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Puberty is the critical developmental transition to reproductive capability driven by the activation of gonadotropin‐releasing hormone (GnRH) neurons. The complex neural mechanisms underlying pubertal activation of GnRH secretion still remain unknown, yet likely include kisspeptin neurons. However, kisspeptin neurons reside in several hypothalamic areas and the specific kisspeptin population timing pubertal onset remains undetermined. To investigate this, we strategically capitalized on the differential ontological expression of the Kiss1 gene in different hypothalamic nuclei to selectively ablate just arcuate kisspeptin neurons (aka KNDy neurons) during the early juvenile period, well before puberty, while sparing RP3V kisspeptin neurons. Both male and female transgenic mice with a majority of their KNDy neurons ablated (KNDyABL) by diphtheria toxin treatment in juvenile life demonstrated significantly delayed puberty onset and lower peripubertal LH secretion than controls. In adulthood, KNDyABL mice demonstrated normal in vivo LH pulse frequency with lower basal and peak LH levels, suggesting that only a small subset of KNDy neurons is sufficient for normal GnRH pulse timing but more KNDy cells are needed to secrete normal LH concentrations. Unlike prior KNDy ablation studies in rats, there was no alteration in the occurrence or magnitude of estradiol‐induced LH surges in KNDyABL female mice, indicating that a complete KNDy neuronal population is not essential for normal LH surge generation. This study teases apart the contributions of different kisspeptin neural populations to the control of puberty onset, demonstrating that a majority of KNDy neurons in the arcuate nucleus are necessary for the proper timing of puberty in both sexes. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovarian syndrome (PCOS) is a metabolic disorder, and its pathogenesis is still unclear, but the changes in the hypothalamicpituitary-gonadal (HPG) axis are considered one of the main causes in the development of PCOS. Kisspeptin is a peptide encoded by the KISS gene that regulates the hypothalamus-pituitary-gonadal (HPG), which may be concerned with the pathogenesis of PCO. Aim: To identify the relation between serum Kisspeptin and sex hormones and metabolic parameters among normal and PCO women. Methods: A prospective case-control study was conducted among 64 subjects (32 with PCO and 32 with the control group). The serum Kisspeptin level was measured using enzyme-linked immunosorbent assay (ELISA) and correlated with other hormones such as LH, FSH, DHEA, testosterone, and prolactin. Results: Serum kisspeptin level was significantly higher in the PCOS group when compared to the control group. There was a statistically significant positive correlation between kisspeptin and each of HOMA IR, LH, FSH, DHEA, testosterone, and prolactin. Conclusions: The increase in kisspeptin level may play a role in pathogenesis of PCOS, and may represent a novel link between metabolic and hormonal disturbance in PCOS females since this peptide was correlated with HOMA-IR, LH, FSH, DHEA, testosterone and prolactin. [ABSTRACT FROM AUTHOR]

The peptide hormone kisspeptin attenuates liver steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and fibrosis in mouse models by signaling via the kisspeptin 1 receptor (KISS1R). However, whether kisspeptin impacts fibrogenesis in the human liver is not known. We investigated the impact of a potent kisspeptin analog (KPA) on fibrogenesis using human precision-cut liver slices (hPCLS) from fibrotic livers from male patients, in human hepatic stellate cells (HSCs), LX-2, and in primary mouse HSCs. In hPCLS, 48 h and 72 h of KPA (3 nM, 100 nM) treatment decreased collagen secretion and lowered the expression of fibrogenic and inflammatory markers. Immunohistochemical studies revealed that KISS1R is expressed and localized to HSCs in MASH/fibrotic livers. In HSCs, KPA treatment reduced transforming growth factor b (TGFβ)-the induced expression of fibrogenic and inflammatory markers, in addition to decreasing TGFβ-induced collagen secretion, cell migration, proliferation, and colony formation. Mechanistically, KISS1R signaling downregulated TGFβ signaling by decreasing SMAD2/3 phosphorylation via the activation of protein phosphatases, PP2A, which dephosphorylates SMAD 2/3. This study revealed for the first time that kisspeptin reverses human hepatic fibrogenesis, thus identifying it as a new therapeutic target to treat hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Functional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea, resulting in anovulation and infertility, and is a low estrogen state that increases the risk of cardiovascular disease and impairs bone health. FHA is characterized by acquired suppression of physiological pulsatile gonadotropin‐releasing hormone (GnRH) release by the hypothalamus in the absence of an identifiable structural cause, resulting in a functional hypogonadotropic hypogonadism. FHA results from either decreased energy intake and/or excessive exercise, leading to low energy availability and weight loss—often in combination with psychological stress on top of a background of genetic susceptibility. The hypothalamic neuropeptide kisspeptin is a key component of the GnRH pulse generator, tightly regulating pulsatile GnRH secretion and the downstream reproductive axis. Here, we review the physiological regulation of pulsatile GnRH secretion by hypothalamic kisspeptin neurons and how their activity is modulated by signals of energy status to affect reproductive function. We explore endocrine factors contributing to the suppression of GnRH pulsatility in the pathophysiology of FHA and how hypothalamic kisspeptin neurons likely represent a final common pathway through which these factors affect GnRH pulse generation. Finally, we discuss the therapeutic potential of kisspeptin as a novel treatment for women with FHA. [ABSTRACT FROM AUTHOR]

The neuropeptide kisspeptin and its cognate receptor have been extensively studied in reproductive physiology, with diverse and well‐established functions, including as an upstream regulator of pubertal onset, reproductive hormone secretion, and sexual behavior. Besides classical reproduction, both kisspeptin and its receptor are extensively expressed in bone‐resorbing osteoclasts and bone‐forming osteoblasts, which putatively permits direct bone effects. Accordingly, this sets the scene for recent compelling findings derived from in vitro experiments through to in vivo and clinical studies revealing prominent regulatory interactions for kisspeptin signaling in bone metabolism, as well as certain oncological aspects of bone metabolism. Herein, we comprehensively examine the experimental evidence obtained to date supporting the interaction between kisspeptin and bone. A comprehensive understanding of this emerging facet of kisspeptin biology is fundamental to exploiting the future therapeutic potential of kisspeptin‐based medicines as a novel strategy for treating bone‐related disorders. [ABSTRACT FROM AUTHOR]

Here, we reflect on the long career in neuroendocrinology of a single, highly productive scientist ('Bob' Millar), by analysing his oeuvre of published papers through the lens of citation metrics. We use citation network analysis in a novel manner to identify the specific topics to which his papers have made a particular contribution, allowing us to compare the citations of his papers with those of contemporary papers on the same topic, rather than on the same broad field as generally used to normalise citations. It appears that citation rates are highest for topics on which Bob has published a relatively large number of papers that have become core to a tightly‐knit community of authors that cite each other. This analysis shows that an author's impact depends on the existence of a receptive community that is alert to the potential utility of papers from that author, and which uses, amplifies, extends and qualifies the contents of their papers—activities that entail reciprocal citation between authors. The obvious conclusion is that a scientist's impact depends on the use that his or her contemporaries make of his or her contributions, rather than on the contributions in themselves. [ABSTRACT FROM AUTHOR]

The roles of initially kisspeptin and subsequently neurokinin B pathways in the regulation of human reproduction through the control of GnRH secretion were first identified 20 years ago, as essential for the onset of puberty in both boys and girls. Within that short time we already now have the first licence for clinical use for a neurokinin antagonist in a related indication, for menopausal vasomotor symptoms. Between these two markers of the start and end of the reproductive lifespan, it is clear that these pathways underlie many of the aspects of the hypothalamic regulation of reproduction which had hitherto been enigmatic. In this review, we describe the data currently available from studies designed to elucidate the roles of kisspeptin and neurokinin B in human ovarian function, specifically the regulation of follicle development leading up to ovulation, and in the control of the mid‐cycle GnRH/LH surge that triggers ovulation. These studies, undertaken with only very limited pharmacological tools, provide evidence that the neurokinin B pathway is important in controlling the hypothalamic contribution to the precise gonadotropic drive to the ovary that is necessary for mono‐ovulation, whereas the switch from negative to positive estrogenic feedback results in kisspeptin‐mediated increased GnRH secretion. Potential therapeutic opportunities in conditions characterised by disordered hypothalamic/pituitary function, polycystic ovary syndrome, and functional hypothalamic amenorrhoea, and in the induced LH surge that is a necessary part of IVF treatment are discussed. [ABSTRACT FROM AUTHOR]

Copyright of Gynäkologische Endokrinologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Gynäkologische Endokrinologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Ovarian function is controlled by pituitary secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which in turn are governed by gonadotropin releasing hormone (GnRH) secreted from the brain. A fundamental principle of reproductive axis regulation is negative feedback signaling by gonadal sex steroids back to the brain to fine-tune GnRH and gonadotropin secretion. Endogenous negative feedback effects can be mimicked by exogenous steroid treatments, including androgens, in both sexes. Indeed, a growing number of clinical and animal studies indicate that high levels of exogenous androgens, in the typically male physiological range, can inhibit LH secretion in females, as occurs in males. However, the mechanisms by which male-level androgens inhibit GnRH and LH secretion still remain poorly understood, and this knowledge gap is particularly pronounced in transgender men (individuals designated female at birth but identifying as male). Indeed, many transgender men take long-term gender-affirming hormone therapy that mimics male-level testosterone levels. The impact of such gender-affirming testosterone on the reproductive axis, both at the ovarian and neuroendocrine level, is a long-understudied area that still requires further investigation. Importantly, the few concepts of androgen actions in females mostly come from studies of polycystic ovary syndrome, which does not recapitulate a similar androgen milieu or a pathophysiology of inhibited LH secretion as occurs in testosterone-treated transgender men. This review summarizes clinical evidence indicating that exogenous androgens can impair neuroendocrine reproductive function in both female individuals and transgender men and highlights emerging experimental data supporting this in recently developed transgender rodent models. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is a major pregnancy metabolic disorder and is strongly linked with obesity. Kisspeptin is a hormone that increases several thousand-fold in the maternal circulation during human pregnancy, with placenta as its main source. Studies have suggested that kisspeptin regulates trophoblast invasion and promotes pancreatic insulin secretion and peripheral insulin sensitivity. In a well-characterized cohort of pregnant South African women and molecular and histological techniques, this study explored the impact and interaction of maternal obesity and GDM on kisspeptin (KISS1) signalling in relation to placental morphology and maternal and neonatal parameters. We found that GDM had no effect on placental KISS1 and KISS1R (KISS1 receptor) mRNA and/or protein expression. However, obesity reduced placental KISS1R mRNA expression even though overall KISS1 protein abundance or localization was not different from the non-obese group. Maternal and cord circulating KISS1 concentrations did not vary with obesity or GDM, but maternal circulating KISS1 was positively correlated with placenta weight in non-GDM obese women, and negatively correlated with placental intervillous space volume in non-GDM non-obese women. Cord serum KISS1 was positively correlated with infant weight in GDM obese women, but negatively correlated with maternal BMI in the non-obese GDM group. Placental syncytiotrophoblast extracellular vesicles exhibited detectable KISS1 and its abundance was ∼50 % lower in those from obese GDM compared to non-GDM women. This study shows maternal obesity and GDM can modulate placental kisspeptin signalling and placental morphological development with potential pathophysiological implications for clinically-relevant pregnancy and perinatal outcomes. • Maternal obesity and gestational diabetes (GDM) are increasingly common. • Maternal obesity and GDM did not affect placental kisspeptin expression. • Obesity reduced the known signalling receptor for kisspeptin, KISS1R. • Syncytiotrophoblast extracellular vesicles from women with GDM had lower kisspeptin. • Obesity and GDM affected the relationships between kisspeptin, placenta morphology and pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Obesity, which leads to metabolic dysregulation and body function impairment, emerges as one of the pressing health challenges worldwide. Excessive body fat deposits comprise a dynamic and biologically active organ possessing its own endocrine function. One of the mechanisms underlying the pathophysiology of obesity is low-grade systemic inflammation mediated by pro-inflammatory factors such as free fatty acids, lipopolysaccharides, adipokines (including leptin, resistin and visfatin) and cytokines (TNF-α, IL-1β, Il-6), which are secreted by adipose tissue. Together with obesity-induced insulin resistance and hyperandrogenism, the exacerbated immune response has a negative impact on the hypothalamic–pituitary–gonadal axis at all levels and directly affects reproduction. In women, it results in disrupted ovarian function, irregular menstrual cycles and anovulation, contributing to infertility. This review focuses on the abnormal intracellular communication, altered gene expression and signaling pathways activated in obesity, underscoring its multifactorial character and consequences at a molecular level. Extensive presentation of the complex interplay between adipokines, cytokines, immune cells and neurons may serve as a foundation for future studies in search of potential sites for more targeted treatment of reproductive disorders related to obesity. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Do hyperactive kisspeptin neurons contribute to abnormally high LH secretion and downstream hyperandrogenemia in polycystic ovary syndrome (PCOS)-like conditions and can inhibition of kisspeptin neurons rescue such endocrine impairments? SUMMARY ANSWER Targeted inhibition of endogenous kisspeptin neuron activity in a mouse model of PCOS reduced the abnormally hyperactive LH pulse secretion and hyperandrogenemia to healthy control levels. WHAT IS KNOWN ALREADY PCOS is a reproductive disorder characterized by hyperandrogenemia, anovulation, and/or polycystic ovaries, along with a hallmark feature of abnormal LH hyper-pulsatility, but the mechanisms underlying the endocrine impairments remain unclear. A chronic letrozole (LET; aromatase inhibitor) mouse model recapitulates PCOS phenotypes, including polycystic ovaries, anovulation, high testosterone, and hyperactive LH pulses. LET PCOS-like females also have increased hypothalamic kisspeptin neuronal activation which may drive their hyperactive LH secretion and hyperandrogenemia, but this has not been tested. STUDY DESIGN, SIZE, DURATION Transgenic KissCRE+/hM4Di female mice or littermates Cre− controls were treated with placebo, or chronic LET (50 µg/day) to induce a PCOS-like phenotype, followed by acute (once) or chronic (2 weeks) clozapine- N -oxide (CNO) exposure to chemogenetically inhibit kisspeptin cells (n = 6 to 10 mice/group). PARTICIPANTS/MATERIALS, SETTING, METHODS Key endocrine measures, including in vivo LH pulse secretion patterns and circulating testosterone levels, were assessed before and after selective kisspeptin neuron inhibition and compared between PCOS groups and healthy controls. Alterations in body weights were measured and pituitary and ovarian gene expression was determined by qRT-PCR. MAIN RESULTS AND THE ROLE OF CHANCE Acute targeted inhibition of kisspeptin neurons in PCOS mice successfully lowered the abnormally hyperactive LH pulse secretion (P  < 0.05). Likewise, chronic selective suppression of kisspeptin neuron activity reversed the previously high LH and testosterone levels (P  < 0.05) down to healthy control levels and rescued reproductive gene expression (P  < 0. 05). LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Ovarian morphology was not assessed in this study. Additionally, mouse models can offer mechanistic insights into neuroendocrine processes in PCOS-like conditions but may not perfectly mirror PCOS in women. WIDER IMPLICATIONS OF THE FINDINGS These data support the hypothesis that overactive kisspeptin neurons can drive neuroendocrine PCOS-like impairments, and this may occur in PCOS women. Our findings complement recent clinical investigations using NKB receptor antagonists to lower LH in PCOS women and suggest that pharmacological dose-dependent modulation of kisspeptin neuron activity may be a valuable future therapeutic target to clinically treat hyperandrogenism and lower elevated LH in PCOS women. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by NIH grants R01 HD111650, R01 HD090161, R01 HD100580, P50 HD012303, R01 AG078185, and NIH R24 HD102061, and a pilot project award from the British Society for Neuroendocrinology. There are no competing interests. [ABSTRACT FROM AUTHOR]

Kisspeptin‐10 is a peptide hormone capable of increasing circulating follicle‐stimulating hormone, luteinizing hormone and testosterone levels in humans. Clinically, these effects suggest its use as a treatment for infertility. However, its testosterone‐increasing effect indicates potential misuse in sports. As such, it is included in the 2024 World Anti‐Doping Agency Prohibited List. This work describes the successful validation of an initial testing procedure (screening) and a confirmation procedure for kisspeptin‐10 in urine using liquid chromatography–mass spectrometry. Additionally, kisspeptin‐10 was incubated in human serum to mimic endogenous metabolism to improve method sensitivity, as previous research had demonstrated a rapid elimination time of only 30 min after injection (in rats). Four metabolites, corresponding to peptide fragments y9, y8, y7 and y5, were found and added to the ITP in full scan mode. A degradation product discovered during early experimentation was found to probably be caused by oxidation of the tryptophan residue into a kynurenine residue. Further research should elucidate the kinetic parameters of the reaction to improve product stability. Using the validated confirmation procedure, a black‐market vial of kisspeptin‐10 was analysed. The product contained no unexpected impurities, although it appeared to have undergone more degradation than the purchased reference standard. [ABSTRACT FROM AUTHOR]

Abstract Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive age, characterised by its multifactorial nature and intricate interplay of genetic, hormonal, and environmental factors. As the search for reliable biomarkers intensifies, serum kisspeptin emerges as a promising candidate due to its central role in regulating the hypothalamic-pituitary-gonadal (HPG) axis. This review aims to consolidate the evolving understanding of kisspeptin as a potential PCOS biomarker, comprehensively exploring its physiological basis, diagnostic challenges in PCOS, and clinical implications. Diagnostic challenges in PCOS are addressed, underscoring the limitations of current criteria and the need for objective and standardised biomarkers. Kisspeptin’s introduction as a potential biomarker brings forth both promises and challenges in terms of its diagnostic utility. The review recognises the importance of standardisation in research methodologies and emphasises the exploration of genetic polymorphisms to enhance kisspeptin’s robustness as a diagnostic tool.

In the early 2000s, metastin, an endogenous ligand for G protein-coupled receptor 54 (GPR54), was discovered in human placental extracts. In 2003, GPR54 receptor mutations were found in a family with congenital hypogonadotropic hypogonadism. Metastin was subsequently renamed kisspeptin after its coding gene, Kiss1. Since then, studies in mice and other animals have revealed that kisspeptin is located at the apex of the hypothalamic-pituitary-gonadal axis and regulates reproductive functions by modulating gonadotropin-releasing hormone (GnRH). In rodents, kisspeptin (Kiss1) neurons localize to two regions, the hypothalamic arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV). ARC Kiss1 neurons co-express neurokinin B (NKB) and dynorphin and are thus termed KNDy neurons. Kiss1 neurons in humans are concentrated in the infundibular nucleus (equivalent to the ARC), with few Kiss1 neurons localized to the preoptic area (equivalent to the AVPV), and the mechanisms underlying GnRH surge secretion in humans are poorly understood. However, peripheral administration of kisspeptin to humans promotes gonadotropin secretion, and administration of kisspeptin to patients with hypothalamic amenorrhea or congenital hypogonadotropic hypogonadism restores the pulsatile secretion of GnRH/luteinizing hormone. Thus, kisspeptin undoubtedly plays an important role in reproductive function in humans. Studies are currently underway to develop kisspeptin receptor agonists or antagonists for clinical application. Modification of KNDy neurons by NKB agonists/antagonists is also being attempted to develop therapeutic agents for various menstrual abnormalities, including polycystic ovary syndrome and menopausal hot flashes. Here, we review the role of kisspeptin in humans and its clinical applications.

Background Kisspeptin and delta-like 1 homolog (DLK1) are neuropeptides that reportedly play an important role in pubertal timing by activating and inhibiting the hypothalamic-pituitary-gonadal axis, respectively. Consequently, serum kisspeptin and DLK1 levels may be novel biomarkers for differentiating between central precocious puberty (CPP) and premature thelarche (PT) in girls and used to monitor CPP treatment. Purpose To compare baseline serum kisspeptin and DLK1 levels in girls with CPP at diagnosis and after treatment to age-matched girls with PT. Methods This prospective longitudinal study included girls with precocious puberty and girls with PT who experienced breast development before 8 years of age and peak luteinizing hormone levels of ≥6 versus

Kisspeptin, a key neuropeptide derived from the KISS1R gene, is renowned for its critical role in regulating the hypothalamic–pituitary–gonadal axis and reproductive hormone secretion. Beyond its primary function in reproductive biology, emerging research has illuminated its influence in various cancers, mediating significant effects through its interaction with the G protein-coupled receptor, kisspeptin receptor. This interaction has been implicated in modulating cellular processes such as proliferation and metastasis, making it a potential target for therapeutic intervention. Our study initially screened ten kisspeptin-10 analogs through cytotoxic effects of kisspeptin-10 (KP10) and its analogs in several cancer types, including cervical, prostate, breast, and gastric cancers, with a particular focus on cervical cancer, where the most profound effects were observed. Further exploration using kinase array assays revealed that these analogs specifically alter key kinases involved in cancer progression. Migration assays demonstrated a substantial decrease in cell motility, and Bioluminescence Resonance Energy Transfer assays confirmed these analogs' strong interactions with the kisspeptin receptor. Overall, our results indicate that these KP10 analogs not only hinder cervical cancer cell proliferation but also curtail migration through targeted modulation of kinase signaling, suggesting their potential as therapeutic agents in managing cervical cancer progression. This comprehensive approach underscores the therapeutic promise of exploiting kisspeptin signaling in cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a gaseous molecule that regulates various reproductive functions. It is a well-recognized regulator of GnRH-FSH/LH-sex steroid secretion in vertebrates including fish. Kisspeptin is a recently discovered neuropeptide which also regulates GnRH secretion. Nitrergic and kisspeptin neurons are reported in close physical contact in the mammalian brain suggesting their interactive role in the release of GnRH. The existence of kisspeptin and NOS is also demonstrated in vertebrate gonads, but information on their reciprocal relation in gonads, if any, is obscure. Therefore, attempts were made to evaluate the functional reciprocal relation between nitric oxide and kisspeptin in the catfish gonads, if any, by administering the nitric oxide synthase (NOS) inhibitor, L-NAME {N(G)-nitro-l-arginine methyl ester}, which reduces NO production, and kisspeptin agonist (KP-10) and assessing their impacts on the expressions of kisspeptin1, different NOS isoforms, NO and steroid production in the gonadal tissue. The results revealed that L-NAME suppressed the expression of kiss1 in gonads of the catfish establishing the role of NO in kisspeptin expression. However, KP-10 increased the expression of all the isoforms of NOSs (iNOS, eNOS, nNOS) and concurrently NO and steroids in the ovary and testis. In vitro studies also indicate that kisspeptin stimulates the production of NO and estradiol and testosterone levels in the gonadal explants and medium. Thus, in vivo results clearly suggest a reciprocal interaction between kisspeptin and NO to regulate the gonadal activity of the catfish. The in vitro findings further substantiate our contention regarding the interactive role of kisspeptin and NO in gonadal steroidogenesis. [ABSTRACT FROM AUTHOR]

The objective of this study was to elucidate the intricate interplay among miR-105–1, kisspeptin, and their synergistic influence on basic ovarian granulosa cell functions. The effects of miR-105–1 mimics or miR-105–1 inhibitor, kisspeptin (0, 1, and 10 ng/ml), and its combinations with miR-105–1 mimics on porcine granulosa cells were assessed. The expression levels of miR-105–1, viability, proliferation (accumulation of PCNA, cyclin B1, XTT-, and BrdU-positive cells), apoptosis (accumulation of bcl-2, bax, caspase 3, p53, TUNEL-positive cells), proportion of kisspeptin-positive cells, and the release of steroid hormones and IGF-I were analyzed. Transfection of cells with miR-105–1 mimics promoted cell viability and proliferation, the occurrence of kisspeptin, and the release of progesterone and IGF-I; in contrast, miR-105–1 mimics inhibited apoptosis and estradiol output. MiR-105–1 inhibitor had the opposite effect. Kisspeptin amplified the expression of miR-105–1, cell viability, proliferation, steroid hormones, and IGF‐I release and reduced apoptosis. Furthermore, the collaborative action of miR-105–1 mimics and kisspeptin revealed a synergistic relationship wherein miR-105–1 mimics predominantly supported the actions of kisspeptin, while kisspeptin exhibited a dual role in modulating the effects of miR-105–1 mimics. These findings not only affirm the pivotal role of kisspeptin in regulating basic ovarian cell functions but also represent the inaugural evidence underscoring the significance of miR-105–1 in this regulatory framework. Additionally, our results show the ability of kisspeptin to promote miR-105–1 expression and the ability of miR‐105–1 to promote the occurrence and effects of kisspeptin and, therefore, indicate the existence of the self‐stimulating kisspeptin‐miR‐105–1 axis. [ABSTRACT FROM AUTHOR]

ObjectiveMethodsResultsConclusionsThe hallmarks of Hashimoto’s thyroiditis (HT) include the destruction of thyroid cells by leading to insulin resistance (IR), hypothyroidism, and metabolic abnormalities. Kisspeptin, spexin, and galanin control appetite and body weight (BW) to regulate metabolisms. Here, we sought to determine if galanin, kisspeptin, and spexin are linked to the pathophysiology of HT in euthyroid female individuals.Forty-five women with HT and 45 healthy control women of the same age participated in the current study. The enzyme-linked immunosorbent assay (ELISA) method was used to measure the serum levels of galanin, spexin, and kisspeptin.In comparison to the controls, HT patients had significantly higher levels of kisspeptin (p < 0.01), galanin (p < 0.01), anti-thyroid peroxidase (anti-TPO) (p < 0.001), anti-thyroglobulin (anti-Tg) (p < 0.001), and body mass index (BMI) (p < 0.05). The two groups were comparable in terms of spexin, free triiodothyronine-3 (fT3), fT4, thyroid-stimulating hormone (TSH) levels, and homeostatic model assessment for insulin resistance (HOMA-IR). Galanin and kisspeptin were seen to have a positive correlation (p < 0.01; r = 0.786).Euthyroid women with HT were found to have higher levels of kisspeptin and galanin. These results imply that kisspeptin and galanin may be linked to the pathogenesis of hypothyroidism, and as a result, we believe that these markers may be beneficial in the early detection and treatment of HT patients. [ABSTRACT FROM AUTHOR]

Obesity, a chronic, preventable disease, has significant comorbidities that are associated with a great human and financial cost for society. The aim of the present work is to reconstruct the interactomes of non-hereditary obesity to highlight recent advances of its pathogenesis, and discover potential therapeutic targets. Obesity and biological-clock-related genes and/or gene products were extracted from the biomedical literature databases PubMed, GeneCards and OMIM. Their interactions were investigated using STRING v11.0 (a database of known and predicted physical and indirect associations among genes/proteins), and a high confidence interaction score of >0.7 was set. We also applied virtual screening to discover natural compounds targeting obesity- and circadian-clock-associated proteins. Two updated and comprehensive interactomes, the (a) stress- and (b) inflammation-induced obesidomes involving 85 and 93 gene/gene products of known and/or predicted interactions with an average node degree of 9.41 and 10.8, respectively, were produced. Moreover, 15 of these were common between the two non-hereditary entities, namely, ADIPOQ, ADRB2/3, CCK, CRH, CXCL8, FOS, GCG, GNRH1, IGF1, INS, LEP, MC4R, NPY and POMC, while phelligridin E, a natural product, may function as a potent FOX1-DBD interaction blocker. Molecular networks may contribute to the understanding of the integrated regulation of energy balance/obesity pathogenesis and may associate chronopharmacology schemes with natural products. [ABSTRACT FROM AUTHOR]

Context: There is mounting evidence implicating kisspeptin signalling in placental development and function. Aims: This study aimed to elucidate kisspeptin's role in trophoblast invasion and migration using three experimental models. Methods: First, we examined the mouse fetus and placenta in a kisspeptin receptor (Kiss1r) knockout (KO) model. Fetal/placental weights and gene expression (quantitative polymerase chain reaction) were assessed. Second, we determined kisspeptin effects on a human trophoblast (BeWo) cell line in vitro. Third, we examined KISS1 and KISS1R gene expression in human placenta from term and pre-term pregnancies. Key results: No difference was found in fetal or placental weight between Kiss1r KO and wildtype mice. However, expression of the trophoblast invasion marker, Mmp2 mRNA, was greater in the placental labyrinth zone of Kiss1r KO mice. BeWo cell models of villus cytotrophoblast and syncytiotrophoblast cells exhibited kisspeptin protein expression, with greater expression in syncytiotrophoblast, consistent with KISS1 mRNA. Kisspeptin treatment inhibited the migratory potential of cytotrophoblast-like cells. Finally, while no difference was seen in KISS1 and KISS1R mRNA between term and pre-term placentas, we saw a difference in the relative expression of each gene pre-term. We also observed a positive correlation between KISS1 expression and maternal body mass index. Conclusions: Our results indicate that kisspeptin may inhibit trophoblast invasion. Implications: Further investigation is required to clarify specific regulatory mechanisms. There is mounting evidence implicating kisspeptin signalling in placental development and function. We sought to elucidate kisspeptin's role in the placenta using three experimental models: a mouse kisspeptin receptor knockout model, culture of human BeWo trophoblast cells, and a human placenta punch biopsy. Our results indicate that kisspeptin may inhibit trophoblast invasion, although further investigation is required to clarify specific regulatory mechanisms. Image by and adapted from M. Arvola and R. Mattsson (). [ABSTRACT FROM AUTHOR]

Kisspeptin signaling regulates energy homeostasis. Adiposity is the principal source and receiver of peripheral Kisspeptin, and adipose Kiss1 metastasis suppressor (Kiss1) gene expression is stimulated by exercise. However, whether the adipose Kiss1 gene regulates energy homeostasis and plays a role in adaptive alterations during prolonged exercise remains unknown. Here, we investigated the role of Kiss1 role in mice and adipose tissues and the adaptive changes it induces after exercise, using adipose‐specific Kiss1 knockout (Kiss1adipoq−/−) and adeno‐associated virus‐induced adipose tissue Kiss1‐overexpressing (Kiss1adipoq over) mice. We found that adipose‐derived kisspeptin signal regulates lipid and glucose homeostasis to maintain systemic energy homeostasis, but in a sex‐dependent manner, with more pronounced metabolic changes in female mice. Kiss1 regulated adaptive alterations of genes and proteins in tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OxPhos) pathways in female gWAT following prolonged aerobic exercise. We could further show that adipose Kiss1 deficiency leads to reduced peroxisome proliferator‐activated receptor gamma co‐activator 1 alpha (PGC‐1α) protein content of soleus muscle and maximum oxygen uptake (VO2 max) of female mice after prolonged exercise. Therefore, adipose Kisspeptin may be a novel adipokine that increases organ sensitivity to glucose, lipids, and oxygen following exercise. [ABSTRACT FROM AUTHOR]

Obesity is associated with hypogonadism in males, characterized by low testosterone and sperm number. Previous studies determined that these stem from dysregulation of hypothalamic circuitry that regulates reproduction, by unknown mechanisms. Herein, we used mice fed chronic high-fat diet, which mimics human obesity, to determine mechanisms of impairment at the level of the hypothalamus, in particular gonadotropin-releasing hormone (GnRH) neurons that regulate luteinizing hormone (LH), which then regulates testosterone. Consistent with obese humans, we demonstrated lower LH, and lower pulse frequency of LH secretion, but unchanged pituitary responsiveness to GnRH. LH pulse frequency is regulated by pulsatile GnRH secretion, which is controlled by kisspeptin. Peripheral and central kisspeptin injections, and DREADD-mediated activation of kisspeptin neurons, demonstrated that kisspeptin neurons were suppressed in obese mice. Thus, we investigated regulators of kisspeptin secretion. We determined that the LH response to NMDA was lower in obesemice, corresponding to fewer glutamate receptors in kisspeptin neurons, which may be critical for kisspeptin synchronization. Given that kisspeptin neurons also interact with anorexigenic POMC neurons, which are affected by obesity, we examined their cross talk, and determined that the LH response to either DREADD-mediated activation of POMC neurons or central injection of αMSH, a product of POMC, is abolished in obese mice. This was accompanied by diminished levels of αMSH receptor, MC4R, in kisspeptin neurons. Together, our studies determined that obesity leads to the downregulation of receptors that regulate kisspeptin neurons, which is associated with lower LH pulse frequency, leading to lower LH and hypogonadism. [ABSTRACT FROM AUTHOR]

The neuropeptides kisspeptin, neurokinin B, and dynorphin A are imperative for the pulsatile secretion of gonadotropin-releasing hormone and luteinizing hormone to ultimately regulate reproductive cyclicity. A population of neurons co-expressing these neuropeptides, KNDy neurons, within the arcuate nucleus of the hypothalamus (ARC) are positioned to integrate energy status from afferent neuronal and glial cells. We hypothesized that KNDy expressing neurons in the ARC of mature ewes are influenced by energy balance. To test this hypothesis, ovary-intact, mature ewes were fed to lose, maintain, or gain body weight and hypothalamic tissue harvested during the luteal phase of the estrous cycle. Fluorescent, multiplex immunohistochemistry with direct antibody conjugation was employed to identify and quantify neurons expressing a single neuropeptide, as well as for the first time report co-expression of kisspeptin, neurokinin B, and dynorphin A protein in the ARC. Previous reports using this population of ewes demonstrated that concentrations of insulin and leptin differed between ewes fed to achieve different body weights and that ewes fed to gain body weight had increased concentrations of progesterone. Moreover, within this population of ewes tanycyte density and cellular penetration into the ARC was increased in ewes fed to gain body weight. Within the current report we have revealed that the number of neurons in the ARC expressing kisspeptin, neurokinin B, and dynorphin A protein was increased in ewes fed to gain body weight. Moreover, the number of KNDy neurons in the ARC expressing all three neuropeptides within a single neuron was decreased in ewes fed to lose body weight and increased in ewes fed to gain body weight when compared to ewes fed to maintain body weight. The cumulative findings of this experimental model suggest that expression of kisspeptin, neurokinin B, and dynorphin A protein in the ARC during the luteal phase of the estrous cycle are influenced by energy balance-induced alterations in circulating concentrations of progesterone that drive changes in morphology and density of tanycytes to ultimately regulate central perception of global energy status. Moreover, these results demonstrate that changes in KNDy neurons within the ARC occur as an adaptation to energy balance, potentially regulated divergently by metabolic milieu via proopiomelanocortin afferents. [ABSTRACT FROM AUTHOR]

Background: Kisspeptin and delta-like 1 homolog (DLK1) are neuropeptides that reportedly play an im portant role in pubertal timing by activating and inhibiting the hypothalamic-pituitary-gonadal axis, respectively. Consequently, serum kisspeptin and DLK1 levels may be novel biomarkers for differentiating between central precocious puberty (CPP) and premature thelarche (PT) in girls and used to monitor CPP treatment. Purpose: To compare baseline serum kisspeptin and DLK1 levels in girls with CPP at diagnosis and after treatment to age-matched girls with PT. Methods: This prospective longitudinal study included girls with precocious puberty and girls with PT who experienced breast development before 8 years of age and peak luteinizing hormone levels of =6 versus <6 IU/L after a gonadotropin-releasing hormone (GnRH) stimulation test. Serum kisspeptin and DLK1 levels were determined in both groups at baseline and after 6 months of GnRH analog treatment in the CPP group and analyzed by enzyme-linked immunosorbent assay. Results: The study divided a total of 48 girls into CPP (n=24; mean age, 7.7±0.7 years) and PT (n=24; mean age, 7.4±0.8 years) groups. The baseline median serum kisspeptin levels were 50.5 pg/mL (range, 38.2-77 pg/mL) and 49.5 pg/mL (range, 39.7-67.6 pg/mL), respectively (P=0.89), while the baseline median serum DLK1 levels were 6.5 ng/mL (range, 5.9-7.5 ng/mL) and 6 ng/mL (4.4-14.4 ng/mL), respectively (P=0.68). After 6 months of GnRH analog treatment in the CPP group, the median serum kisspeptin level was lower (46.4 ng/mL; range, 37.1-60 ng/mL) than that at baseline (P=0.002), while the median serum DLK1 level was higher (7 ng/mL; range, 6.7-8.9) than that at baseline (P=0.002). Conclusion: Our findings suggest that baseline serum kisspeptin and DLK1 levels are not reliable biomarkers for differentiating between CPP and PT. However, significant changes in serum kisspeptin and DLK1 levels may be used to monitor CPP treatment. [ABSTRACT FROM AUTHOR]

This study evaluated whether the treatment of pseudopregnancy in bitches with vitamin B6 modulates uterine expression of receptors for progesterone (PR), oestrogen (ERα), androgen (AR), thyroid hormone (TRα) and the kisspeptin/Kiss1r system. Eighteen pseudopregnant bitches were treated for 20 days in groups receiving placebo (n = 6); cabergoline (5 μg/kg/day; n = 6); or vitamin B6 (50 mg/kg/day; n = 6). Blood was collected on the 1st day of drug administration and 120 h later to measure serum prolactin (PRL). After treatment, they were ovariohysterectomized and uterine fragments were collected for histomorphometry and immunohistochemical evaluation of PR, ERα, AR, TRα, Kiss1 and Kiss1r. After 120 h of cabergoline or vitamin B6 treatment, PRL levels were reduced in the bitches, confirming the antiprolactinemic effect of these drugs. Furthermore, regardless of treatment, the animals exhibited uterine histomorphometry consistent with dioestrus. The PR showed strong immunostaining in all regions and an increase in scores was observed for this receptor in animals treated with vitamin B6 in deep glands. In contrast, ERα and Kiss1R receptors showed weak to no immunostaining in all uterine regions and no changes between groups. Regarding AR, most animals treated with vitamin B6 showed increased trends in the deep gland and myometrium marking scores. In contrast, in both vitamin B6 and cabergoline treatments, a reduction in TRα marking scores was observed compared to the control group. In addition, on the endometrial surface, a reduction was observed in the marked area of Kiss1 after administration of cabergoline when compared to the pseudopregnant control group. These findings shed valuable insight into the use of vitamin B6 as a drug with actions similar to cabergoline in reducing PRL and uterine modulation in bitches. [ABSTRACT FROM AUTHOR]

Kisspeptin is a neuropeptide that governs the reproductive axis upstream to GnRH. Present study was undertaken to compare the effect of different doses of kisspeptin on release of luteinizing hormone (LH) in Murrah buffaloes during pre-pubertal period. Twenty four pre-pubertal buffalo heifers were selected and divided into 4 groups (Control, T1, T2 and T3), having 6 animals in each group. Kisspeptin-10 was administered at the dose of 2 µg/kg body weight, 1.5 µg/ kg body weight, 1µg/kg body weight respectively in T1, T2 and T3 group along with administration of equal volume of NSS in control group. Blood sampling was done at every 20 minutes interval beginning with zero minutes up to 2 hours and analyzed for LH concentration. Results indicated that LH concentration was significantly (p<0.05) higher in T1 group. The peak level of LH was recorded at 20 minutes post administration and falls to basal level at 60 minutes post administration. Although increased LH concentration was observed in other treatment groups but it was lower than T1 group. No LH peak or rise in LH level was observed in control group. The result of this study indicates that during the pre-pubertal period, administration of Kisspeptin causes dose dependent increase in LH concentration and peak level was seen at 2 µg/kg body weight of dose. [ABSTRACT FROM AUTHOR]

This review highlights the recent developments regarding neuroendocrine mechanisms controlling teleost reproduction. In teleosts, the pituitary gland receives major neuronal innervations from Gnrh neurons as well as minor innervations from small population of neurons that will secrete neurotransmitters and/or neuropeptides. The diversity of Kiss/Kissr system in various teleost species and their actions in the context of HPG axis and reproduction has been extensively covered. In teleost model systems, zebrafish and medaka, mutant lines for key components of the HPG axis have been generated through targeted mutagenesis but surprisingly most of the mutants developed normally without major defects in reproduction; these mutant phenotypes are described. In the last decade, complex role of diverse neuropeptides in teleost reproduction is being revealed. A brief overview about the reproductive functions of neuropeptides is presented. Finally, the effects of environmental factors namely photoperiodism and temperature on the functions of HPG axis is summarised.

Abstract In mammals reproduction is regulated by many factors, among others by the peptides belonging to the RFamide peptide family. However, the knowledge concerning on the impact of recently identified member of this family (QRFP43) on the modulation of the gonadotrophic axis activity is still not fully understood and current research results are ambiguous. In the present study we tested the in vivo effect of QRFP43 on the secretory activity of the gonadotrophic axis at the hypothalamic-pituitary level in Polish Merino sheep. The animals (n = 48) were randomly divided into three experimental groups: controls receiving an icv infusion of Ringer-Locke solution, group receiving icv infusion of QRFP43 at 10 μg per day and 50 μg per day. All sheep received four 50 min icv infusions at 30 min intervals, on each of three consecutive days. Hypothalamic and pituitaries were collected and secured for further immunohistochemical and molecular biological analysis. In addition, during the experiment a blood samples have been collected for subsequent RIA determinations. QRFP43 was found to downregulate Kiss mRNA expression in the MBH and reduce the level of IR material in ME. This resulted in a reduction of GnRH IR material in the ME. QRFP43 increased plasma FSH levels while decreasing LH levels. Our findings indicate that QRFP43 inhibits the activity of the gonadotropic axis in the ovine at the level of the hypothalamus and may represent another neuromodulator of reproductive processes in animals.

Abstract 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.

Reproduction is regulated through the hypothalamic-pituitary-gonadal (HPG) axis, largely via the action of kisspeptin neurons in the hypothalamus. Importantly, Kiss1 neurons have been identified in other brain regions, including the medial amygdala (MeA). Though the MeA is implicated in regulating aspects of both reproductive physiology and behavior, as well as non-reproductive processes, the functional roles of MeA Kiss1 neurons are largely unknown. Additionally, besides their stimulation by estrogen, little is known about how MeA Kiss1 neurons are regulated. Using a RiboTag mouse model in conjunction with RNA-seq, we examined the molecular profile of MeA Kiss1 neurons to identify transcripts that are co-expressed in MeA Kiss1 neurons of female mice and whether these transcripts are modulated by estradiol (E2) treatment. RNA-seq identified >13,800 gene transcripts co-expressed in female MeA Kiss1 neurons, including genes for neuropeptides and receptors implicated in reproduction, metabolism, and other neuroendocrine functions. Of the >13,800 genes co-expressed in MeA Kiss1 neurons, only 45 genes demonstrated significantly different expression levels due to E2 treatment. Gene transcripts such as Kiss1, Gal, and Oxtr increased in response to E2 treatment, while fewer transcripts, such as Esr1 and Cyp26b1, were downregulated by E2. Dual RNAscope and immunohistochemistry was performed to validate co-expression of MeA Kiss1 with Cck and Cartpt. These results are the first to establish a profile of genes actively expressed by MeA Kiss1 neurons, including a subset of genes regulated by E2, which provides a useful foundation for future investigations into the regulation and function of MeA Kiss1 neurons.

The presence of Kisspeptin (Kp) and its receptors in the corpus luteum (CL) of buffalo has recently been demonstrated. In this study, we investigated the role of Kp in the modulation of progesterone (P 4) synthesis in vitro. The primary culture of bubaline luteal cells (LCs) was treated with 10, 50, and 100 nM of Kp and Kp antagonist (KpA) alongside a vehicle control. The combined effect of Kp and KpA was assessed at 100 nM concentration. Intracellular response to Kp treatment in the LCs was assessed by examining transcript profiles (LHR, STAR, CYP11A1, HSD3B1 , and ERK1/2) using quantitative polymerase chain reaction (qPCR). In addition, the immunolocalization of ERK1/2 and phosphorylated ERK1/2 (p -ERK1/2) in the LCs was studied using immunocytochemistry. Accumulation of P 4 from the culture supernatant was determined using enzyme-linked immunosorbent assay (ELISA). The results indicated that LCs had a greater p -ERK1/2 expression in the Kp treatment groups. A significant increase in the P 4 concentration was recorded at 50 nM and 100 nM Kp, while KpA did not affect the basal concentration of P 4. However, the addition of KpA to the Kp-treated group at 100 nM concentration suppressed the Kp-induced P 4 accumulation into a concentration similar to the control. There was significant upregulation of ERK1/2 and CYP11A1 expressions in the Kp-treated LCs at 100 nM (18.1 and 37fold, respectively, p < 0.01). However, the addition of KpA to Kp-treated LCs modulated ERK1/2, LHR, STAR, CYP11A1, and HSD3B1 at 100 nM concentration. It can be concluded that Kp at 100 nM stimulated P 4 production, while the addition of KpA suppressed Kp-induced P 4 production in the buffalo LCs culture. Furthermore, an increment in p -ERK1/2 expression in the LCs indicated activation of the Kp signaling pathway was associated with luteal steroidogenesis. • Kisspeptin (Kp) activates ERK1/2 pathway in the bubaline luteal cells in vitro. • Kp upregulated steroidogenic factors and progesterone (P 4) production. • Kp antagonist suppressed Kp-induced P 4 production. [ABSTRACT FROM AUTHOR]

Introduction: Postweaning social isolation (PWSI) in rodents is an advanced psychosocial stress model in early life. Some psychosocial stress, such as restrain and isolation, disrupts reproductive physiology in young and adult periods. Mechanisms of early-life stress effects on central regulation of reproduction need to be elucidated. We have investigated the effects of PWSI on function of arcuate kisspeptin (ARCKISS1) neurons by using electrophysiological techniques combining with monitoring of puberty onset and estrous cycle in male and female Kiss1-Cre mice. Methods: Female mice were monitored for puberty onset with vaginal opening examination during social isolation. After isolation, the estrous cycle of female mice was monitored with vaginal cytology. Anxiety-like behavior of mice was determined by an elevated plus maze test. Effects of PWSI on electrophysiology of ARCKISS1 neurons were investigated by the patch clamp method after intracranial injection of AAV-GFP virus into arcuate nucleus of Kiss1-Cre mice after the isolation period. Results: We found that both male and female isolated mice showed anxiety-like behavior. PWSI caused delay in vaginal opening and extension in estrous cycle length. Spontaneous-firing rates of ARCKISS1 neurons were significantly lower in the isolated male and female mice. The peak amplitude of inhibitory postsynaptic currents to ARCKISS1 neurons was higher in the isolated mice, while frequency of excitatory postsynaptic currents was higher in group-housed mice. Conclusion: These findings demonstrate that PWSI alters pre- and postpubertal reproductive physiology through metabolic and electrophysiological pathways. [ABSTRACT FROM AUTHOR]

This review highlights the recent developments regarding neuroendocrine mechanisms controlling teleost reproduction. In teleosts, the pituitary gland receives major neuronal innervations from Gnrh neurons as well as minor innervations from small population of neurons that will secrete neurotransmitters and/or neuropeptides. The diversity of Kiss/Kissr system in various teleost species and their actions in the context of HPG axis and reproduction has been extensively covered. In teleost model systems, zebrafish and medaka, mutant lines for key components of the HPG axis have been generated through targeted mutagenesis but surprisingly most of the mutants developed normally without major defects in reproduction; these mutant phenotypes are described. In the last decade, complex role of diverse neuropeptides in teleost reproduction is being revealed. A brief overview about the reproductive functions of neuropeptides is presented. Finally, the effects of environmental factors namely photoperiodism and temperature on the functions of HPG axis is summarised. [ABSTRACT FROM AUTHOR]

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In mammals reproduction is regulated by many factors, among others by the peptides belonging to the RFamide peptide family. However, the knowledge concerning on the impact of recently identified member of this family (QRFP43) on the modulation of the gonadotrophic axis activity is still not fully understood and current research results are ambiguous. In the present study we tested the in vivo effect of QRFP43 on the secretory activity of the gonadotrophic axis at the hypothalamic-pituitary level in Polish Merino sheep. The animals (n = 48) were randomly divided into three experimental groups: controls receiving an icv infusion of Ringer-Locke solution, group receiving icv infusion of QRFP43 at 10 μg per day and 50 μg per day. All sheep received four 50 min icv infusions at 30 min intervals, on each of three consecutive days. Hypothalamic and pituitaries were collected and secured for further immunohistochemical and molecular biological analysis. In addition, during the experiment a blood samples have been collected for subsequent RIA determinations. QRFP43 was found to downregulate Kiss mRNA expression in the MBH and reduce the level of IR material in ME. This resulted in a reduction of GnRH IR material in the ME. QRFP43 increased plasma FSH levels while decreasing LH levels. Our findings indicate that QRFP43 inhibits the activity of the gonadotropic axis in the ovine at the level of the hypothalamus and may represent another neuromodulator of reproductive processes in animals. [ABSTRACT FROM AUTHOR]

To understand better the role that kisspeptin plays in regulating seasonal and estrous cycle changes in the mare, this study investigated the number, location and interactions between GnRH, kisspeptin and RFRP-3 neurons in the equine hypothalamus. Hypothalami were collected from mares during the non-breeding season, vernal transition and various stages of the breeding season. Fluorescent immunohistochemistry was used to label the neuropeptides of interest. GnRH cells were observed primarily in the arcuate nucleus (ARC), while very few labeled cells were identified in the pre-optic area (POA). Kisspeptin cells were identified primarily in the ARC, with a small number of cells observed dorsal to the ARC, surrounding the third ventricle (3V). The mean number of kisspeptin cells varied between animals and typically showed no pattern associated with season or stage of estrous cycle, but a seasonal difference was identified in the ARC population. Small numbers of RFRP-3 cells were observed in the ARC, ventromedial hypothalamus (VMH) and dorsomedial hypothalamus (DMH). The mean number of RFRP-3 cells appeared higher in pre-ovulatory animals compared to all other stages. The percentage of GnRH cell bodies with kisspeptin appositions did not change with season or stage of estrous cycle. The percentage of kisspeptin cells receiving inputs from RFRP-3 fibers did not vary with season or stage of estrous cycle. These interactions suggest the possibility of the presence of an ultra-short loop feedback system between these three peptides. The changes in RFRP-3 neurons suggest the possibility of a role in the regulation of reproduction in the horse, but it is unlikely to be as a gonadotropin inhibitory factor. • Study investigated the number, location and interactions between GnRH, kisspeptin and RFRP-3 neurons in the hypothalamus of the mare. • Compared numbers across the estrous cycle and between seasons. [ABSTRACT FROM AUTHOR]

Kisspeptin is a peptide that plays a crucial function in the regulation of puberty initiation, by sexual immaturity and slowed puberty advancement. Infertility is a result of hyperprolactinemia, which inhibits the pulsatile release of GnRH from the brain and lowers the pulsatile production of LH from the pituitary. In type 1 diabetes, also known as autoimmune diabetes, pancreatic cells die off and the body cannot produce enough insulin, leading to high blood sugar levels. Obese people are more likely to suffer from hyperinsulinemia, hyperlipidemia, hyperleptinemia, chronic inflammation, menstrual abnormalities, pregnancy troubles, and infertility. So, this study aims to know the reproductive status of women by estimating kisspeptin and other hormones. The study was conducted on 92 women, ages (20-40) years, Samples were collected from the AL-Sader Teaching Hospital, Maysan for Child and Birth Hospital, the specialized Centre for Diabetes and Endocrinology and some private clinics and centres, the period June 2022 to February of 2023. The women were divided equally into four groups: control group (with regular menstrual cycles), hyperprolactinemia group (hyper serum prolactin), obesity group (have a BMI over 30 kg.m–2), and type 1 diabetes group. The results showed the values of kisspeptin did not differ significantly (P>0.05) in all groups, values of GnRH in hyperprolactinemia, obesity and type 1 DM groups increased significantly (P≤0.05) compared with the control group, Prolactin, estradiol and progesterone in the hyperprolactinemia group increased significantly (P≤0.05) in comparison with other groups. According to the above results, we conclude that high levels of prolactin, also obesity and type 1 DM influence the reproductive hormones in women. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The RFamide family of peptides represents an important class of GPCR ligand neuropeptides covering a wide range of biological functions. While many analogues of the highly conserved C‐terminal RFamide motif within this peptide class have been synthesized and their functional significance elucidated, additional exploration of the structure activity relationship is of value. We have developed a novel linker for solid phase peptide synthesis (SPPS) which is able to anchor amine functionalised compounds for further elaboration. The acid labile benzofuranone based amine (ALBA) linker (5‐(3‐aminopropylcarbamoyl)‐2‐[[tert‐butyl(diphenyl)silyl]oxymethyl]benzoic acid) is compatible with Fmoc based SPPS and has two cleavage modes. As a proof of concept, the ALBA linker was used to successfully synthesise a novel analogue of Kisspeptin 10, the natural ligand for GPCR54, whereby the natural RFamide motif was replaced with an RFamine. Biological evaluation of the amine‐containing analogue revealed that the group is not compatible with receptor activation. [ABSTRACT FROM AUTHOR]

Multiple factors, such as stress, excessive deviations in body weight (obesity and cachexia), eating disorders, including anorexia nervosa, energy-deficient conditions and insulin resistance affect women's reproductive health due to dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis and the following ovulatory dysfunction, categorized as hypothalamic hypogonadism, that may present with menstrual cycle disturbances and/ or infertility. The kisspeptinergic system is the one that links stress, nutrition and reproductive signals and plays a key role in maintaining normal pulsatility of gonadotropin-releasing hormone (GnRH) and ovulation. In addition to leptin and insulin, elevated corticotropin-releasing hormone (CRH) and the activation of hypothalamic-pituitary-adrenal (HPA) axis are thought to be key modulators of ovulatory dysfunction. Neuroendocrine regulation of the reproductive processes is a subject of intense research, having in mind the global increase in the incidence of infertility. The purpose of this review is to present the effector elements of the HPG and HPA axis, to gather the available information about the markers and regulators, that are known to date - kiss-peptins, adipocytokines, appetite modulators, as well as to present some newly discovered neuro-peptides (spexin and phoenixin), that are involved in the modulation of reproductive functions, with the potential to reveal new mechanisms in the pathogenesis and to discover new possibilities for the treatment of ovulatory dysfunctions. [ABSTRACT FROM AUTHOR]

Although the immuno-modulatory and stress-relieving properties of β-glucan is well elucidated in humans and other animal models, including fish, its role as a dietary supplement on reproduction is extremely scarce. Therefore, in this study, adult female fish were fed one of four test diets having 0 (control), 0.5, 1, and 1.5% β-d-glucan for 130 days and its effect on reproductive performance, ovarian and liver histology, sex hormones, and transcript abundance of selected reproduction-related genes was assessed. Low dietary intake of β-glucan improved fertilization and hatching rates (p<0.05). The relative fecundity and percentage of spawning females were higher (non-significant) in 0.5% β-glucan-fed groups. Surprisingly, even after 130 days, spawning did not occur in 1.5% β-glucan-fed individuals. Irrespective of β-glucan intake, all the brooders recorded similar plasma 17β-estradiol and maturation-inducing hormone (p>0.05). Higher intake of β-glucan (1.5%) upregulated aromatase genes without a parallel increase in 17β-estradiol. However, plasma vitellogenin increased with increasing β-glucan up to 1.0% then declined at 1.5% (p<0.05). The fish that received control, 0.5, and 1.5% β-glucan recorded similar vitellogenin levels in their plasma. Significantly higher plasma cortisol was evidenced in 1.5% β-glucan fed brooders (p<0.05). Histologically, higher follicular atresia and leaking of yolk material was evidenced in 1.5% β-glucan-fed group. Liver histology revealed the highest nutrient/lipid accumulation in fish that received 1.0% and 1.5% β-glucan. This study demonstrated the stimulatory effect of β-glucan intake at a lower dose (0.5%) on reproduction. However, higher intake (1.5%) could perturb normal reproductive function in a fish model and caused an increased number of atretic follicles leading to spawning/reproductive failure. [ABSTRACT FROM AUTHOR]

The neuroendocrine system that controls the preovulatory surge of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH), which triggers ovulation in female mammals, is sexually differentiated in rodents. A transient increase in circulating testosterone levels in male rats within a few hours of birth is primarily responsible for the defeminization of anteroventral periventricular nucleus (AVPV) kisspeptin neurons, which are critical regulators of the GnRH/LH surge. The present study aimed to determine whether neonatal estradiol-17β (E2) converted from testosterone by aromatase primarily causes the defeminization of AVPV kisspeptin neurons and the surge of GnRH/LH in male rodents. The results of the present study showed that the neonatal administration of letrozole (LET), a nonsteroidal aromatase inhibitor, within 2 hours of birth rescued AVPV Kiss1 expression and the LH surge in adult male rats, while the neonatal administration of testosterone propionate (TP) irreversibly attenuated AVPV Kiss1 expression and the LH surge in adult female rats. Furthermore, the neonatal LET-treated Kiss1 - Cre –activated tdTomato reporter males exhibited a comparable number of AVPV Kiss1 - Cre –activated tdTomato-expressing cells to that of vehicle-treated female rats, while neonatal TP-treated females showed fewer AVPV Kiss1 - Cre –activated tdTomato-expressing cells than vehicle-treated females. Moreover, neonatal TP administration significantly decreased the number of arcuate Kiss1 -expressing and Kiss1 - Cre –activated tdTomato-positive cells and suppressed LH pulses in adult gonadectomized female rats; however, neonatal LET administration failed to affect them. These results suggest that E2 converted from neonatal testosterone is primarily responsible for the defeminization of AVPV kisspeptin neurons and the subsequent GnRH/LH surge generation in male rats. [ABSTRACT FROM AUTHOR]

The endocrine disruptor hexavalent chromium [Cr(VI)] is a proven reproductive toxicant. We recently demonstrated that prenatal Cr(VI) exposure causes testicular resistance to gonadotropins, resulting in hypergonadotropic hypoandrogenism in F1 rats. However, the mechanism driving hypergonadotropism in F1 rats exposed to Cr (VI) prenatally remains an enigma. Therefore, we hypothesized that 'Prenatal Cr(VI) exposure may disrupt steroid hormones-mediated negative feedback regulation of the hypothalamic GnRH, and its receptor in the pituitary of F1 rats, leading to hypergonadotropism.' We administered potassium dichromate (50, 100, or 200 mg/L) to pregnant rats through drinking water between days 9 and 14, and their male F1 offspring were euthanized at 60 days of age. Prenatal Cr(VI) exposure in F1 rats resulted in the accumulation of Cr in the hypothalamus and pituitary. Western blot detected decreased hypothalamic GnRH, Kisspeptin1, and its receptor GPR54, along with diminished ERα, AR, aromatase, and 5α reductase, and GnRH regulatory transcription factors Pit-1 and GATA-4 proteins. Immunohistochemical studies revealed increased immunopositivity of GnRH receptor, AR, 5α reductase, ERα, ERβ, and aromatase proteins in the pituitary, whereas decreased Kisspeptin1, GPR54, and inhibin β. Our findings imply that Cr(VI) exposure during the prenatal period disrupts the hypothalamic Kisspeptin-GPR54-Pit-1/GATA4-GnRH network, boosting the pituitary GnRH receptor. We conclude that prenatal exposure to Cr(VI) alters GnRH expression in the hypothalamus and its receptor in the pituitary of F1 progeny through interfering with the negative feedback effect of androgens and estrogens. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: In this study, it is aimed to investigate the relationship between serum adiponectin and kisspeptin levels and insulin resistance in patients with PCOS. Methods: 144 patients diagnosed with PCOS in a tertiary center, were included in the study. At the first visit, the height and weight measurements were recorded and menstrual functions were questioned. After ultrasonographic evaluation and hormonal assessment, patients were divided into groups according to insulin resistance (IR), then were compared in terms of hormonal parameters. Results: Weight and BMI were significantly higher in the insulin-resistant group (p=0.018, p=0.012). Mean fasting glucose, fasting insulin levels and HOMA indexes of the insulin-re)sistant group were significantly higher than the non-resistant group, respectively (p<0.001). LH/FSH ratios were significantly lower in the IR+ group (1.33 vs 1.58, p<0.05). No significant difference was observed between the groups in terms of adiponectin and kisspeptin levels, but the mean kisspeptin level in the IR- group was higher than the IR+ group (32.72 vs 19.36, p=0.067). Adiponectin and kisspeptin were both found to have a very weak positive relation)ship with FSH (r=0.169 and 0.171). Conclusion: Adiponectin is known to decrease in obesity and type 2 diabetes, but does not show the difference in insulin-resistant PCOS patients. Kisspeptin, which is a hypotha)lamic peptide and associated with increased LH levels in patients with PCOS, was found to be lower in the IR+ group. In order to clarify the role of kisspeptin and adiponectin in the mechanisms of PCOS and insulin resistance, it is needed to be examined in a larger sample with BMI-matched healthy controls. [ABSTRACT FROM AUTHOR]