kiss1-protein--human and Polycystic-Ovary-Syndrome

Topics: Arcuate Nucleus of Hypothalamus; Female; Gonadotropin-Releasing Hormone; Humans; Hypothalamus; Kisspeptins; Neurokinin B; Neurons; Polycystic Ovary Syndrome

Polycystic ovarian syndrome (PCOS) affects 5-20% of females and is the most common cause of anovulatory infertility. Leptin seems to have an important role in reproduction. Many reproductive pathologies such as preeclampsia, PCOS, and endometriosis are associated to plasma adiponectin levels. Kisspeptin levels are increased in PCOS women.. A review of the literature was completed through the PubMed database aiming to find articles regarding leptin, adiponectin and kisspeptin and if they are related to PCOS pathogenesis.. Even today it is not clear what is the role of leptin in women with PCOS, although most of the researchers found increased levels of leptin as well as leptin resistance in PCOS (both obese and lean individuals). Many more longitudinal studies should be done to discover the usefulness of measuring adiponectin in prepubertal women who apparently have a possibility to develop PCOS to find out if they finally develop PCOS. Most of the researchers found that PCOS women have decreased levels of adiponectin unrelated to BMI levels. Nevertheless, not all studies had the same result. Moreover, it is necessary more studies to be made to investigate the connection between kisspeptin and other metabolic factors such as LH and insulin resistance.. In general, it remains inconclusive whether leptin, adiponectin, and kisspeptin can be used as clinical and/or biochemical markers of PCOS. Therefore, it is essential to review the current data with regards to the association between PCOS and circulating leptin, adiponectin, and kisspeptin in women with PCOS.

Topics: Adiponectin; Female; Humans; Kisspeptins; Leptin; Obesity; Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and is the leading cause of anovulatory subfertility. Increased gonadotrophin releasing hormone (GnRH) pulsatility in the hypothalamus results in preferential luteinizing hormone (LH) secretion from the pituitary gland, leading to ovarian hyperandrogenism and oligo/anovulation. The resultant hyperandrogenism reduces negative feedback from sex steroids such as oestradiol and progesterone to the hypothalamus, and thus perpetuates the increase in GnRH pulsatility. GnRH neurons do not have receptors for oestrogen, progesterone, or androgens, and thus the disrupted feedback is hypothesized to occur via upstream neurons. Likely candidates for these upstream regulators of GnRH neuronal pulsatility are Kisspeptin, Neurokinin B (NKB), and Dynorphin neurons (termed KNDy neurons). Growing insight into the neuroendocrine dysfunction underpinning the heightened GnRH pulsatility seen in PCOS has led to research on the use of pharmaceutical agents that specifically target the activity of these KNDy neurons to attenuate symptoms of PCOS. This review aims to highlight the neuroendocrine abnormalities that lead to increased GnRH pulsatility in PCOS, and outline data on recent therapeutic advancements that could potentially be used to treat PCOS. Emerging evidence has investigated the use of neurokinin 3 receptor (NK3R) antagonists as a method of reducing GnRH pulsatility and alleviating features of PCOS such as hyperandrogenism. We also consider other potential mechanisms by which increased GnRH pulsatility is controlled, which could form the basis of future avenues of research.

Topics: Female; Gonadotropin-Releasing Hormone; Humans; Hyperandrogenism; Kisspeptins; Luteinizing Hormone; Polycystic Ovary Syndrome; Progesterone

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women and a major cause of anovulatory infertility. A diagnosis of PCOS is established based the presence of two out of three clinical symptoms, which are criteria accepted by the ESHRE/ASRM (European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine). Gonadotropin-releasing hormone (GnRH) is responsible for the release of luteinizing hormone, and follicle stimulating hormone from the pituitary and contributes a leading role in controlling reproductive function in humans. The goal of this review is to present the current knowledge on neuroendocrine determinations of PCOS. The role of such neurohormones as GnRH, and neuropeptides kisspeptin, neurokinin B, phoenixin-14, and galanin is discussed in this aspect. Additionally, different neurotransmitters (gamma-aminobutyric acid (GABA), glutamate, serotonin, dopamine, and acetylcholine) can also be involved in neuroendocrine etiopathogenesis of PCOS. Studies have shown a persistent rapid GnRH pulse frequency in women with PCOS present during the whole ovulatory cycle. Other studies have proved that patients with PCOS are characterized by higher serum kisspeptin levels. The observations of elevated serum kisspeptin levels in PCOS correspond with the hypothesis that overactivity in the kisspeptin system is responsible for hypothalamic-pituitary-gonadal axis overactivity. In turn, this causes menstrual disorders, hyperandrogenemia and hyperandrogenism. Moreover, abnormal regulation of Neurokinin B (NKB) is also suspected of contributing to PCOS development, while NKB antagonists are used in the treatment of PCOS leading to reduction in Luteinizing hormone (LH) concentration and total testosterone concentration. GnRH secretion is regulated not only by kisspeptin and neurokinin B, but also by other neurohormones, such as phoenixin-14, galanin, and Glucagon-like peptide-1 (GLP-1), that have favorable effects in counteracting the progress of PCOS. A similar process is associated with the neurotransmitters such as GABA, glutamate, serotonin, dopamine, and acetylcholine, as well as the opioid system, which may interfere with secretion of GnRH, and therefore, influence the development and severity of symptoms in PCOS patients. Additional studies are required to explain entire, real mechanisms responsible for PCOS neuroendocrine background.

Topics: Acetylcholine; Dopamine; Female; Galanin; gamma-Aminobutyric Acid; Glutamic Acid; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Luteinizing Hormone; Neurokinin B; Neurotransmitter Agents; Polycystic Ovary Syndrome; Serotonin; United States

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy and cause of infertility in women of reproductive age worldwide. Despite diagnostic features of anovulation, polycystic ovarian morphology, and high androgen secretion indicating the syndrome are the result of ovarian dysfunction, alterations to central neuroendocrine circuits that control reproductive capacity may drive PCOS symptoms. Resistance of gonadotrophin-releasing hormone (GnRH) neurons in the hypothalamus to inhibition by sex steroid hormone-negative feedback leads to a rapid frequency of pulsatile gonadotrophin secretion, which, in turn, drives the ovarian features of the disease. As GnRH neurons do not express steroid hormone receptors, impaired negative feedback is hypothesized to occur within an upstream network that controls GnRH pulse generation. This review will discuss the latest work from preclinical animal models of PCOS used to dissect the specific central mechanisms involved in impaired steroid hormone feedback. In particular, this review will focus on research that indicates neurons in the arcuate nucleus of the hypothalamus that express Kisspeptin, Neurokinin B and Dynorphin (KNDy cells) or γ-aminobutyric acid are targets of androgen-mediated impairment of steroid hormone feedback. Finally, this review will explore the development of therapeutic agents targeting neurons that control LH pulse frequency to resolve PCOS symptoms in the clinic.

Topics: Androgens; Animals; Feedback; Female; Fertility; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Luteinizing Hormone; Polycystic Ovary Syndrome; Steroids

Kisspeptin is the leading upstream regulator of pulsatile and surge Gonadotrophin-Releasing Hormone secretion (GnRH) in the hypothalamus, which acts as the key governor of the hypothalamic-pituitary-ovary axis.. Exogenous kisspeptin or its receptor agonist can stimulate GnRH release and subsequent physiological gonadotropin secretion in humans. Based on the role of kisspeptin in the hypothalamus, a broad application of kisspeptin and its receptor agonist has been recently uncovered in humans, including central control of ovulation, oocyte maturation (particularly in women at a high risk of ovarian hyperstimulation syndrome), test for GnRH neuronal function, and gatekeepers of puberty onset. In addition, the kisspeptin analogs, such as TAK-448, showed promising agonistic activity in healthy women as well as in women with hypothalamic amenorrhoea or polycystic ovary syndrome.. More clinical trials should focus on the therapeutic effect of kisspeptin, its receptor agonist and antagonist in women with reproductive disorders, such as hypothalamic amenorrhoea, polycystic ovary syndrome, and endometriosis.

Topics: Amenorrhea; Female; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Polycystic Ovary Syndrome; Receptors, Kisspeptin-1; Reproduction

This systematic review and meta-analysis aimed to summarize the available evidence regarding circulating kisspeptin and anti-müllerian hormone (AMH) and the homeostasis model assessment of insulin resistance (HOMA-IR) index in adolescents and women with and without polycystic ovary syndrome (PCOS).. We performed a comprehensive literature search in Medline, Embase, Cochrane, Scopus, and Web of Science for studies evaluating circulating kisspeptin levels in women with and without PCOS published until September 24th, 2020. Co-primary outcomes were the HOMA-IR index and AMH. The quality of included studies was assessed using the Newcastle-Ottawa Scale. Random-effects models were used to estimate outcomes, and effects reported as mean difference (MD) or standardized MD (SMD) and their 95 % confidence interval (CI). The systematic review and meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as number CRD42020205030.. We evaluated 18 studies including, 1282 PCOS cases and 977 controls. Participants with PCOS were younger (MD = -2.38 years, 95 %CI -4.32 to -0.44), with higher BMI (MD = 1.16, 95 % CI 0.54-1.78), waist-to-hip ratio (MD = 0.04, 95 %CI 0.02 to 0.05), circulating kisspeptin (SMD = 1.15, 95 %CI 0.68-1.62), luteinizing hormone (SMD = 1.29, 95 %CI 0.76-1.83), AMH (SMD = 0.97, 95 %CI 0.60-1,34), total testosterone (SMD = 2.48, 95 %CI 1.73-3.23), free testosterone (SMD = 1.37, 95 %CI 0.56-2.17), and dehydroepiandrosterone sulphate (SMD = 0.72, 95 %CI 0.32-1.13) levels, and Ferriman-Gallwey score (SMD = 5.08, 95 %CI 2.76-7.39), and lower sex hormone-binding globulin level (SMD = -1.34, 95 %CI -2.15 to -0.52). Besides, participants with PCOS had higher HOMA-IR index (SMD = 0.76, 95 %CI 0.35-1.17), and circulating insulin (SMD = 0.75, 95 %CI 0.30-1.19), leptin (SMD = 2.82, 95 %CI 1.35-4.29), and triglycerides (SMD = 2.15, 95 %CI 1.08-3.23) levels than participants without the syndrome. The meta-regression did not identify significant factors influencing circulating kisspeptin.. Patients with PCOS showed higher kisspeptin, LH, insulin, AMH, and androgen levels and HOMA-IR index, and lower sex hormone-binding globulin levels than those without the syndrome.

Topics: Adolescent; Anti-Mullerian Hormone; Female; Humans; Insulin Resistance; Kisspeptins; Polycystic Ovary Syndrome

To clarify the association of serum kisspeptin levels in women with polycystic ovary syndrome (PCOS) by meta-analysis.. Two English databases and two Chinese databases were searched for the relationship between kisspeptin and PCOS published from 2009. After the studies screening according to specific principles, we used STATA 12.0 for meta-analysis. Standardized mean difference (SMD) and its 95% confidence intervals (95% CIs) were used as the effect size and STATA 12.0 software was performed by this meta-analysis.. Nine articles were included in the end, with a total of 1282 participants (699 patients and 583 controls). Heterogeneity between studies was statistically significant. Therefore, the random effects model was used to combine the effects. Meta-analysis showed statistically significant differences in serum kisspeptin levels between the PCOS patients and controls (SMD = 0.57, 95% CI [0.32, 0.82]), which indicated that there is a strong association between serum kisspeptin levels and PCOS. The source of high heterogeneity between the inclusion studies (I. Serum kisspeptin levels in PCOS patients were higher than non-PCOS patients. It is a hint to indicate us that kisspeptin might be an independent biomarker of PCOS patients.

Topics: Biomarkers; Female; Humans; Kisspeptins; Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) affects 6% to 20% of reproductive age women and is the most frequent cause of anovulatory infertility. Its physiopathology may result in part from hypothalamic alterations in the pulsatile secretion of gonadotropin-releasing hormone (GnRH). The neuropeptide kisspeptin participates in the mechanism through stimulation of the hormone's production. The purpose of this study was to review the articles which compared kisspeptin levels in women with PCOS with those of controls. A systematic review of observational studies was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) recommendations. The selected studies encompassed a population of patients with PCOS and controls, whose serum kisspeptin levels were evaluated. The studies were retrieved from the Medline, Cochrane, and Embase databases, and four of them were chosen for the review. In most studies, the serum kisspeptin levels were higher in women with PCOS than in controls notwithstanding the BMI. One of the articles showed that circulating plasma levels of kisspeptin were significantly higher in women with PCOS whose BMI was lower than 25 than in obese and overweight women. Our data suggest a higher concentration of serum kisspeptin in women with PCOS irrespective of their BMI. Further experimental and clinical studies are needed to ascertain the role of kisspeptin in PCOS.

Topics: Animals; Female; Humans; Kisspeptins; Observational Studies as Topic; Polycystic Ovary Syndrome

In recent years, it has been found that kisspeptin plays some key roles in the physiological processes of the brain, such as gender differentiation, positive and negative feedback of sex hormones, onset of puberty, and transduction of energy signals in the body, which suggests that kisspeptin may be a key molecule for the maturation and regulation of female reproductive function. In addition to the systemic roles of the kisspeptin, its local roles in reproductive organs are constantly being discovered. With the discovery that kisspeptin is involved in the pathological process of reproductive endocrine diseases such as isolated hypogonadotropic hypogonadism (IHH), polycystic ovary syndrome (PCOS), premature ovarian failure (POF) and pathological hyperprolactinemia, exogenous application of kisspeptin to solve reproductive problems has become a new hot topic. The review focuses on the research progress of kisspeptin in the female reproductive system, especially on its application in assisted reproduction.

Topics: Female; Gonadal Steroid Hormones; Humans; Hyperprolactinemia; Hypogonadism; Kisspeptins; Polycystic Ovary Syndrome; Pregnancy; Primary Ovarian Insufficiency; Reproductive Techniques, Assisted

A close association between Kisspeptin-1 (KISS-1) and reproductive physiology has been reported, but the results on circulatory KISS-1 are ambiguous in patients with polycystic ovary syndrome (PCOS). A systematic review and meta-analysis were conducted to evaluate the association between KISS-1 and PCOS, and to test its diagnostic test accuracy (DTA) through DTA meta-analysis.. Relevant studies were identified by searching PubMed and other databases in addition to manual searching of cross-references. Random-effects model was used to obtain standardized mean differences (SMD), pooled correlation coefficients and summary of DTA. Meta-regression and sub-group analyses were conducted to explore heterogeneity. The presence of publication bias was tested using funnel plot analysis.. This meta-analysis finally included 12 studies. Compared with controls, women with PCOS showed significantly increased circulatory KISS-1 levels (SMD = 0.47; P = 0.002). Meta-analysis of correlations showed positive associations between KISS-1 and anti-Müllerian hormone (AMH) (P = 0.03), testosterone (P < 0.001) and dehydroepiandrosterone (P = 0.004). The pooled diagnostic odds ratio and area under curve were 13.71 and 0.835, respectively. A one-study leave-out sensitivity analysis indicated that no single study had a significant influence on the overall outcome, suggesting the robustness of this meta-analysis.. This meta-analysis showed significantly increased KISS-1 level in PCOS, and its association with AMH reflects its role in reproductive physiology. In our DTA meta-analysis, KISS-1 showed good accuracy for PCOS detection. Further large-scale studies are required to establish its validity.

Topics: Anti-Mullerian Hormone; Case-Control Studies; Diagnostic Techniques, Endocrine; Diagnostic Tests, Routine; Female; Humans; Kisspeptins; Polycystic Ovary Syndrome; Predictive Value of Tests; Reproducibility of Results; Testosterone

The pulsatility of GnRH release is essential for reproductive function. The key events in reproductive function, such as puberty onset and ovulatory cycles, are regulated by the frequency and amplitude modulation of pulsatile GnRH release. Abnormal patterns of GnRH pulsatility are seen in association with disease states, such as polycystic ovarian syndrome and anorexia nervosa. Recent studies with physiological, track-tracing, optogenetic and electrophysiological recording experiments indicate that a group of kisspeptin neurons in the arcuate nucleus (ARC) of the hypothalamus are responsible for pulsatile GnRH release. Thus, the kisspeptin neuron in the ARC has been called the "GnRH pulse-generator." However, a few pieces of evidence do not quite fit into this concept. This article reviews some old works and discusses unresolved issues on the mechanism of GnRH pulse generation.

Topics: Animals; Anorexia Nervosa; Female; Gonadotropin-Releasing Hormone; Kisspeptins; Polycystic Ovary Syndrome; Primates; Reproduction; Sexual Maturation

Polycystic ovarian syndrome (PCOS) is a complex and not fully elucidated pathology. This prevalent endocrinopathy affects patients in reproductive age, impacts on estrogen-dependent diseases, as well as in infertility. In this context, Kisspeptin (KP) may be considered a potential biomarker for PCOS diagnosis and follow-up. Here, we aimed to verify the levels of KP in obese and non-obese patients with PCOS, their relationship with other hormones, in comparison to healthy controls.. A systematic review and meta-analysis were performed according to the PRISMA guidelines. We searched MEDLINE, EMBASE, PsycINFO, Global Health, The Cochrane Library, Health Technology Assessment Database, and Web of Science for eligible studies. A random effects model meta-analysis of standardized mean difference (SMD) was conducted and the I. A total of 12 studies were included, comprising 660 PCOS patients and 600 controls. The KP levels were lower in the control group (0.76: 0.17-1.35; 95% CI). In the subgroup analyses, patients were divided in non-overweight/obese (BMI < 25) and overweight/obese (BMI ≥ 25) groups. The meta-regression revealed a difference between the obese and non-obese groups (z = 2.81; p = 0.0050).. PCOS patients showed higher KP levels than control, and obese non-PCOS patients also showed altered KP levels. All studies had poor descriptions of sample collection, pre-analytical and analytical procedures, which is critical considering structural characteristics of the KP molecule.

Topics: Adult; Biomarkers; Female; Humans; Kisspeptins; Polycystic Ovary Syndrome; Risk Assessment

Over the last decade, huge achievements have been made in the fields of neurophysiology, molecular endocrinology, and biochemistry, as well as in the successful translation of clinical research into diseases into clinical practice. As regards female reproduction, most of the advances made in this area were achieved in gonadal axis regulation, regulation of behavior through sex steroids, reproductive genetics, preservation of ovarian reproductive function, steroid profiling, and metabolic and overall reproductive outcomes. The coming years are expected to bring further understanding of the relationships between nutrition, energy metabolism, and reproductive function and to succeed in identifying new genetic markers linked to adverse metabolic and unfavorable cardiovascular outcomes in women. From our perspective, future research in the field of female reproduction should be directed toward doing research into genetic reproductive abnormalities and neuroendocrine diseases, pathophysiology, long-term health outcomes for oligo/amenorrhea, hyperandrogenism, and ovulatory dysfunction. It is additionally expected that a better understanding will be gained of the endocrinology of the placenta and of pregnancy, the role of the microbiome in female reproduction, the role of insulin sensitizers, anti-obesity and anti-diabetic drugs, and various advances in the prevention of ovarian damage caused by various oncology therapies, while new therapeutic options for the treatment of infertility, including kisspeptin, will be developed.

Topics: Anti-Mullerian Hormone; Endocrinology; Female; Gonadal Steroid Hormones; History, 21st Century; Humans; Hyperandrogenism; Hypothalamic Hormones; Kisspeptins; Polycystic Ovary Syndrome; Reproductive Physiological Phenomena

Polycystic ovary syndrome (PCOS) is a highly prevalent heterogeneous disease characterized by ovulatory dysfunction, hyperandrogenism, and metabolic alterations. Women with PCOS commonly display dysregulated gonadotropin secretion with higher LH pulsatility and perturbed LH-FSH ratios, which likely contributes to the ovarian phenotype and might be indicative of disrupted GnRH secretory activity. Although the involvement of altered androgen and insulin levels in the pathogenesis of the neuroendocrine alterations of PCOS has been explored in various experimental and clinical settings, the ultimate mechanisms whereby such neurohormonal perturbations take place remain partially unknown. In recent years, kisspeptins, the products of the Kiss1 gene that operate via the surface receptor Gpr54, have emerged as essential elements of the reproductive brain that play an indispensable role in the control of gonadotropin secretion and ovulation. In addition, Kiss1 neurons in the brain are targets and transmitters of the regulatory actions of sex steroids and metabolic cues on the reproductive axis during early organizing periods and adulthood. Furthermore, Kiss1/kisspeptin expression has been documented in the ovary in various species, including humans; yet clear evidence for the involvement of kisspeptin signaling in the control of ovulation, or its alterations, is still pending. Based on these physiologic features, we discuss the putative pathophysiologic implications of alterations of the Kiss1 system in the generation of PCOS and summarize the scarce experimental and clinical evidence that might support such a role.

Topics: Animals; Female; Gonadal Steroid Hormones; Humans; Kisspeptins; Polycystic Ovary Syndrome; Signal Transduction

Leptin, a key hormone in energy homeostasis and neuroendocrine function, has a permissive role in initiating puberty and is crucial in the pathogenesis of reproductive dysfunction in several disease states of energy imbalance. KiSS1 neurons have recently been suggested to mediate leptin's effect on the reproductive system. New insights from recent animal studies and clinical trials are discussed.. Alterations in the expression profile of the KiSS1 gene and the kisspeptin receptor have been linked to reproductive dysfunction in leptin-deficient states. Neuroendocrine, including reproductive, dysfunction can be restored in humans and animals by leptin-replacement therapy. These insights have significantly advanced our understanding of hormonal systems needed to maintain normal reproduction. These data, if confirmed, also suggest a role for leptin as a novel therapeutic approach in several disease states.. Recent proof-of-concept studies involving leptin administration to humans underline the critical role of leptin not only in regulating energy homeostasis, but also in maintaining normal reproductive function. Leptin-replacement therapy is currently under intensive investigation as a potential novel therapeutic option for several conditions associated with reproductive dysfunction due to hypoleptinemia.

Topics: Amenorrhea; Animals; Anorexia Nervosa; Energy Metabolism; Female; Gonads; Humans; Hypothalamo-Hypophyseal System; Infertility; Kisspeptins; Leptin; Male; Menarche; Obesity; Polycystic Ovary Syndrome; Puberty; Reproduction; Sex Characteristics; Tumor Suppressor Proteins

What is the role of the hypothalamic neuropeptide neurokinin B (NKB) and its interaction with kisspeptin on GnRH/LH secretion in women with polycystic ovary syndrome (PCOS)?. Administration of neurokinin 3 receptor antagonist (NK3Ra) for 7 days reduced LH and FSH secretion and LH pulse frequency in women with PCOS, whilst the stimulatory LH response to kisspeptin-10 was maintained.. PCOS is characterized by abnormal GnRH/LH secretion. NKB and kisspeptin are master regulators of GnRH/LH secretion, but their role in PCOS is unclear.. The NK3Ra MLE4901, 40 mg orally twice a day, was administered to women with PCOS for 7 days (n = 8) (vs no treatment, n = 7). On the last day of NK3Ra administration or the equivalent day in those not treated, women were randomized to 7-h kisspeptin-10 (4 µg/kg/h i.v.) or vehicle infusion. This was repeated with the alternate infusion in a subsequent cycle.. Subjects were women with PCOS, studied in a Clinical Research Facility. Reproductive hormones were measured before and after NK3Ra administration. On the last day of NK3Ra administration (or the equivalent cycle day in untreated women), all women attended for an 8-h frequent blood sampling to allow analysis of the pulsatile LH secretion.. NK3Ra reduced LH secretion (4.0 ± 0.4 vs 6.5 ± 0.8 IU/l, P < 0.05) and pulse frequency (0.5 ± 0.1 vs 0.8 ± 0.1 pulses/h, P < 0.05); FSH secretion was also reduced (2.0 ± 0.3 vs 2.5 ± 0.4 IU/l, P < 0.05). Without NK3Ra pre-treatment, kisspeptin-10 increased LH secretion (5.2 ± 0.5 to 7.8 ± 1.0 IU/L, P < 0.05), with a positive relationship to oestradiol concentrations (r2 = 0.59, P < 0.05). After NK3Ra administration, the LH response to kisspeptin-10 was preserved (vehicle 3.5 ± 0.3 vs 9.0 ± 2.2 IU/l with kisspeptin-10, P < 0.05), but the positive correlation with oestradiol concentrations was abolished (r2 = 0.07, ns. after NK3Ra). FSH secretion was increased by kisspeptin-10 after NK3Ra treatment, but not without NK3Ra treatment.. The study did not explore the dose relationship of the effect of NK3R antagonism. The impact of obesity or other aspects of the variability of the PCOS phenotype was not studied due to the small number of subjects.. These data demonstrate the interactive regulation of GnRH/LH secretion by NKB and kisspeptin in PCOS, and that the NKB system mediates aspects of oestrogenic feedback.. Wellcome Trust through Scottish Translational Medicine and Therapeutics Initiative (102419/Z/13/A) and MRC grants (G0701682 to R.P.M. and R.A.A.) and MR/N022556/1 to the MRC Centre for Reproductive Health. This work was performed within the Edinburgh Clinical Research Facility. J.T.G. has undertaken consultancy work for AstraZeneca and Takeda Pharmaceuticals and is an employee of Boehringer Ingelheim. R.P.M. has consulted for Ogeda and was CEO of Peptocrine. R.A.A. has undertaken consultancy work for Merck, Ferring, NeRRe Therapeutics and Sojournix Inc. J.D.V. and K.S. have nothing to disclose.. N/A.

Topics: Female; Humans; Kisspeptins; Luteinizing Hormone; Male; Neurokinin B; Polycystic Ovary Syndrome

BACKGROUNDKisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders.METHODSWe conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP1) and Ca2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices.RESULTSIn healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).CONCLUSIONTaken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATIONInternational Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDINGNational Institute for Health Research and NIH.

Topics: Adolescent; Adult; Amenorrhea; Calcium Signaling; Cell Line; Female; Humans; Hypothalamus; Kisspeptins; Luteinizing Hormone; Peptide Fragments; Polycystic Ovary Syndrome; Receptors, Kisspeptin-1

Can kisspeptin treatment induce gonadotrophin responses and ovulation in preclinical models and anovulatory women with polycystic ovary syndrome (PCOS)?. Kisspeptin administration in some anovulatory preclinical models and women with PCOS can stimulate reproductive hormone secretion and ovulation, albeit with incomplete efficacy.. PCOS is a prevalent, heterogeneous endocrine disorder, characterized by ovulatory dysfunction, hyperandrogenism and deregulated gonadotrophin secretion, in need of improved therapeutic options. Kisspeptins (encoded by Kiss1) are master regulators of the reproductive axis, acting mainly at GnRH neurons, with kisspeptins being an essential drive for gonadotrophin-driven ovarian follicular maturation and ovulation. Altered Kiss1 expression has been found in rodent models of PCOS, although the eventual pathophysiological role of kisspeptins in PCOS remains unknown.. Gonadotrophin and ovarian/ovulatory responses to kisspeptin-54 (KP-54) were evaluated in three preclinical models of PCOS, generated by androgen exposures at different developmental windows, and a pilot exploratory cohort of anovulatory women with PCOS.. Three models of PCOS were generated by exposure of female rats to androgens at different periods of development: PNA (prenatal androgenization; N = 20), NeNA (neonatal androgenization; N = 20) and PWA (post-weaning androgenization; N = 20). At adulthood (postnatal day 100), rats were subjected to daily treatments with a bolus of KP-54 (100 μg/kg, s.c.) or vehicle for 11 days (N = 10 per model and treatment). On Days 1, 4, 7 and 11, LH and FSH responses were assessed at different time-points within 4 h after KP-54 injection, while ovarian responses, in terms of follicular maturation and ovulation, were measured at the end of the treatment. In addition, hormonal (gonadotrophin, estrogen and inhibin B) and ovulatory responses to repeated KP-54 administration, at doses of 6.4-12.8 nmol/kg, s.c. bd for 21 days, were evaluated in a pilot cohort of anovulatory women (N = 12) diagnosed with PCOS, according to the Rotterdam criteria.. Deregulated reproductive indices were detected in all PCOS models: PNA, NeNA and PWA. Yet, anovulation was observed only in NeNA and PWA rats. However, while anovulatory NeNA rats displayed significant LH and FSH responses to KP-54 (P < 0.05), which rescued ovulation, PWA rats showed blunted LH secretion after repeated KP-54 injection and failed to ovulate. In women with PCOS, KP-54 resulted in a small rise in LH (P < 0.05), with an equivalent elevation in serum estradiol levels (P < 0.05). Two women showed growth of a dominant follicle with subsequent ovulation, one woman displayed follicle growth but not ovulation and desensitization was observed in another patient. No follicular response was detected in the other women.. While three different preclinical PCOS models were used in order to capture the heterogeneity of clinical presentations of the syndrome, it must be noted that rat models recapitulate many but not all the features of this condition. Additionally, our pilot study was intended as proof of principle, and the number of participants is low, but the convergent findings in preclinical and clinical studies reinforce the validity of our conclusions.. Our first-in-rodent and -human studies demonstrate that KP-54 administration in anovulatory preclinical models and women with PCOS can stimulate reproductive hormone secretion and ovulation, albeit with incomplete efficacy. As our rat models likely reflect the diversity of PCOS phenotypes, our results argue for the need of personalized management of anovulatory dysfunction in women with PCOS, some of whom may benefit from kisspeptin-based treatments.. This work was supported by research agreements between Ferring Research Institute and the Universities of Cordoba and Edinburgh. K.S. was supported by the Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative (STMTI). Some of this work was undertaken in the MRC Centre for Reproductive Health which is funded by the MRC Centre grant MR/N022556/1. M.T.-S. is a member of CIBER Fisiopatología de la Obesidad y Nutrición, which is an initiative of Instituto de Salud Carlos III. Dr Mannaerts is an employee of Ferring International PharmaScience Center (Copenhagen, Denmark), and Drs Qi, van Duin and Kohout are employees of the Ferring Research Institute (San Diego, USA). Dr Anderson and Dr Tena-Sempere were recipients of a grant support from the Ferring Research Institute, and Dr Anderson has undertaken consultancy work and received speaker fees outside this study from Merck, IBSA, Roche Diagnostics, NeRRe Therapeutics and Sojournix Inc. Dr Skorupskaite was supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative 102419/Z/13/A. The other authors have no competing interest.

Topics: Adult; Animals; Disease Models, Animal; Female; Follicle Stimulating Hormone; Humans; Kisspeptins; Luteinizing Hormone; Ovulation; Pilot Projects; Polycystic Ovary Syndrome; Rats, Wistar; Young Adult

Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder affecting women of reproductive age. Its aetiology, though yet unclear, is presumed to have an oligogenic basis interacting with environmental factors. Kisspeptins are peptide products of Kiss1 gene that control the hypothalamic pituitary (HPG) axis by acting via G protein-coupled receptor known as GPR54. There is paucity of data on the role of Kiss1 and GPR54 gene in PCOS. We aimed to identify the polymorphisms in Kiss1 and GPR54 genes and explore their association with serum kisspeptin levels among Sri Lankan women with well-characterized PCOS. Consecutive women with PCOS manifesting from adolescence (n=55) and adult controls (n=110) were recruited. Serum kisspeptin and testosterone levels were determined by ELISA method. Whole gene sequencing was performed to identify the polymorphisms in Kiss1 and GPR54 genes. Serum kisspeptin and testosterone concentrations were significantly higher in women with PCOS than controls: kisspeptin 4.873nmol/L versus 4.127nmol/L; testosterone 4.713nmol/L versus 3.415 nmol/L, p<0.05. Sequencing the GPR54 gene revealed 5 single nucleotide polymorphisms (SNPs), rs10407968, rs1250729403, rs350131, chr19:918686, and chr19:918735, with two novel SNPs (chr19:918686 and chr19:918735), while sequencing the Kiss1 gene revealed 2 SNPs, rs5780218 and rs4889. All identified SNPs showed no significant difference in frequency between patients and controls. GPR54 gene rs350131 polymorphism (G/T) was detected more frequently in our study population. The heterozygous allele (AG) of GPR54 gene novel polymorphism chr19:918686 showed a marginal association with serum kisspeptin levels (p=0.053). Genetic variations in GPR54 and Kiss1 genes are unlikely to be associated with PCOS among Sri Lankan women manifesting from adolescence. Meanwhile the heterozygous allele of chr19:918686 is probably associated with serum kisspeptin concentrations, which suggests a potential role in the aetiology of PCOS.

Topics: Adolescent; Adult; Alleles; Child; Female; Heterozygote; Humans; Kisspeptins; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Receptors, Kisspeptin-1; Sri Lanka

Kisspeptin has recently emerged as a key regulator of the reproductive axis in women. Kisspeptin, acting centrally via the kisspeptin receptor, stimulates the secretion of the gonadotrophin-releasing hormone (GnRH).. To investigate serum kisspeptin levels in infertility patients for its clinical utilisation in management and understanding of the pathophysiology of infertility in a wide array of patients.. This prospective case-control study analysis involved 92 primary infertile women with PCOS, diminished ovarian reserve (DOR), unexplained infertility (UEI), and male factor infertility between 20 and 42 years of age. Serum samples were collected between the second and fifth day of the menstrual cycle. The kisspeptin level was determined using a human kisspeptin ELISA kit according to the manufacturer's procedure.. The median value of serum kisspeptin in the PCOS infertility group was significantly higher than that in the UEI group (p = 0.011). There was a statistically significant (p = 0.015, r =  -0.182) negative weak correlation found between serum kisspeptin levels and age. The optimal cutoff value obtained to differentiate the UEI from others (PCOS infertility + DOR + male factor infertility) according to the serum kisspeptin level was 214.3 ng/L with a sensitivity of 55% and specificity of 80.9%.. Understanding the role of kisspeptin may lead to its use as a biomarker in infertility diagnosis in UEI patients and might guide the use of kisspeptin analogues in selected patients for infertility management.

Topics: Case-Control Studies; Female; Gonadotropin-Releasing Hormone; Humans; Infertility, Female; Infertility, Male; Kisspeptins; Male; Polycystic Ovary Syndrome

The development of polycystic ovary syndrome (PCOS) is closely correlated with apoptosis and oxidative stress in ovarian granulosa cells. Kisspeptin plays an important role in reproductive organ function. This study aimed to explore the role of kisspeptin in PCOS and oxidative stress-triggered apoptosis of ovarian granular cells.. A PCOS rat model was established by injecting dehydroepiandrosterone (DHEA) and feeding the rats a high-fat diet. The RNA and protein levels of kisspeptin were analysed by quantitative PCR, western blotting, and histological staining. Tissue damage was evaluated using haematoxylin and eosin (H&E) staining. The viability and proliferation of human granulosa cell KGN were measured using the cell counting kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays. Cell cycle and apoptosis were analysed by flow cytometry. Oxidative stress was analysed by measuring reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) levels.. Kisspeptin was downregulated in the ovarian granulosa cells of PCOS rats compared to those of control rats. Kisspeptin overexpression enhanced KGN cell proliferation and inhibited apoptosis. ROS generation was suppressed by kisspeptin, along with decreased levels of MDA and increased levels of the antioxidants GSH, SOD, and CAT. Kisspeptin activates PI3K/AKT and ERK signalling, and inactivation of ERK1/2 suppresses the protective role of kisspeptin in ovarian granulosa cells.. Kisspeptin improves proliferation and alleviates apoptosis and oxidative stress in ovarian granulosa cells by activating PI3K/AKT and ERK signalling.

Topics: Animals; Apoptosis; Cell Proliferation; Female; Granulosa Cells; Humans; Kisspeptins; Phosphatidylinositol 3-Kinases; Polycystic Ovary Syndrome; Proto-Oncogene Proteins c-akt; Rats; Reactive Oxygen Species; Superoxide Dismutase

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, anovulation, and polycystic ovaries. Electroacupuncture (EA) can effectively improve hyperandrogenism and increase ovulation frequency in patients with PCOS. Pieces of suggest that androgen activity in the brain is associated with impaired steroid negative feedback in such patients. Studies have shown that EA regulated androgen receptor (AR) expression and local factor levels (such as anti-Müllerian hormone and inhibin B) in the ovary of PCOS rats. However, few studies have explored the effect of EA on androgen activity in the brain.. This study investigated the effect of EA on the kisspeptin-gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) neural circuit and sex hormone receptor expression in the hypothalamus of PCOS rats.. PCOS signs were induced by letrozole administration, and the induced rats were treated with low-frequency EA at Guan Yuan acupoint (CV4). The effect of EA on PCOS-like signs was evaluated by observing changes in the body weight, ovarian quality, ovarian morphology, and serum sex hormone levels in rats. To explore the mechanism of the effect of EA on PCOS-like signs, the neuropeptide content of the kisspeptin-GnRH/LH neural circuit was assessed using enzyme-linked immunosorbent assay(ELISA); AR and estrogen receptor α (ERα) coexpression on kisspeptin/neurokinin B/dynorphin (KNDy) neurons was determined via triple-label immunofluorescence; and protein and mRNA expression of Kiss1, Ar, Esr1, and kisspeptin receptor (Kiss1r) was evaluated via western blotting and Reverse Transcription-Polymerase Chain Reaction (RT-PCR).. The results revealed that the estrous cycle of rats in the EA treatment group recovered, and their body and ovary weight reduced; ovarian morphology improved; serum testosterone and LH levels significantly decreased; and kisspeptin, GnRH, and dynorphin levels in hypothalamic arcuate nucleus significantly decreased. Compared with controls, the number of AR/Kiss1-positive cells increased, number of ERα/Kiss1-positive cells decreased, and protein and mRNA expression of Kiss1, Ar, and Kiss1r significantly increased in PCOS rats. However, EA treatment reversed these changes and reduced the expression of Kiss1, Ar, and Kiss1r significantly.. Improvement in the reproductive hallmarks of PCOS rats via EA may be achieved by regulating the kisspeptin-GnRH/LH circuit via androgen activity attenuation. Thus, the results provide an experimental basis for acupuncture as an adjuvant medical therapy on PCOS.

Topics: Androgens; Animals; Dynorphins; Electroacupuncture; Estrogen Receptor alpha; Female; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Humans; Hyperandrogenism; Kisspeptins; Luteinizing Hormone; Neurokinin B; Neurons; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley; Receptors, Androgen; Receptors, Kisspeptin-1; RNA, Messenger

Polycystic ovary syndrome (PCOS) is a pathophysiological disease affecting reproductive and metabolic indicators. Research has shown that kisspeptin might be involved in the regulation of pituitary hormone secretion and energy metabolism. The aim of this study was to investigate the relationship between serum kisspeptin levels and abnormal metabolism in PCOS.. Fifty patients with PCOS and 50 control patients were recruited for this study. Serum kisspeptin levels were measured via ELISA. High-performance liquid chromatography-tandem mass spectrometry metabolomics was used to study the changes in serum metabolism between the PCOS and control groups.. Serum kisspeptin levels were significantly elevated in individuals with PCOS compared with those in healthy controls (p = 0.011) and positively correlated with LH, T, FFA, BA, and LEP levels (p < 0.05). Significantly dysregulated expression of several metabolites was observed in the intergroup comparisons of the high-kisspeptin PCOS, low-kisspeptin PCOS, and healthy control groups. These primarily consisted of lipid, amino acid, and carbohydrate metabolites, among which palmitic acid and N-formylkynurenine levels were lower in the high-kisspeptin group than in controls. Metabolite set enrichment analysis was also performed based on metabolites in the KEGG database. The results showed that owing to the differences in kisspeptin concentrations in individuals with PCOS, there was a significant difference in amino acid and pyruvate metabolism.. Kisspeptin could be a potential biomarker for the diagnosis of PCOS and plays an important role in metabolic regulation in individuals with PCOS. In addition, metabolomics provides a promising method for the study of metabolic abnormalities in individuals with PCOS, which might contribute to our understanding of its mechanisms.

Topics: Amino Acids; Female; Humans; Kisspeptins; Luteinizing Hormone; Metabolomics; Polycystic Ovary Syndrome

Kisspeptin is a neuropeptide that has an important role in the female reproductive cycle which is indicated by its role in regulating the hypothalamic-pituitary-gonadal axis.. To analyze the correlation between serum kisspeptin levels, ovarian kisspeptin expression, and ovarian Bone Morphogenic Protein-15 (BMP15) expression in polycystic ovary syndrome (PCOS) model rats.. The research was accurate experimental research with a post-test design-only control group and was carried out from August to October 2022 at the Faculty of Veterinary Medicine Universitas Airlangga. 32. Serum kisspeptin levels and ovarian kisspeptin expression of the PCOS model group were not significantly higher than those of the control group (. Serum kisspeptin levels and ovarian kisspeptin expression of the PCOS model group were not higher than those of the control group, and the ovarian BMP15 expression of the PCOS model group was not lower than that of the control group. There was no correlation between serum kisspeptin levels with ovarian kisspeptin expression and ovarian BMP15 expression. However, a significant correlation was found between ovarian kisspeptin expression and ovarian BMP15 expression.

Topics: Animals; Bone Morphogenetic Protein 15; Female; Kisspeptins; Polycystic Ovary Syndrome; Rats

Polycystic ovarian syndrome (PCOS) is the leading cause of anovulatory infertility and is a heterogenous condition associated with a range of reproductive and metabolic impairments. While its etiology remains unclear, hyperandrogenism and impaired steroid negative feedback have been identified as key factors underpinning the development of PCOS-like features both clinically and in animal models. We tested the hypothesis that androgen signaling in kisspeptin-expressing neurons, which are key drivers of the neuroendocrine reproductive axis, is critically involved in PCOS pathogenesis. To this end, we used a previously validated letrozole (LET)-induced hyperandrogenic mouse model of PCOS in conjunction with Cre-lox technology to generate female mice exhibiting kisspeptin-specific deletion of androgen receptor (KARKO mice) to test whether LET-treated KARKO females are protected from the development of reproductive and metabolic PCOS-like features. LET-treated mice exhibited hyperandrogenism, and KARKO mice exhibited a significant reduction in the coexpression of kisspeptin and androgen receptor mRNA compared to controls. In support of our hypothesis, LET-treated KARKO mice exhibited improved estrous cyclicity, ovarian morphology, and insulin sensitivity in comparison to LET-treated control females. However, KARKO mice were not fully protected from the effects of LET-induced hyperandrogenism and still exhibited reduced corpora lutea numbers and increased body weight gain. These data indicate that increased androgen signaling in kisspeptin-expressing neurons plays a critical role in PCOS pathogenesis but highlight that other mechanisms are also involved.

Topics: Androgens; Animals; Disease Models, Animal; Female; Hyperandrogenism; Kisspeptins; Letrozole; Mice; Neurons; Polycystic Ovary Syndrome; Receptors, Androgen

Topics: Anti-Mullerian Hormone; Biomarkers; Body Mass Index; Case-Control Studies; Female; Follicle Stimulating Hormone; Humans; Kisspeptins; Luteinizing Hormone; Obesity; Polycystic Ovary Syndrome; Triglycerides

Polycystic ovary syndrome (PCOS) is a female endocrine disorder that is associated with prenatal exposure to excess androgens. In prenatally androgenized (PNA) mice that model PCOS, GABAergic neural transmission to and innervation of GnRH neurons is increased. Evidence suggests that elevated GABAergic innervation originates in the arcuate nucleus (ARC). We hypothesized that GABA-GnRH circuit abnormalities are a direct consequence of PNA, resulting from DHT binding to androgen receptor (AR) in the prenatal brain. However, whether prenatal ARC neurons express AR at the time of PNA treatment is presently unknown. We used RNAScope in situ hybridization to localize AR mRNA (Ar)-expressing cells in healthy gestational day (GD) 17.5 female mouse brains and to assess coexpression levels in specific neuronal phenotypes. Our study revealed that less than 10% of ARC GABA cells expressed Ar. In contrast, we found that ARC kisspeptin neurons, critical regulators of GnRH neurons, were highly colocalized with Ar. Approximately 75% of ARC Kiss1-expressing cells also expressed Ar at GD17.5, suggesting that ARC kisspeptin neurons are potential targets of PNA. Investigating other neuronal populations in the ARC we found that ~50% of pro-opiomelanocortin (Pomc) cells, 22% of tyrosine hydroxylase (Th) cells, 8% of agouti-related protein (Agrp) cells and 8% of somatostatin (Sst) cells express Ar. Lastly, RNAscope in coronal sections showed Ar expression in the medial preoptic area (mPOA), and the ventral part of the lateral septum (vLS). These Ar-expressing regions were highly GABAergic, and 22% of GABA cells in the mPOA and 25% of GABA cells in the vLS also expressed Ar. Our findings identify specific neuronal phenotypes in the ARC, mPOA, and vLS that are androgen sensitive in late gestation. PNA-induced functional changes in these neurons may be related to the development of impaired central mechanisms associated with PCOS-like features.

Topics: Androgens; Animals; Arcuate Nucleus of Hypothalamus; Brain; Female; GABAergic Neurons; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Mice; Polycystic Ovary Syndrome; Pregnancy; Receptors, Androgen; Virilism

To observe the effects of electroacupuncture （EA） on hormone secretion function of ovarian granulosa cells and theca cells, as well as the expression changes of kisspeptin and kiss1r in rats with polycystic ovarian syndrome （PCOS）, so as to explore the mechanism of EA for relieving ovarian dysfunction in PCOS rats.. Forty-eight SD female rats were randomly divided into control group, model group, EA group and flutamide group, with 12 rats in each group. PCOS rat model was replicated with the gavage of letrozole （0.1 mg/mL, 10 mL•kg. Compared with the control group, the body and ovarian weights, ovarian index, the contents of T and LH in serum and that of T in the culture medium of theca cells, as well as the content and positive expression of kisspeptin in ovary were all increased （. EA regulates the serum sex hormone levels, the secretion function of the ovarian granulosa cells and theca cells, and the ovarian kisspeptin/kiss1r protein expression in PCOS rats, showing the similar effect as receptor blockade intervention. It is suggested that the improvement of EA in ovarian dysfunction of PCOS rats may be related to the kisspeptin/kiss1r system.

Topics: Animals; Electroacupuncture; Female; Flutamide; Humans; Kisspeptins; Luteinizing Hormone; Polycystic Ovary Syndrome; Rats

To identify the effects of metformin and kisspeptin structural polymorphism on the risk of polycystic ovary syndrome (PCOS) in Iraqi women.. Samples were collected at the family planning center of Al-Hassan Teaching Hospital (infertility clinic), Iraq. Hormonal and hematological parameters were measured. Kisspeptin structural polymorphisms were analyzed by polymerase chain reaction using a conventional thermal cycler and Phyre2 predictions. Kisspeptin concentrations were assessed by an enzyme-linked immunosorbent assay.. Follicle-stimulating hormone (FSH) was the only sex hormone that changed in women with PCOS after metformin treatment. FSH concentrations were significantly increased after therapy compared with before therapy (9.39 ± 2.1 vs 5.13 ± 1.53 IU/L). We found that a single nucleotide polymorphism substituting G to C was related to PCOS. The kisspeptin structural polymorphism showed that the C allele was related to low FSH concentrations after treatment (6.92 ± 2.2 IU/L to 5.34 ± 1.58 IU/L). Kisspeptin concentrations were significantly lower after metformin treatment than before metformin treatment (395.44 ± 67.83 vs 273.18 ± 42.98 ng/mL).. A variation in the

Topics: Female; Follicle Stimulating Hormone, Human; Humans; Iraq; Kisspeptins; Metformin; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide

Polycystic ovary syndrome (PCOS) is characterized by ovarian dysfunction, clinical and/or biochemical hyperandrogenism, and polycystic ovaries. Its pathogenesis is still unclear. This study aimed to investigate the relationship between kisspeptin, leptin, neuropeptide Y (NPY), and neurokinin B (NKB) levels for evaluating the pathogenesis of PCOS.. Levels of these parameters were analyzed in 20 patients with PCOS, and 16 healthy adolescents.. Serum NPY levels were significantly higher in the obese and non-obese PCOS group (p<0.01). There was a negative correlation between the kisspeptin and the NKB levels (p<0.01) in the PCOS group but not in the control group. This negative correlation was also found in both PCOS groups (p<0.01). In the obese PCOS group, serum kisspeptin levels were significantly lower than the control and non-obese PCOS groups (p<0.05) although serum leptin and NPY levels were significantly higher in the obese PCOS group (p<0.01).. The high NPY levels in both obese and non-obese patients with PCOS indicate that NPY plays a role in the pathogenesis independently from obesity. Significantly high leptin and low kisspeptin levels in the obese PCOS group suggested that they may be associated with obesity rather than PCOS.

Topics: Adolescent; Body Mass Index; Female; Humans; Kisspeptins; Leptin; Neurokinin B; Neuropeptide Y; Polycystic Ovary Syndrome

Polycystic ovary syndrome often starts in puberty, and its pathogenesis is not clear. This study aimed to explore the pathogenesis of pubertal polycystic ovary syndrome (PCOS) and assess the therapeutic effect of electroacupuncture on pubertal PCOS.. Dihydrotestosterone (DHT) was used to induce rat models of pubertal PCOS. pubertal rats with PCOS were randomly divided into a model group (M), an electroacupuncture group (EA), and a sham acupuncture group (SA). Age-matched normal rats were regarded as normal controls (N). Rats were treated with EA or SA five times a week for 25 minutes during their 6th-7th week. At the end of the experiment, we observed any changes in ovarian morphology; detected levels of metabolic indices in serum, the hypothalamus and pancreas.. EA significantly improved estrous cycle disorders and the ovarian polycystic morphology in pubertal rats with PCOS, but SA only improved disorders of the estrous cycle. The serum levels of insulin, neuropeptide Y(NPY) and fasting blood glucose(FBG) increased significantly (both p < 0.01), while the serum levels of ghrelin(GHRL) decreased in the model group (p < 0.01). After treatment with EA, the levels of NPY (p < 0.01) and FBG (p < 0.05) went into decrease, whereas the levels of GHRL (p < 0.05) and insulin (p < 0.01) increased. There was few differences in the hypothalamic expression of galanin (GAL), galanin-like peptide (GALP) and ghrelin receptor(GHSR) between the four groups. The upregulation of NPY mRNA and neuropeptide Y2 receptor(NPY2R) mRNA and the downregulation of GHRL protein and mRNA in the hypothalamus, and the increased expression of NPY and NPY2R as well as the decreased expression of GHRL in the arcuate nucleus (ARC) can be rescued by EA. But, surprisingly, SA seem to make no difference to the levels of FBG and insulin, and the protein expression of ghrelin in the hypothalamus and ARC. Co-expression of kisspeptin and GHSR, and co-expression of gonadotrophin releasing hormone(GnRH) and NPY2R were observed in ARC. No differences were found between groups in protein of GAL, GALP and GHRL expression in the pancreas. Neither EA nor SA can attenuate the upregulated kisspeptin protein expression in the pancreas of PCOS model rats.. EA and SA improved the symptoms of pubertal PCOS rats, and the mechanism might be associated with regulating hypothalamic NPY and ghrelin levels.

Topics: Animals; Electroacupuncture; Female; Ghrelin; Humans; Hypothalamus; Insulins; Kisspeptins; Neuropeptide Y; Polycystic Ovary Syndrome; Rats; RNA, Messenger; Sexual Maturation

Polycystic ovary syndrome (PCOS) is a heterogeneous condition that increases the risk for serious health complications among women. Thus, in this study, we aimed to identify polymorphisms in the KiSS-1 and GPR54 genes and investigate the associations between KiSS-1, BMI, FSH, LH, and estradiol in Chinese women with PCOS.. This study recruited women with PCOS (. Compared with the controls, endocrine and metabolic disturbances in women with PCOS were reflected in significantly higher levels of BMI, LH, LH-FSH ratio, prolactin, and testosterone. Serum kisspeptin levels were significantly higher and positively correlated with LH and T levels (. These results suggest that kisspeptin plays a potential role in the etiology of PCOS.

Topics: China; Estradiol; Female; Follicle Stimulating Hormone; Humans; Kisspeptins; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Progesterone; Prolactin; Receptors, Kisspeptin-1; Testosterone

Polycystic ovary syndrome (PCOS) is associated with elevated androgen and luteinizing hormone (LH) secretion and with oligo/anovulation. Evidence indicates that elevated androgens impair sex steroid hormone feedback regulation of pulsatile LH secretion. Hyperandrogenemia in PCOS may also disrupt the preovulatory LH surge. The mechanisms through which this might occur, however, are not fully understood. Kisspeptin (KISS1) neurons of the rostral periventricular area of the third ventricle (RP3V) convey hormonal cues to gonadotropin-releasing hormone (GnRH) neurons. In rodents, the preovulatory surge is triggered by these hormonal cues and coincident timing signals from the central circadian clock in the suprachiasmatic nucleus (SCN). Timing signals are relayed to GnRH neurons, in part,

Topics: Androgens; Animals; Arginine; Arginine Vasopressin; Female; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Luteinizing Hormone; Mice; Neurons; Polycystic Ovary Syndrome; Pregnancy; Suprachiasmatic Nucleus; Vasopressins

Polycystic ovary syndrome (PCOS) is a complex reproductive event that is delineated by endocrine/metabolic disorders. Alteration of kisspeptin status in the hypothalamus and adipose tissue is critical to increased endocrine/metabolic derangements in PCOS individuals, aggravating the clinical manifestation of PCOS and its complications. Short chain fatty acids (SCFAs) are crucial modulators of metabolic homeostasis. However, the role of SCFAs, particularly acetate on hypothalamic-adipose kisspeptin status (HAKS) in PCOS model is unknown. The present study hypothesized acetate as a key player in restoration of deranged HAKS, associated with experimental PCOS model.. Three groups (n = 6/group) of female Wistar rats (120-150 g) were used. The groups were treated (po) for 21 days with vehicle, letrozole (1 mg/kg) with/without acetate (200 mg/kg) respectively.. Letrozole-treated animals had impaired glucose homeostasis, elevated testosterone, leptin and LH/FSH ratio and decreased GnRH and adiponectin with ovarian tissues revealing degenerated follicles and disrupted morphology. These animals also showed increased concentration of hypothalamic triglyceride (TG)/total cholesterol (TC), free fatty acid (FFA), and decreased concentration of TG/TC/FFA in visceral adipose tissue (VAT) with an increase in hypothalamic and VAT malondialdehyde, NF-κB/TNF-α and decreased glutathione/G6PD and hypothalamic but not VAT kisspeptin. Immunohistochemical analysis revealed the expression of NLRP3 inflammasome in the hypothalamus and VAT and all these changes were attenuated by acetate.. Altogether, the present results demonstrate that PCOS is characterized with hypothalamic-adipose inflammation, associated with immunohistochemical expression of NLRP3 with significant alteration of hypothalamic but not adipose kisspeptin. The results suggest that acetate restores kisspeptin status in PCOS animals. This beneficial effect is accompanied by repressed NLRP3 immunoreactivity.

Topics: Acetates; Animals; Female; Kisspeptins; Letrozole; NLR Family, Pyrin Domain-Containing 3 Protein; Polycystic Ovary Syndrome; Rats; Rats, Wistar

Polycystic ovary syndrome (PCOS) is a common endocrine disease among women in the reproductive age that is associated with consequences such as insulin resistance and hyperandrogenemia. This study was aimed to assess the association of sex hormone profile and kisspeptin levels in PCOS women in Gorgan, Iran.. In this case-control study, 43 women with diagnosed PCOS between the ages of 15 and 37 years and 40 healthy demographically matched controls were recruited. Sex hormone profile and kisspeptin levels were measured in these subjects using ELISA assay kits.. Follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG), and kisspeptin levels were significantly lower in cases than in controls. Luteinizing hormone (LH), free-testosterone (FT), 17-OH-progesterone (17-OH-P), dehydroepiandrosterone sulfate (DHEA-S), estradiol (E2), and free androgen index (FAI) were higher in PCOS significantly. There was a significant positive correlation between kisspeptin levels and LH and E2 in cases (p = 0.037 and p = 0.024, respectively). The results of the regression analysis have shown a significant association between the LH and kisspeptin concentrations in PCOS group (r = 0.275, p = 0.037).. PCOS patients had lower plasma kisspeptin level that was positively correlated with LH and estradiol levels. Also, higher levels of free androgens were demonstrated in these patients. It is suggested that kisspeptin may be involved in complex interactions of the sex hormone endocrine system of PCOS.

Topics: Adolescent; Adult; Case-Control Studies; Estradiol; Female; Gonadal Steroid Hormones; Humans; Kisspeptins; Luteinizing Hormone; Polycystic Ovary Syndrome; Young Adult

Recent evidence suggests that vasomotor symptoms (VMS) or hot flashes in the postmenopausal reproductive state and polycystic ovary syndrome (PCOS) in the premenopausal reproductive state emanate from the hyperactivity of Kiss1 neurons in the hypothalamic infundibular/arcuate nucleus (KNDy neurons).. We demonstrate in 2 murine models simulating menopause and PCOS that a peripherally restricted kappa receptor agonist (PRKA) inhibits hyperactive KNDy neurons (accessible from outside the blood-brain barrier) and impedes their downstream effects.. Case/control.. Academic medical center.. Mice.. Administration of peripherally restricted kappa receptor agonists and frequent blood sampling to determine hormone release and body temperature.. LH pulse parameters and body temperature.. First, chronic administration of a PRKA to bilaterally ovariectomized mice with experimentally induced hyperactivity of KNDy neurons reduces the animals' elevated body temperature, mean plasma LH level, and mean peak LH per pulse. Second, chronic administration of a PRKA to a murine model of PCOS, having elevated plasma testosterone levels and irregular ovarian cycles, suppresses circulating levels of LH and testosterone and restores normal ovarian cyclicity.. The inhibition of kisspeptin neuronal activity by activation of kappa receptors shows promise as a novel therapeutic approach to treat both VMS and PCOS in humans.

Topics: Animals; Buprenorphine; Disease Models, Animal; Female; Hot Flashes; Humans; Kisspeptins; Meloxicam; Menopause; Mice; Neurons; Polycystic Ovary Syndrome; Receptors, Opioid, kappa; Vasomotor System

To measure serum Kisspeptin levels in women with Polycystic Ovary Syndrome and compare it with that of normal fertile women.. A case-control study was done at Al-Yarmouk Teaching Hospital /Baghdad, Iraq for nine months duration from March 2019 to December 2019. It included 45 patients with Polycystic Ovary Syndrome (case group) and 45 fertile women at least having one child as (control group). Blood samples were obtained from all women in the study to measure luteinizing Hormone (LH), Follicular Stimulating Hormone (FSH). Anti-Müllerian Hormone (AMH), Thyroid Stimulating Hormone (TSH), Prolactin (PRL) and Kisspeptin. Random blood glucose was also esrimated in both groups and the results were compared.. Mean of Kisspeptin levels in women with polycystic ovary syndrome was significantly higher than that in fertile women (312.8±88.55 versus 131.6±61.94 pg/ml, P= 0.001). Statistically significant moderate positive correlation were detected between Kisspeptin level and each of anti Müllerian hormone, luteinizing hormone and antral follicle count (R 0.443, 0.49 and 0.687 respectively) and statistical significant weak positive correlation were detected between Kisspeptin level and each of prolactin and thyroid stimulating hormone (R 0.256 and 0.245 respectively). Statistical significant moderate negative correlations was detected between Kisspeptin level and follicular stimulating hormone (R -0.394).. Kisspeptin level was significantly increased in women with PCOS. The cut point of kisspeptin level was 189 pg/ml in PCOS. Thus kisspeptin at level > 189pg/ml can be used to predict the diagnosis of PCOS.

Topics: Adult; Anti-Mullerian Hormone; Case-Control Studies; Female; Follicle Stimulating Hormone; Humans; Kisspeptins; Luteinizing Hormone; Polycystic Ovary Syndrome

This was a prospective, cross-sectional, comparative study that included 70 women with PCOS and 58 non PCOS controls. PCOS patients were diagnosed according to the Rotterdam criteria. Age, body mass index (BMI), number of menstrual cycles per year, and the Ferriman-Gallwey Score were determined for each woman. Serum levels of kisspeptin, follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), estradiol, total testosterone, dehydroepiandrosterone sulfate. Women with PCOS were younger (. Serum kisspeptin levels were similar in women with and without PCOS but positively correlated with AMH serum levels in PCOS women.

Topics: Adult; Anti-Mullerian Hormone; Epidemiologic Studies; Female; Humans; Kisspeptins; Polycystic Ovary Syndrome; Young Adult

Topics: Animals; Cadmium; Female; Humans; Kisspeptins; Ovarian Follicle; Polycystic Ovary Syndrome; Primary Ovarian Insufficiency; Rats

In order to find links between. rs12998 G > A was linked to PCOS in dominant (p < 0.001), recessive (p < 0.001), co-dominant (p < 0.001), and allelic models (p < 0.001). In addition, rs4889 C > G was linked in recessive, dominant, co-dominant, and allelic models (p < 0.001). rs35431622 A > G was not linked to PCOS. Further analysis indicated that C-G-G haplotype was more common and G-A-G haplotype was less prevalent in cases compared with controls.

Topics: Alleles; Case-Control Studies; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Kisspeptins; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide

To explore the effects and mechanism of action of electroacupuncture (EA) in a rat model of pubertal polycystic ovary syndrome (PCOS).. Female offspring of Sprague-Dawley rats receiving dihydrotestosterone (DHT) during pregnancy (days 16-19), as a model of prenatal androgenization, were divided randomly into three groups: model group (M), EA group, and sham acupuncture (SA) group (n = 8 each). A normal (N) group comprising female offspring of healthy pregnant rats not receiving DHT (n = 8) was added. EA was administered at CV6 and bilateral SP6/ST36 with 2 Hz frequency and 2 mA intensity. SA consisted of superficial needling at different locations without electrical stimulation.. EA improved the disturbed estrous cycles, while it could not be concluded that SA was effective in this respect. EA improved ovarian morphology including the number of corpora lutea and area of the ovary, whereas SA did not. However, both EA and SA attenuated the increased luteinizing hormone and decreased estradiol and gonadotropin-releasing hormone levels in the serum of PCOS model rats. Levels of testosterone, follicle-stimulating hormone, and progesterone did not significantly differ between groups. EA and SA alleviated the upregulation of kisspeptin protein and mRNA levels in the hypothalamus and kisspeptin protein level in the arcuate nucleus (ARC). No differences were found between groups in protein or mRNA expression of dynorphin (DYN) or neurokinin B (NKB) in the hypothalamus. Co-expression of kisspeptin, NKB, and DYN were observed in ARC. The GnRH level in the median eminence decreased and could be rescued by EA and SA. Intriguingly, kisspeptin levels in the granulosa cells of the ovary decreased in the model group and could be rescued by EA but not SA. Levels of kisspeptin, NKB, and DYN protein and mRNA in the ovary did not differ between any groups.. Both EA and SA appeared to improve symptoms of PCOS at puberty by modulating the kisspeptin system in the hypothalamus. EA also had an effect on ovarian kisspeptin expression and a more comprehensive effect with respect to improving PCOS at puberty than SA.

Topics: Acupuncture Points; Animals; Dynorphins; Electroacupuncture; Estrous Cycle; Female; Follicle Stimulating Hormone; Humans; Hypothalamus; Kisspeptins; Luteinizing Hormone; Neurokinin B; Ovary; Polycystic Ovary Syndrome; Pregnancy; Puberty; Rats; Rats, Sprague-Dawley

Eucommia ulmoides Oliv. leaves are the dry leaves of Eucommia ulmoides Oliv. Modern studies have shown that Eucommia ulmoides Oliv. leaves and its extracts have many pharmacological effects, such as regulating hypothalamus pituitary ovary (HPO) axis function, estrogen like effects, correcting insulin resistance (IR), regulating lipids, and reducing weight, which are consistent with the clinical manifestations in polycystic ovary syndrome (PCOS) patients. PCOS patients often have HPO axis disorder, low estrogen, high androgen, high IR complication rate, and obesity. Previous preclinical studies have shown that total flavonoids from Eucommia ulmoides Oliv. leaves (TFEL) can improve the imbalance in sex hormone secretion in perimenopausal animal models by regulating the function of the HPO axis. Thus, it is important to understand if flavonoids are the active parts of Eucommia ulmoides Oliv. leaves that interfere with polycystic ovary syndrome with insulin resistance (PCOS-IR), and determine the regulatory role they play in sex hormones and IR?. Investigate the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway in the ovary and kisspeptin/insulin like growth factor/leptin receptor1/androgen receptor (Kiss1/IGF-1/LEPR/AR) in the HPO axis to determine the mechanism of TFEL intervention in a rat model of PCOS-IR model rats.. A rat model of PCOS-IR was established using a high-fat diet (49 d) combined with letrozole (1 mg/kg·d, for 28 d). Then, metformin (300 mg/kg·d) and TFEL (220 mg/kg·d, 110 mg/kg·d, and 55 mg/kg·d) were administered continuously for 21 days. At the end of the experiment, samples were taken and the related indexes were measured.. TFEL reduced the body weight, Lee's index, ovarian index, ovarian area and ovarian volume, increased serum E. TFEL can inhibit ovarian hyperplasia, regulate disorders of glucose and lipid metabolism and improve the secretion of sex hormones, by regulating the expression of PI3K/AKT signaling pathway-related proteins in the ovary and Kiss1/IGF-1/LEPR/AR in the HPO axis.

Topics: Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Eucommiaceae; Female; Flavonoids; Gonadal Steroid Hormones; Hypothalamus; Insulin Resistance; Insulin-Like Growth Factor I; Kisspeptins; Letrozole; Metformin; Ovary; Pancreas; Phosphatidylinositol 3-Kinases; Pituitary Gland; Plant Extracts; Plant Leaves; Polycystic Ovary Syndrome; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Receptors, Androgen; Receptors, Leptin

To investigate the effect of electroacupuncture (EA) on the expression of Kisspeptin protein and activities of the hypothalamic-pituitary-ovarian axis(HPOA) in rats with Letrozole-induced polycystic ovary syndrome (PCOS).. Female SD rats were randomly divided into normal control, PCOS model and EA groups (n=6 rats in each group). The PCOS model was established by continuous gavage of letrozole for 21 d. EA(2 Hz/100 Hz, 0.6-1.4 mA) was applied to bilateral "Daimai" (GB26) for 20 min, once every day for 15 d. Body mass was measured every 4 days. Serum follicular stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and testosterone (T) were detected by radioimmunoassay. Histopathological changes of the ovarian were observed after H.E. staining, and the expression level of Kisspeptin protein in the hypothalamus was detected by Western blot.. Following modeling, the body mass, serum T and LH contents, hypothalamic Kisspeptin protein expression and the number of ovarian follicles were significantly increased (P<0.05, P<0.01), while the number of ovarian corpus luteum was apparently decreased in comparison with the normal group (P<0.01). After EA intervention, the serum T, LH and E2 contents, the expression of Kisspeptin protein and the number of ovarian follicles were notably down-regulated (P<0.05, P<0.01), and the number of corpus luteum was significantly increased (P<0.01) in comparison with the model group.. EA can regulate the levels of sex hormones and HPOA of PCOS rats, which may be related to its effect in down-regulating the expression of Kisspeptin protein in the hypothalamus.

Topics: Acupuncture Points; Animals; Electroacupuncture; Female; Humans; Hypothalamus; Kisspeptins; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley

Topics: Female; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Neurokinin B; Polycystic Ovary Syndrome

Polycystic ovarian syndrome (PCOS), the most common endocrinopathy affecting women worldwide, is characterized by elevated luteinizing hormone (LH) pulse frequency due to the impaired suppression of gonadotrophin-releasing hormone (GnRH) release by steroid hormone negative feedback. Although neurons that co-express kisspeptin, neurokinin B, and dynorphin (KNDy cells) were recently defined as the GnRH/LH pulse generator, little is understood about their role in the pathogenesis of PCOS. We used a prenatal androgen-treated (PNA) mouse model of PCOS to determine whether changes in KNDy neurons or their afferent network underlie altered negative feedback. First, we identified elevated androgen receptor gene expression in KNDy cells of PNA mice, whereas progesterone receptor and dynorphin gene expression was significantly reduced, suggesting elevated androgens in PCOS disrupt progesterone negative feedback via direct actions upon KNDy cells. Second, we discovered GABAergic and glutamatergic synaptic input to KNDy neurons was reduced in PNA mice. Retrograde monosynaptic tract-tracing revealed a dramatic reduction in input originates from sexually dimorphic afferents in the preoptic area, anteroventral periventricular nucleus, anterior hypothalamic area and lateral hypothalamus. These results reveal 2 sites of neuronal alterations potentially responsible for defects in negative feedback in PCOS: changes in gene expression within KNDy neurons, and changes in synaptic inputs from steroid hormone-responsive hypothalamic regions. How each of these changes contribute to the neuroendocrine phenotype seen in in PCOS, and the role of specific sets of upstream KNDy afferents in the process, remains to be determined.

Topics: Afferent Pathways; Androgens; Animals; Disease Models, Animal; Dynorphins; Female; Kisspeptins; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurokinin B; Neurons; Neurons, Afferent; Neurosecretory Systems; Polycystic Ovary Syndrome; Pregnancy; Prenatal Exposure Delayed Effects

Endoplasmic reticulum (ER) stress, with adaptive unfolded protein response (UPR), is a key link between obesity, insulin resistance and type 2 diabetes, all of which are often present in the most common endocrine-metabolic disorder in women of reproductive age, polycystic ovary syndrome (PCOS), which is characterized with hyperandrogenism. However, the link between excess androgen and endoplasmic reticulum (ER) stress/insulin resistance in patients with polycystic ovary syndrome (PCOS) is unknown. An unexpected role of kisspeptin was reported in the regulation of UPR pathways and its involvement in the androgen-induced ER stress in hypothalamic neuronal cells. To evaluate the relationship of kisspeptin and ER stress, we detected kisspeptin and other factors in blood plasm of PCOS patients, rat models and hypothalamic neuronal cells. We detected higher testosterone and lower kisspeptin levels in the plasma of PCOS than that in non-PCOS women. We established a PCOS rat model by dihydrotestosterone (DHT) chronic exposure, and observed significantly downregulated kisspeptin expression and activated UPR pathways in PCOS rat hypothalamus compared to that in controls. Inhibition or knockdown of kisspeptin completely mimicked the enhancing effect of DHT on UPR pathways in a hypothalamic neuronal cell line, GT1-7. Kp10, the most potent peptide of kisspeptin, effectively reversed or suppressed the activated UPR pathways induced by DHT or thapsigargin, an ER stress activator, in GT1-7 cells, as well as in the hypothalamus in PCOS rats. Similarly, kisspeptin attenuated thapsigargin-induced Ca

Topics: Androgens; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Female; Hypothalamus; Insulin Resistance; Kisspeptins; Neurons; Obesity; Polycystic Ovary Syndrome; Rats; Testosterone; Unfolded Protein Response

Polycystic ovary syndrome represents a significant cause of female infertility. The aim of this study was to investigate the expression of anti-Mul-lerian hormone (AMH), kisspeptin 1 (KISS-1), and kisspeptin 1 receptor (KISS1r) in rat models of polycystic ovary syndrome (PCOS) and controlled ovarian stimulation (COS). For this purpose, 28 rats were assigned into four groups. Estrus and Diestrus groups consisted of rats in estrus and diestrus phases, respectively, while COS and PCOS groups consisted of rats with induced COS and PCOS, respectively. The serum AMH, KISS-1, and estradiol levels, and ovarian KISS1r levels were analyzed by enzyme-linked immunosorbent assay. Furthermore, histopathological analysis of the ovary tissue was done and ovarian KISS-1 expression was determined by immunohistochemical assay. The results revealed that ovarian KISS1r levels were higher in the Estrus (1271.43±51.98 pg/mL) and COS (1191.43±85.67 pg/mL) groups, compared to Diestrus and PCOS groups. The highest level of AMH was found in the Estrus group (16.91±2.12 ng/mL). The results indicate that AMH had no effect on the development of COS and PCOS, while KISS-1 was found to affect the development of COS in rats.

Topics: Animals; Anti-Mullerian Hormone; Diestrus; Disease Models, Animal; Estrus; Female; Kisspeptins; Ovulation Induction; Polycystic Ovary Syndrome; Rats; Receptors, Kisspeptin-1

Polycystic ovary syndrome (PCOS), a common reproductive disorder in women, is characterized by hyperandrogenemia, chronic anovulation, cystic ovarian follicles, and luteinizing hormone (LH) hyper-pulsatility, but the pathophysiology isn't completely understood. We recently reported a novel mouse model of PCOS using chronic letrozole (LET; aromatase inhibitor). Letrozole-treated females demonstrate multiple PCOS-like phenotypes, including polycystic ovaries, anovulation, and elevated circulating testosterone and LH, assayed in "one-off" measures. However, due to technical limitations, in vivo LH pulsatile secretion, which is elevated in PCOS women, was not previously studied, nor were the possible changes in reproductive neurons. Here, we used recent technical advances to examine in vivo LH pulse dynamics of freely moving LET female mice versus control and ovariectomized (OVX) mice. We also determined whether neural gene expression of important reproductive regulators such as kisspeptin, neurokinin B (NKB), and dynorphin, is altered in LET females. Compared to controls, LET females exhibited very rapid, elevated in vivo LH pulsatility, with increased pulse frequency, amplitude, and basal levels, similar to PCOS women. Letrozole-treated mice also had markedly elevated Kiss1, Tac2, and Pdyn expression and increased Kiss1 neuronal activation in the hypothalamic arcuate nucleus. Notably, the hyperactive LH pulses and increased kisspeptin neuron measures of LET mice were not as elevated as OVX females. Our findings indicate that LET mice, like PCOS women, have markedly elevated LH pulsatility, which likely drives increased androgen secretion. Increased hypothalamic kisspeptin and NKB levels may be fundamental contributors to the hyperactive LH pulse secretion in the LET PCOS-like condition and, perhaps, in PCOS women.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Aromatase Inhibitors; Disease Models, Animal; Dynorphins; Female; Gene Expression; Kisspeptins; Letrozole; Luteinizing Hormone; Mice; Neurokinin B; Neurons; Polycystic Ovary Syndrome

Topics: Adolescent; Adult; Endocrine System Diseases; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Kisspeptins; Metabolic Diseases; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Young Adult

The purpose of this study was to determine changes in the expression levels of kisspeptin-1 (Kiss1) in the hypothalamus during the development of polycystic ovary syndrome (PCOS) and after treatment with sleeve gastrectomy (SG).. This study used chronic dehydroepiandrosterone (DHEA) alone and DHEA plus a high-fat diet (HFD) to generate a PCOS rat model. Subsequently, SG was performed in the animals with PCOS and the effects on glucose tolerance, insulin sensitivity, sex hormones, estrous cyclicity, adiponectin, and Kiss1 expression in the hypothalamus were investigated.. Impaired glucose tolerance, decreased insulin sensitivity, reduced adiponectin levels, disrupted estrous cyclicity, and elevated sex hormone levels associated with PCOS models were restored to normal following SG. In addition, SG was able to restore the increase in the expression of Kiss1 mRNA and Kiss1-positive neurons in the arcuate nucleus of rats with PCOS. Interestingly, although SG did not result in a significant loss of body weight in rats administered DHEA under a chow diet, it resulted in comparable metabolic improvements and Kiss1 expression in rats that had been administered DHEA along with an HFD.. The recovery of normal levels of Kiss1 expression in the hypothalamus after SG in this study suggests that Kiss1 might play an important role in the development of PCOS and its improvement by SG.

Topics: Animals; Female; Gastrectomy; Humans; Hypothalamus; Kisspeptins; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley

Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder, affecting millions of women worldwide. The role of genetic polymorphisms of the KISS1 gene on the development of PCOS is still obscure. This study was designed to investigate the probable influence of KISS1 gene polymorphisms on PCOS and its associated variables: BMI, waist-hip ratio, kisspeptin, LH, FSH, and LH-FSH ratio.. The study comprised 104 PCOS women and 109 controls, with age ranging from 19 to 36 years. BMI, waist-hip ratio, and circulating levels of kisspeptin, LH, and FSH were measured. DNA was extracted, and genotyping of the KISS1 gene was carried out by nucleotide sequencing. The PCOS-associated variables were analyzed in different genotypes of single nucleotide polymorphisms (SNPs) of the KISS1 gene.. The values of waist-hip ratio (WHR), LH, and LH-FSH ratio were significantly higher in PCOS women than controls. BMI, kisspeptin, and FSH levels exhibited no significant difference between the groups. Six novel SNPs of KISS1 gene were identified. Three: rs372790354G > A, rs12998G > A, and rs35431622A > T were investigated. Among these SNPs, the genotype and allele frequencies of rs372790354 showed significant association with PCOS (GA: p = 0.018, AA: p = 0.022, mutant allele-A: p = 0.021) and the G allele was protective. The values of LH, kisspeptin, and WHR of PCOS women were significantly influenced (p < 0.05) by the AA genotype of rs372790354. The other two SNPs rs12998G > A and rs35431622A > T revealed no significant influence on PCOS and associated variables. Haplotypes were constructed, but there was no significant difference between the patients and controls.. In conclusion, this is the first study, which reports a significant influence of KISS1 gene polymorphism (rs372790354G > A) on PCOS and its associated variables. However, more extensive research is necessary to confirm these findings.

Topics: Adult; Body Mass Index; Female; Follicle Stimulating Hormone; Genotype; Humans; Kisspeptins; Luteinizing Hormone; Phenotype; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Saudi Arabia; Waist-Hip Ratio; Young Adult

Prenatal testosterone (T)-treated female sheep display reproductive deficits similar to women with polycystic ovarian syndrome (PCOS), including an increase in LH pulse frequency due to actions of the central GnRH pulse generator. In this study, we used multiple-label immunocytochemistry to investigate the possibility of changes in the γ-aminobutyric acid (GABA) neurotransmitter system at two key components of the GnRH pulse generator in prenatal T-treated sheep: kisspeptin/neurokinin B/dynorphin (KNDy) neurons of the arcuate nucleus, and GnRH neurons in the preoptic area (POA) and mediobasal hypothalamus (MBH). We observed a significant decrease and increase, respectively, in the number of GABAergic synapses onto POA and MBH GnRH neurons in prenatal T-treated ewes; additionally, there was a significant increase in the number of GABAergic inputs onto KNDy neurons. To determine the actions of GABA on GnRH and KNDy neurons, we examined colocalization with the chloride transporters NKCC1 and KCC2, which indicate stimulatory or inhibitory activation of neurons by GABA, respectively. Most GnRH neurons in both POA and MBH colocalized NKCC1 cotransporter whereas none contained the KCC2 cotransporter. Most KNDy neurons colocalized either NKCC1 or KCC2, and 28% of the KNDy population contained NKCC1 alone. Therefore, we suggest that, as in the mouse, GABA in the sheep is stimulatory to GnRH neurons, as well as to a subset of KNDy neurons. Increased numbers of stimulatory GABAergic inputs to both MBH GnRH and KNDy neurons in prenatal T-treated animals may contribute to alterations in steroid feedback control and increased GnRH/LH pulse frequency seen in this animal model of PCOS.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Disease Models, Animal; Dynorphins; Female; GABAergic Neurons; Gonadotropin-Releasing Hormone; K Cl- Cotransporters; Kisspeptins; Neurokinin B; Polycystic Ovary Syndrome; Pregnancy; Prenatal Exposure Delayed Effects; Preoptic Area; Sheep; Solute Carrier Family 12, Member 2; Symporters; Testosterone

Kisspeptin (KP), a hypothalamic peptide, is known as an important marker for neuroendocrine regulation during the human reproduction process. The unexplained infertility (UI) group comprised 30 patients, polycystic ovary syndrome (PCOS) group comprised 29 patients and the male factor infertility (MFI) group comprised 27 patients. An observational cohort study was conducted. The basic characteristics of the study population, BMI, and serum FSH, LH, E2, AMH, KP, TSH, and PRL levels and antral follicle count (AFC) on the 3rd menstruation day were evaluated. The mean KP level was 281.98 ± 73.9 ng/ml in the UI group, 525.49 ± 164.17 ng/ml in the PCOS group, and 354.313 ± 111.38 ng/ml in the MFI group (p < .001). KP levels were significantly higher in the PCOS group than in the UI and MFI groups (p < .001 for both). AUC was 83% (95% CI: 73%-93%), with 375.15 (pg/ml) as the cutoff value in the PCOS group with 83% sensitivity and 79% specificity. UI may be treated by KP injection therapies and higher levels of KP may be a reliable marker for AFC and diagnosis of PCOS. Clinical Trials registration number: NCT03018314.

Topics: Adult; Anti-Mullerian Hormone; Biomarkers; Estradiol; Female; Follicle Stimulating Hormone; Humans; Infertility, Female; Kisspeptins; Luteinizing Hormone; Polycystic Ovary Syndrome; Prolactin; Thyrotropin; Young Adult

A cross-sectional study was performed in 46 healthy women and 43 PCOS women undergoing controlled ovarian stimulation. MGCs and CCs were collected from pre-ovulatory follicles after transvaginal ultrasound-guided oocyte retrieval and the expression of the genes encoding NKB (TAC3), NK3R (TACR3), KISS1, and its receptor (KISS1R) was analyzed using real-time quantitative RT-PCR.. TAC3, TACR3, and KISS1 mRNA levels were decreased in MGCs and CCs of PCOS women. TAC3 positively correlated with KISS1 in MGCs of healthy women and TACR3 was positively associated with KISS1R in CCs from healthy women. These associations were not observed in PCOS women.. The NKB/NK3R and KISS1/KISS1R systems are dysregulated in MGCs and CCs of PCOS women. The lower expression of these systems in GCs could contribute to the abnormal follicle development and defective ovulation that characterize the pathogenesis of PCOS.

Topics: Adult; Case-Control Studies; Cells, Cultured; Cross-Sectional Studies; Cumulus Cells; Female; Gene Expression Regulation; Granulosa Cells; Humans; Kisspeptins; Neurokinin B; Polycystic Ovary Syndrome; Receptors, Kisspeptin-1; Receptors, Neurokinin-3; Young Adult

Kisspeptins are a family of neuropeptides that are essential for fertility. Recent experimental data suggest a putative role of kisspeptin signaling in the direct control of ovarian function. To explore the expression of KISS1 and KISS1 receptor (KISS1R) in human granulosa lutein cells and the potential role of KISS1/KISS1R system in the pathogenesis of polycystic ovary syndrome (PCOS), we measured the concentration of KISS1 in follicular fluid, the expression of KISS1 and KISS1R in granulosa lutein cells, and the circulating hormones. The expression levels of KISS1 and KISS1R were significantly upregulated in human granulosa lutein cells obtained from women with PCOS. The expression levels of KISS1 in human granulosa lutein cells highly correlated with those of KISS1R in non-PCOS patients, but not in patients with PCOS, most likely due to the divergent expression patterns in women with PCOS. Additionally, the expression levels of KISS1 highly correlated with the serum levels of anti-Müllerian hormone (AMH). The expression levels of KISS1 and KISS1R, as well as the follicular fluid levels of KISS1, were not significantly different between the pregnant and nonpregnant patients in both PCOS and non-PCOS groups. In conclusion, the increased expression of KISS1 and KISS1R in human granulosa lutein cells may contribute to the pathogenesis of PCOS. The expression levels of KISS1 highly correlated with the serum levels of AMH. The KISS1 and KISS1R system in the ovary may not have a remarkable role in predicting the in vitro fertilization (IVF) outcome.

Topics: Adult; Cells, Cultured; Female; Fertilization in Vitro; Gene Expression; Granulosa Cells; Humans; Kisspeptins; Luteal Cells; Polycystic Ovary Syndrome; Pregnancy; Receptors, Kisspeptin-1; Young Adult

Kisspeptin has been shown to participate in the regulation of pituitary hormone secretion and energy metabolism. In PCOS patients, there are disorders in pituitary hormone secretion and energy metabolism. The aim of this study was to investigate the serum kisspeptin and its relationship with abnormal metabolism in PCOS. This restrospective case-control study included 73 cases with PCOS and 63 control cases. All subjects were divided into obese and nonobese groups based on BMI. The serum kisspeptin levels, Cor, DHEA-S, plasma concentrations of glucose were tested. We found that the level of kisspeptin in PCOS group was higher than it in control group. The kisspeptin levels in nonobese PCOS group increased most obviously over than the other groups. The kisspeptin levels of all the subjects were positively correlated with LH levels, negatively correlated with the glucose-AUC, the insulin-AUC, and triglyceride levels. The findings of this study suggest that kisspeptin may play an important role in ovulation disorders in PCOS patients through regulating the level of LH and it could regulate the body's energy metabolism by regulating glucose and lipid metabolism.

Topics: Adult; Body Mass Index; Case-Control Studies; Dehydroepiandrosterone Sulfate; Energy Metabolism; Female; Follicle Stimulating Hormone; Humans; Kisspeptins; Luteinizing Hormone; Obesity; Obesity, Abdominal; Polycystic Ovary Syndrome; Retrospective Studies

To investigate association of kisspeptin levels in infertile women with different ovarian reserve patterns.. In this prospective cross-sectional study, 157 participants were recruited. The women were divided into three groups: (i) adequate ovarian reserve (AOR) (n = 57), (ii) high ovarian reserve (PCOS) (n = 60), (iii) diminished ovarian reserve (DOR) (n = 40). Weight, height, waist circumference (WC), hip circumference (HC), body mass index (BMI), waist/hip ratio (WHR) were measured. The blood samples were analyzed for estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone (TT), 17-hydroxy progesterone (17OHP), dehydroepiandrosterone sulfate (DHEAS), antimullerian hormone (AMH), kisspeptin measurements.. FSH concentration was higher and AMH concentration was lower in DOR group (p < .001, p < .001, respectively). The mean LH, TT and DHEAS levels were higher in PCOS group (p = .001, p < .00 and p = .003, respectively). The 17OHP level did not differ among the groups (p = .15). Women with PCOS possessed the highest kisspeptin level (p = .01). The kisspeptin level was negatively correlated with FSH level (r = -0.18, p = .02) and positively correlated with TT and DHEAS levels (r = 0.17, p = .02 and r = 0.23, p = .003, respectively).. Women with PCOS had increased serum kisspeptin levels. Kisspeptin concentrations were negatively correlated with serum FSH and positively correlated with serum TT and DHEAS levels.

Topics: Adult; Body Mass Index; Cross-Sectional Studies; Dehydroepiandrosterone Sulfate; Female; Follicle Stimulating Hormone; Hospitals, University; Humans; Infertility, Female; Kisspeptins; Outpatient Clinics, Hospital; Ovarian Reserve; Overweight; Polycystic Ovary Syndrome; Prospective Studies; Severity of Illness Index; Testosterone; Turkey; Up-Regulation; Young Adult

To evaluate the temporal coupling between spontaneous kisspeptin and luteinizing hormone (LH) pulsatile releases in polycystic ovary syndrome (PCOS) patients.. We examined 71 patients diagnosed with PCOS. A 2 h pulsatility study was performed to evaluate serum kisspeptin and LH pulse frequency and concentration, sampled every 10 min; baseline follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL), cortisol, 17-hydroksy-progesterone (17OHP), testosterone (T), free testosterone index (FTI, and insulin levels were also measured. Detect and Specific Concordance (SC) algorithms were used to evaluate the temporal coupling associations between spontaneous episodic secretion of kisspeptin and LH.. All PCOS patients demonstrated LH and kisspeptin pulsatile secretions. When the SC index was calculated across the sample of PCOS patients (n = 71), no temporal coupling was observed between kisspeptin and LH pulses. When PCOS patients were subdivided according to their menstrual cyclicity, oligomenorrheic patients demonstrated elevated kisspeptin pulse frequency. Additionally, the SC index reveled a temporal coupling between kisspeptin and LH secretory peaks only in eumenorrheic patients (n = 30, intermenstrual interval < 45 days). Oligomenorrheic PCOS patients (intermenstrual interval > 45 days) did not demonstrate temporal coupling between kisspeptin and LH secretory peaks.. The study of the endogenous kisspeptin and LH pulsatile release revealed the temporal coupling of kisspeptin with LH secretory pulses only in eumenorrheic. This data supports the hypothesis that neuroendocrine impairments in PCOS affect the coupling of kisspeptin with LH pulses and potentially worsen as the disease progresses, becoming unequivocally evident in oligomenorrheic PCOS patients.

Topics: Adult; Algorithms; Disease Progression; Female; Hormones; Humans; Kisspeptins; Luteinizing Hormone; Menstrual Cycle; Menstruation Disturbances; Polycystic Ovary Syndrome; Young Adult

Kisspeptin is involved in female reproduction. This study was designed to i- estimate kisspeptin levels in women with polycystic ovary syndrome (PCOS), in comparison with controls, ii- study the correlations between kisspeptin and PCOS-related reproductive hormones, and iii- investigate the relation between KISS1 gene polymorphisms and hormone levels in women suffering from PCOS.. The investigation was a clinically designed study on 28 women with PCOS, and 30 normal, healthy women with no signs of PCOS as controls. Blood samples were collected between day 3 and day 6 of the menstrual cycle in both groups at 8:00 a.m., and circulating levels of LH, FSH and kisspeptin were estimated. DNA was extracted from whole blood and all coding exons of KISS1 gene were sequenced.. Women with PCOS had higher LH levels and BMI compared to controls. Plasma kisspeptin levels were positively correlated with LH levels. There was no statistically significant difference between the groups in terms of kisspeptin and FSH levels. The SNP rs4889 C/G, a non-synonymous SNP, was investigated in the PCOS group. The frequency of GG genotype was significantly higher in the PCOS compared to the controls. These patients were more obese, had higher kisspeptin and FSH levels.. The results of the study show that the genetic variation of KISS1 gene may be a factor contributing to PCOS development. The association between the gene and the gene variation and PCOS need further validation in large-scaled and functional studies.

Topics: Adult; Body Mass Index; Female; Follicle Stimulating Hormone; Humans; Kisspeptins; Luteinizing Hormone; Obesity; Polycystic Ovary Syndrome; Polymorphism, Genetic; Saudi Arabia; Young Adult

Polycystic ovarian syndrome (PCOS), the most common endocrine disorder of women in reproductive age, is typical with hyperandrogenism and disturbance of the hypothalamus-pituitary-ovary (HPO) axis, i.e. abnormal expression of hypothalamic gonadotropin-releasing hormone (GnRH) followed by the elevated ratio of serum luteinizing hormone (LH) level to follicle-stimulating hormone (FSH) level. This derangement might have a close relationship with hypothalamic kisspeptin expression that is thought to be a key regulator of GnRH. Crocetin, one of the main components of Saffron clinically used as traditional medicine in gynecology diseases, was evaluated for its therapeutic effects on PCOS induced by prenatally exposure to dihydrotestosterone (DHT) in mice. Herein, we found that DHT-treated mice showed a similar phenotype to human PCOS such as heavier ovary, prolonged diestrus, multiple enlarged follicles with fewer corpus luteum, and higher LH and testosterone levels. Kisspeptin expression was lower in anteroventral periventricular nucleus (AVPV) but higher in arcuate nucleus (ARC). Treatment of crocetin prevented the prolongation of diestrus and reduction in corpora luteum, recover the levels of GnRH, FSH, LH, progesterone (P4), estradiol (E2) and testosterone (T), and increase the kisspeptin level in AVPV but reduce that in ARC. The present study provides in vivo evidence that crocetin improved the PCOS in mice via increasing AVPV-kisspeptin and reducing ARC-kisspeptin expression.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Carotenoids; Crocus; Dihydrotestosterone; Disease Models, Animal; Drugs, Chinese Herbal; Estrous Cycle; Female; Hypothalamo-Hypophyseal System; Hypothalamus, Anterior; Kisspeptins; Neurons; Ovary; Polycystic Ovary Syndrome; Vitamin A

This study was planned to test whether follicular fluid (FF) levels of patatin-like phospholipase domain containing 3-gene (PNPLA3:adiponutrin), preptin, kisspeptin, and amylin change in polycystic ovarian syndrome (PCOS). A total of 40 infertile volunteers undergoing IVF/ICSI were included in the study. They were divided into two groups as PCOS (n=20) and control group without PCOS (n=20). The controls were recruited from subjects with a poor ovarian response. The PCOS and control participants were matched according to their body mass index (BMI). Each group of participants underwent ovarian stimulation with GnRH antagonist protocol. Blood and FF samples of one dominant follicle were obtained from each subject during the oocyte pick-up. FF and serum levels of PNPLA3, preptin, kisspeptin and amylin were measured through ELISA. Amylin and adiponutrin median values were not different according to study groups (p>0.05). FF-preptin median values in the control group were similar to the serum preptin values of control and PCOS groups (Z=0.970, p=1.000 and Z=2.631, p=0.051, respectively). Medians of the serum preptin in control and PCOS groups were the same (Z=1.649; p=0.595). FF-preptin median values of PCOS group were significantly lower than the preptin median values of the control group. Serum preptin levels were positively correlated with HOMA-IR, but not with pregnancy rates and the number of retrieved oocytes. Serum kisspeptin levels were negatively correlated with the number of retrieved oocytes and pregnancy rates. While amylin and adiponutrin have no role in the folliculogenesis, kisspeptin and preptin work together for regulating follicle developmental capacity in PCOS.

Topics: Adult; Case-Control Studies; Female; Humans; Insulin-Like Growth Factor II; Islet Amyloid Polypeptide; Kisspeptins; Lipase; Membrane Proteins; Oocytes; Peptide Fragments; Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of the reproductive system characterized by polycystic ovaries and androgen excess. Letrozole is a nonsteroidal aromatase inhibitor that is used in experimental research to induce PCOS. Kisspeptin is an essential protein in regulation of cyclicity. Kisspeptin receptor is expressed in the hypothalamus and pituitary glands, and kisspeptin containing neurons are affected from sex steroid hormones. We aimed to investigate the number of kisspeptin-positive cells in the arcuate (Arc) and anteroventral periventricular nuclei (AVPV) of hypothalamus in the letrozole-induced PCOS.. 40 female Wistar rats were divided into the proestrus control, diestrus control, proestrus vehicle, diestrus vehicle and letrozole. Animals were sacrificed after 3 weeks, and sera, ovary and brain samples were harvested for further evaluations.. Letrozole group had high weight gain, high numbers of ovarian follicular cysts, high levels of luteinizing hormone and testosterone and increase number of kisspeptin-positive cells in the Arc nucleus, as compared with the control groups (P ≤ 0.05 vs. proestrus control and proestrus vehicle). Letrozole group showed a decrease in the number of kisspeptin-positive cells in the AVPV nucleus (P ≤ 0.05 vs. proestrus control and proestrus vehicle).. Our findings show that the number of kisspeptin-positive cells may be affected from letrozole, and that the changes in the number of these cells may be in favor of the appearance of PCOS features in this group.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Female; Gonadal Steroid Hormones; Humans; Hypothalamus; Hypothalamus, Anterior; Kisspeptins; Letrozole; Luteinizing Hormone; Neurons; Nitriles; Pituitary Gland; Polycystic Ovary Syndrome; Rats; Rats, Wistar; Testosterone; Triazoles

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

Topics: Animals; Disease Models, Animal; Down-Regulation; Estradiol; Female; Gene Expression; Gonadotropin-Releasing Hormone; Hypothalamus; Kisspeptins; Luteinizing Hormone; Phenotype; Pituitary Gland; Polycystic Ovary Syndrome; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, Androgen; Receptors, Estrogen; Testosterone; Up-Regulation

Hypersecretion of luteinizing hormone (LH) is a common endocrinological finding of polycystic ovary syndrome (PCOS). This derangement might have a close relationship with hypothalamic kisspeptin expression that is thought to be a key regulator of gonadotropin-releasing hormone (GnRH). We evaluated the relationship between the hypothalamic-pituitary-gonadal axis (HPG axis) and kisspeptin using a rat model of PCOS induced by letrozole. Letrozole pellets (0.4 mg/day) and control pellets were placed subcutaneously onto the backs of 3-week-old female Wistar rats. Body weight, vaginal opening and vaginal smear were checked daily. Blood and tissues of ovary, uterus and brain were collected at 12-weeks of age. An hypothalamic block was cut into anterior and posterior blocks, which included the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC), respectively, in order to estimate hypothalamic kisspeptin expression in each area. The letrozole group showed a similar phenotype to human PCOS such as heavier body weight, heavier ovary, persistent anovulatory state, multiple enlarged follicles with no corpus luteum and higher LH and testosterone (T) levels compared to the control group. Kisspeptin mRNA expression in the posterior hypothalamic block including ARC was higher in the letrozole group than in the control group although its expression in the anterior hypothalamic block was similar between groups. These results suggest that enhanced KNDy neuron activity in ARC contributes to hypersecretion of LH in PCOS and might be a therapeutic target to rescue ovulatory disorder of PCOS in the future.

Topics: Animals; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Hypothalamus, Posterior; Kisspeptins; Letrozole; Nitriles; Polycystic Ovary Syndrome; Rats; Rats, Wistar; RNA, Messenger; Triazoles; Up-Regulation

Hyperandrogenism, disturbance of the hypothalamus-pituitary-ovary axis followed by elevated serum luteinizing hormone (LH) levels, and insulin resistance are involved in the complicated pathophysiology of polycystic ovary syndrome (PCOS). Kisspeptin is coexpressed with neurokinin B (NKB) in the arcuate nucleus (ARC), the center of the gonadotropin-releasing hormone pulse generator that is responsible for pulsatile LH secretion. We compared 2 androgenized rat models of PCOS to evaluate the estrous cycle, hormonal profiles, and expression of kisspeptin and NKB in the ARC. Rats in our postnatal dihydrotestosterone (DHT)-treatment model exhibited weight gain and persistent diestrus with normal LH levels. In contrast, irregular cycles, with elevated LH serum levels and normal body weight, were found in the prenatally DHT-treated rats. We also found increased signals of kisspeptin and NKB in the ARC of the prenatally DHT-treated rats, and not in the postnatally DHT-treated rats. Our results suggest that prenatal exposure to androgens may result in higher kisspeptin and NKB levels in the ARC, which could be associated with 1 phenotype of PCOS that is characterized by normal body weight and higher LH secretion, whereas in postnatally DHT-treated rats, characteristics such as weight gain and normal LH levels are seen in the obese PCOS phenotype.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Dihydrotestosterone; Disease Models, Animal; Estrous Cycle; Female; Gonadal Steroid Hormones; Gonadotropins; Hypothalamo-Hypophyseal System; Hypothalamus, Anterior; Kisspeptins; Ovary; Phenotype; Polycystic Ovary Syndrome; Rats, Wistar

Kisspeptin, a hypothalamic neuropeptide, is expressed in the arcuate nucleus (ARC) that is considered as the center of the gonadotropin-releasing hormone (GnRH)-pulse generator. We hypothesized that kisspeptin expressed in the ARC is implicated in the disturbance of the hypothalamus-pituitary-ovary axis observed in polycystic ovary syndrome (PCOS). To test this hypothesis, we evaluated the hormonal profiles, luteinizing hormone (LH) pulse, and ARC kisspeptin immunoreactivity in a PCOS rat model using the anti-progestin RU486. We found an alteration of the LH pulse, including a trend towards an increased mean LH concentration and area under the curve, and a significant upregulation of the mean LH pulse amplitude. Additionally, a higher number of kisspeptin-positive cells was observed in the ARC of RU486-treated rats than in the ARC of intact rats. These results suggest the possible involvement of hypothalamic kisspeptin in the hypothalamus-pituitary-ovary axis and therefore, in PCOS pathophysiology.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Disease Models, Animal; Estradiol; Female; Follicle Stimulating Hormone; Kisspeptins; Luteinizing Hormone; Mifepristone; Neurons; Polycystic Ovary Syndrome; Progesterone; Rats; Testosterone

Due to the complex relationship between kisspeptin and the hypothalamic-pituitary-gonadal axis, the study was planned to measure the kisspeptin levels in polycystic ovary syndrome (PCOS) and to analyze the correlations between kisspeptin and PCOS-related reproductive, metabolic changes.. The study was designed as a prospective study in Dokuz Eylul University between December 2011 and September 2013. A total of 285 PCOS cases and 162 controls were recruited. After the antropometric measeruments and physcial examination, blood samples were taken for biochemical analysis.. In this study, kisspeptin had a positive correlation with LH and leptin levels in PCOS. In fact, the serum levels of kisspeptin and leptin does not differ statistically between PCOS and healthy women. There are limited data in the literature with regard to changes in kisspeptin levels and its relation with metabolic and hormonal disturbances.

Topics: Adult; Female; Humans; Kisspeptins; Leptin; Luteinizing Hormone; Polycystic Ovary Syndrome; Prospective Studies; Young Adult

Prenatal testosterone (T)-treated ewes display a constellation of reproductive defects that closely mirror those seen in PCOS women, including altered hormonal feedback control of GnRH. Kisspeptin/neurokinin B/dynorphin (KNDy) neurons of the arcuate nucleus (ARC) play a key role in steroid feedback control of GnRH secretion, and prenatal T treatment in sheep causes an imbalance of KNDy peptide expression within the ARC. In the present study, we tested the hypothesis that prenatal T exposure, in addition to altering KNDy peptides, leads to changes in the morphology and synaptic inputs of this population, kisspeptin cells of the preoptic area (POA), and GnRH cells. Prenatal T treatment significantly increased the size of KNDy cell somas, whereas POA kisspeptin, GnRH, agouti-related peptide, and proopiomelanocortin neurons were each unchanged in size. Prenatal T treatment also significantly reduced the total number of synaptic inputs onto KNDy neurons and POA kisspeptin neurons; for KNDy neurons, the decrease was partly due to a decrease in KNDy-KNDy synapses, whereas KNDy inputs to POA kisspeptin cells were unaltered. Finally, prenatal T reduced the total number of inputs to GnRH cells in both the POA and medial basal hypothalamus, and this change was in part due to a decreased number of inputs from KNDy neurons. The hypertrophy of KNDy cells in prenatal T sheep resembles that seen in ARC kisspeptin cells of postmenopausal women, and together with changes in their synaptic inputs and projections to GnRH neurons, may contribute to defects in steroidal control of GnRH observed in this animal model.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Disease Models, Animal; Dynorphins; Female; Gonadotropin-Releasing Hormone; Kisspeptins; Neurokinin B; Neurons; Polycystic Ovary Syndrome; Pregnancy; Prenatal Exposure Delayed Effects; Preoptic Area; Sheep; Testosterone

Polycystic ovary syndrome (PCOS) pathophysiology is poorly understood, due partly to lack of PCOS animal models fully recapitulating this complex disorder. Recently, a PCOS rat model using letrozole (LET), a nonsteroidal aromatase inhibitor, mimicked multiple PCOS phenotypes, including metabolic features absent in other models. Given the advantages of using genetic and transgenic mouse models, we investigated whether LET produces a similar PCOS phenotype in mice. Pubertal female C57BL/6N mice were treated for 5 wk with LET, which resulted in increased serum testosterone and normal diestrus levels of estradiol, similar to the hyperandrogenemia and follicular phase estrogen levels of PCOS women. As in PCOS, ovaries from LET mice were larger, polycystic, and lacked corpora lutea versus controls. Most LET females were acyclic, and all were infertile. LET females displayed elevated serum LH levels and higher Lhb mRNA in the pituitary. In contrast, serum FSH and Fshb were significantly reduced in LET females, demonstrating differential effects on gonadotropins, as in PCOS. Within the ovary, LET females had higher Cyp17, Cyp19, and Fsh receptor mRNA expression. In the hypothalamus, LET females had higher kisspeptin receptor mRNA expression but lower progesterone receptor mRNA levels. LET females also gained more weight than controls, had increased abdominal adiposity and adipocyte size, elevated adipose inflammatory mRNA levels, and impaired glucose tolerance, mirroring the metabolic phenotype in PCOS women. This is the first report of a LET paradigm in mice that recapitulates both reproductive and metabolic PCOS phenotypes and will be useful to genetically probe the PCOS condition.

Topics: Animals; Corpus Luteum; Diestrus; Enzyme Inhibitors; Estrous Cycle; Female; Hyperandrogenism; Hypothalamus; Kisspeptins; Letrozole; Mice; Mice, Inbred C57BL; Nitriles; Phenotype; Pituitary Gland; Polycystic Ovary Syndrome; Pregnancy; Reproduction; Testosterone; Triazoles

The aim of the present study was to evaluate serum concentrations of metastin in relation with hormonal and metabolic profile in patients with and without polycystic ovary syndrome (PCOS).. The study was a clinical study. Eighty-three women with PCOS and 66 body mass index (BMI) matched controls were divided into two groups, based on BMI: overweight and obese (BMI≥25 kg/m(2)) and normal weight. (BMI<25 kg/m(2)) Hirsutism scores, hormonal and metabolic profile as well as metastin levels were evaluated in each subject. Blood samples were collected in the early follicular phase (between day 2 and day 5 of the menstrual cycle) at 9:00 AM, after an overnight fast. Circulating levels of LH, FSH, PRL, TSH, T, fT, DHEAS, 17-OH-P, sex hormone-binding globulin (SHBG), insulin, glucose, lipid profile and metastin were measured.. Metastin levels were significantly higher in the PCOS group compared to controls (2.02 ng/ml versus 1.16 ng/ml, p<0.001). Metastin levels correlated significantly positively with luteinizing hormone (LH), total testosterone (T), dehydroepiandrosteronesulphate (DHEA-SO4) levels, modified Ferriman-Gallwey (mFG) scores and free androgen index (FAI); however, correlated negatively with sex hormone binding globulin (SHBG) levels (p<0.05). When overweight or obese (BMI≥25 kg/m(2)) and normal weight (BMI<25 kg/m(2)) women with PCOS were compared to body mass index (BMI) matched controls, higher metastin levels were also found in PCOS groups (1.94 ng/ml versus 1.18 ng/ml, and 2.06 ng/ml versus 1.08 ng/ml, p<0.05, respectively).. These findings suggest that metastin levels were higher in women with PCOS as compared to controls regardless of BMI. Furthermore, metastin levels can be used as a specific marker for androgenic profile and this marker might play a role in the pathogenesis of PCOS.

Topics: Adolescent; Adult; Blood Glucose; Case-Control Studies; Dehydroepiandrosterone Sulfate; Female; Follicle Stimulating Hormone; Hirsutism; Humans; Insulin Resistance; Kisspeptins; Lipids; Luteinizing Hormone; Obesity; Overweight; Polycystic Ovary Syndrome; Prolactin; Sex Hormone-Binding Globulin; Testosterone; Thyrotropin; Young Adult

To compare plasma kisspeptin, serum leptin, and serum retinol-binding protein 4 (RBP4) levels in women with and without polycystic ovary syndrome (PCOS) and to correlate these among each other and with clinical, hormonal, and metabolic parameters.. Ninety women, including 54 women with PCOS and 36 without PCOS, participated in this study. For all patients, history and physical examinations were performed and blood samples were collected between days 3 and 8 of a spontaneous bleeding episode in the PCOS group and during normal menses of controls. Plasma kisspeptin, serum leptin, and serum RBP4 levels were measured using specific commercial assays.. Kisspeptin, leptin, and RBP4 levels were significantly higher in the PCOS group than in controls. Kisspeptin and RBP4 levels were significantly higher among obese PCOS patients than controls. Leptin levels were higher among obese PCOS patients than non-obese PCOS patients or controls. Kisspeptin and leptin levels of PCOS patients were significantly correlated with RBP4 levels. When only obese PCOS patients were analyzed, kisspeptin levels correlated with only the free androgen index.. These findings suggest that kisspeptin, leptin, and RBP4 are associated with metabolic disturbances in women with PCOS.

Topics: Adolescent; Adult; Blood Glucose; Body Mass Index; Female; Gonadal Steroid Hormones; Humans; Insulin; Kisspeptins; Leptin; Obesity; Polycystic Ovary Syndrome; Retinol-Binding Proteins, Plasma; Young Adult

An intact hypothalamic kiss1/kisspeptin/kiss1r complex is a prerequisite for reproductive competence, and kisspeptin treatment could be a practical therapeutic approach to some problems of infertility. One such disorder is polycystic ovarian syndrome (PCOS), a common cause of infertility affecting more than 100 million women. A rodent model of PCOS is the prepubertal female rat treated for a prolonged period with dihydrotestosterone (DHT), which induces many of the metabolic characteristics of the syndrome. We hypothesized that hypothalamic kiss1 mRNA levels, and kisspeptin immunoreactivity (ir), would be abnormal in these rats. Prepubertal female rats were exposed to DHT for 60 days. Rats were killed in two groups: at 26 and 60 days of DHT exposure. Kiss1 mRNA was quantified in hypothalamus, pituitary, ovary and visceral adipose tissue. Separate groups of rats provided brain tissue for immunohistochemical analysis of kisspeptin-ir. At 26 days of DHT exposure, hypothalamic kiss1 mRNA was severely depleted. In contrast DHT had no effect on pituitary kiss1 expression but it significantly increased levels of kiss1 mRNA in fat (+9-fold; p<0.01) and in ovary (+3-fold; p<0.05). At 60days, kiss1 expression had reverted to normal in hypothalamus and ovary but remained elevated in fat (+4-fold; p<0.05). Immunohistochemical analysis revealed that after 26 days of exposure to DHT, kisspeptin-ir was almost completely absent in the arcuate nucleus and a large depletion in kisspeptin +ve fibers was also seen in the paraventricular nucleus, supraoptic nucleus and in the anteroventral periventricular area. At 60 days, despite restored normal levels of kiss1 mRNA, hypothalamic kisspeptin-ir remained depleted in the treated rats. In summary Kiss1 gene expression is differentially affected in various tissues by chronic exposure to dihydrotestosterone in a rat model of polycystic ovary syndrome. In hypothalamus, specifically, kiss1 mRNA, and levels of kisspeptin immunoreactivity, are significantly reduced. Since these rats exhibit many of the characteristics of polycystic ovary syndrome, we suggest that atypical kiss1 expression may contribute to the multiple tissue abnormalities observed in women with this disorder. However, and of some importance, our data do not appear to be consistent with the elevated levels of LH seen in women with PCOS; i.e. reduced levels of hypothalamic kiss1 mRNA and kisspeptin immunoreactivity observed in DHT-treated rats are unlikely to produce e

Topics: Adipose Tissue; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Dihydrotestosterone; Energy Metabolism; Female; Gonadal Steroid Hormones; Hypothalamus; Immunohistochemistry; Kisspeptins; Ovary; Pituitary Gland; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; RNA, Messenger

This study was designed to: (1) measure metastin levels in women with polycystic ovary syndrome (PCOS) and in adolescent controls; (2) investigate the possible correlations between metastin and PCOS-related reproductive and metabolic disturbances.. The study was a clinical study. Nineteen adolescent women with PCOS, twenty-three adult women with the syndrome, and twenty adolescent controls were selected. Blood samples were collected between day 1 and day 5 of a spontaneous bleeding episode in the PCOS groups and of a menstrual cycle of the controls at 9 a.m. after an overnight fast. Circulating levels of LH, FSH, prolactin, testosterone (T), free testosterone, DHEAS, sex hormone-binding globulin, insulin, glucose and metastin were measured.. Plasma metastin levels are increased in adolescent women with PCOS compared to adolescent controls. Plasma metastin levels were positively correlated with LH levels, 2-h glucose levels and T levels.. These results indicate that metastin is increased in adolescent PCOS women. The increased metastin levels were positively correlated with LH and T levels, and may affect the development of PCOS in adolescents.

Topics: Adolescent; Analysis of Variance; Blood Glucose; Body Mass Index; Female; Glucose Tolerance Test; Humans; Kisspeptins; Luteinizing Hormone; Polycystic Ovary Syndrome; Statistics, Nonparametric; Testosterone; Tumor Suppressor Proteins

This study was designed to investigate the correlationship between plasma metastin and pathogenesis of adolescent women with polycystic ovary syndrome (PCOS).. From Jan. 2006 to Jun. 2006, 42 PCOS patients including 19 adolescent women and 23 adults with syndrome were treated in Second Affiliated Hospital of Sun Yat-Sen University. According to the range of age, those patients were divided into 19 cases in adolescent group ( 19 years). Meanwhile, 20 adolescent women were matched as controls. Blood samples were collected between day 1 and day 5 of a spontaneous bleeding episode in the PCOS groups and a menstrual cycle of the controls. The levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), free T (FT), dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), insulin, glucose, and metastin were detected from day 1 to day 5 of spontaneous bleeding or withdrawal bleeding by progesterone. On the next day, oral glucose tolerance test (75 g) and insulin release test were performed on those above patients and controls. The area under curve (AUC), the ratio of fasting blood glucose to insulin (GIR) and homeostasis model assessment insulin resistance index (HOMA-IR) were calculated.. (1) The level of hormone: the level of LH was in (12 +/- 7) U/L in adult group and (12 +/- 8) U/L in adolescent PCOS group, which were significantly higher than (6 +/- 4) U/L in controls (P < 0.05). The level of FT was (2.3 +/- 1.2) pmol/L in adult group, which was significantly higher than (1.3 +/- 0.8) pmol/L in adolescent group and (1.1 +/- 0.5) pmol/L in control group (P < 0.05). It was observed that the level of (3.1 +/- 2.7)micromol/L in adolescent group was significantly lower than (6.3 +/- 2.7) micromol/L in control group (P < 0.05). Meanwhile, the level of FAI of 5.6 +/- 4.1 in adult group was significantly higher than 3.0 +/- 1.3 in control group (P < 0.05). No significant difference in FSH, T and SHBG levels among three groups were observed (P > 0.05). (2) Metastin and metabolism: Both the levels of fasting blood insulin, 2-hour insulin and AUC of insulin were (13 +/- 7) mU/L, (88 +/- 59) mU/L and (133 +/- 80) mUxL(-1)xmin(-1) in adolescent group, which were significantly higher than (7 +/- 3) mU/L, (57 +/- 29) mU/L and (82 +/- 34) mUxL(-1)xmin(-1) in control group. The fasting blood insulin of (13 +/- 7) mU/L in adolescent group was significantly higher than (9 +/- 5) mU/L in adult group. The level of fasting blood glucose and 2-hour glucose were (5.01 +/- 0.44) mmol/L and (6.48 +/- 1.16) mmol/L in adult group, which were significantly higher than (4.68 +/- 0.29) mmol/L and (5.44 +/- 0.83) mmol/L in control group and (4.67 +/- 0.30) mmol/L and (5.93 +/- 1.44) mmol/L in adolescent group. The glucose AUC of (9.99 +/- 1.85) mmolxL(-1)xmin(-1) in adult group was significantly higher than (8.42 +/- 1.53) mmolxL(-1)xmin(-1) in control group (P < 0.05). HOMA-IR of 2.6 +/- 2.0 in adolescent group was significantly higher than 1.4 +/- 0.7 in control group. GIR of 10 +/- 8 in adolescent group was significantly lower than 16 +/- 10 in control group (P < 0.05). The metastin level of (0.25 +/- 0.19) pmol/L in adolescent group and (0.29 +/- 0.29) pmol/L in adult group were all significantly higher than (0.18 +/- 0.23) pmol/L in control group (PPh glucose were observed (r = 0.256, 0.286 and 0.267. P = 0.044, 0.025 and 0.043).. The expression of metastin in adolescent PCOS women was significantly higher that of normal adolescent women. The increased level of metastin might be associated with pathogenesis of adolescent women with PCOS.

Topics: Adolescent; Blood Glucose; Female; Follicle Stimulating Hormone; Humans; Kisspeptins; Obesity; Polycystic Ovary Syndrome

This study was designed to: [1] measure, for the first time, metastin (kisspeptin) levels in women with polycystic ovary syndrome (PCOS), a condition associated with hypersecretion of LH and hyperandrogenemia; and [2] investigate the possible correlations between metastin and PCOS-related reproductive and metabolic disturbances.. Clinical study.. University hospital.. Twenty-eight obese and overweight (body mass index [BMI] >25 kg/m2) women with PCOS, 28 normal weight (BMI <25 kg/m2) women with the syndrome, and 13 obese and overweight controls (ovulatory women without clinical or biochemical hyperandrogenemia) were selected.. Blood samples were collected between day 3 and day 6 of a spontaneous bleeding episode in the PCOS groups and a menstrual cycle of the controls, at 9:00 AM, after an overnight fast.. Circulating levels of LH, FSH, PRL, T, Delta4-androstenedione (A), DHEAS, 17alpha-OH-P, sex hormone-binding globulin (SHBG), insulin, glucose, and metastin were measured.. Both normal weight women with PCOS and obese controls were less insulin resistant and had significantly higher metastin levels, compared to obese and overweight women with the syndrome. Plasma kisspeptin levels were negatively correlated with BMI, free androgen index, and indices of insulin resistance.. These results indicate that metastin is negatively associated with free androgen levels. The PCOS-associated insulin resistance and consequent hyperinsulinemia probably contribute to this effect by [1] stimulating androgen synthesis by the polycystic ovary (PCO) and [2] suppressing SHBG production in the liver.

Topics: Adolescent; Adult; Androgens; Biomarkers; Female; Greece; Humans; Insulin; Insulin Resistance; Kisspeptins; Obesity; Polycystic Ovary Syndrome; Statistics as Topic; Tumor Suppressor Proteins