positively correlated with the LH/FSH ratio in both analyses. Path analysis showed an association between dynorphin and kisspeptin levels in lean PCOS, while NKB was not correlated with kisspeptin. Furthermore, there was a correlation between AMH and the LH/FSH ratio, but kisspeptin levels did not show a direct significant relationship with the LH/FSH ratio. HOMA-IR was negatively associated with adiponectin levels and positively associated with leptin and FAI levels. In conclusion, AMH positively correlates with FAI levels and is directly associated with the LH/FSH ratio, showing its important role in neuroendocrinology in lean PCOS. From the path analysis, AMH was also an intermediary variable between HOMA-IR and FAI with the LH/FSH ratio. Interestingly, this study found a direct positive correlation between dynorphin and the LH/FSH ratio, while no association between kisspeptin and the LH/FSH ratio was found. Further research is needed to investigate AMH and dynorphin as potential therapeutic targets in the management of lean PCOS patients.
Topics: Female; Humans; Luteinizing Hormone; Polycystic Ovary Syndrome; Dynorphins; Leptin; Kisspeptins; Cross-Sectional Studies; Adiponectin; Neurokinin B; Gonadotropin-Releasing Hormone; Follicle Stimulating Hormone
PubMed: 38589425
DOI: 10.1038/s41598-024-58064-0