Increased Vasoactive Intestinal Peptide (VIP) in polycystic ovary syndrome patients undergoing IVF.

Introduction: Polycystic ovary syndrome (PCOS) is a common multifactorial and polygenic disorder of the endocrine system, affecting up to 20% of women in reproductive age with a still unknown etiology. Follicular fluid (FF) represents an environment for the normal development of follicles rich in metabolites, hormones and neurotransmitters, but in some instances of PCOS the composition can be different. Vasoactive intestinal peptide (VIP) is an endogenous autonomic neuropeptide involved in follicular atresia, granulosa cell physiology and steroidogenesis. Methods: ELISA assays were performed to measure VIP and estradiol levels in human follicular fluids, while AMH, FSH, LH, estradiol and progesterone in the plasma were quantified by chemiluminescence. UHPLC/QTOF was used to perform the untargeted metabolomic analysis. Results: Our ELISA and metabolomic results show: i) an increased concentration of VIP in follicular fluid of PCOS patients (n=9) of about 30% with respect to control group (n=10) (132 ± 28 pg/ml versus 103 ± 26 pg/ml, p=0,03) in women undergoing in vitro fertilization (IVF), ii) a linear positive correlation (p=0.05, r=0.45) between VIP concentration and serum Anti-Müllerian Hormone (AMH) concentration and iii) a linear negative correlation between VIP and noradrenaline metabolism. No correlation between VIP and estradiol (E2) concentration in follicular fluid was found. A negative correlation was found between VIP and noradrenaline metabolite 3,4-dihydroxyphenylglycolaldehyde (DOPGAL) in follicular fluids. Conclusion: VIP concentration in follicular fluids was increased in PCOS patients and a correlation was found with noradrenaline metabolism indicating a possible dysregulation of the sympathetic reflex in the ovarian follicles. The functional role of VIP as noradrenergic modulator in ovarian physiology and PCOS pathophysiology was discussed.

Status of visfatin in female reproductive function under normal and pathological conditions: a mini review.

Adipokines are now well-known to regulate reproduction. Visfatin is an adipokine expressed in the hypothalamus, pituitary, ovary, uterus, and placenta of different species, and since it has been found to modulate the endocrine secretion of the hypothalamus, pituitary gland and ovary, it may be considered a novel regulator of female reproduction. Although the majority of the literature explored its role in ovarian regulation, visfatin has also been shown to regulate uterine remodeling, endometrial receptivity and embryo development, and its expression in the uterus is steroid dependent. Like other adipokines, visfatin expression and levels are deregulated in pathological conditions including polycystic ovary syndrome. Thus, the present mini-review focuses on the role of visfatin in female reproduction under both physiological and pathological conditions.

Interlukin-22 improves ovarian function in polycystic ovary syndrome independent of metabolic regulation: a mouse-based experimental study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a reproductive endocrine disorder with multiple metabolic abnormalities. Most PCOS patients have concomitant metabolic syndromes such as insulin resistance and obesity, which often lead to the development of type II diabetes and cardiovascular disease with serious consequences. Current treatment of PCOS with symptomatic treatments such as hormone replacement, which has many side effects. Research on its origin and pathogenesis is urgently needed. Although improving the metabolic status of the body can alleviate reproductive function in some patients, there is still a subset of patients with metabolically normal PCOS that lacks therapeutic tools to address ovarian etiology. METHODS: The effect of IL-22 on PCOS ovarian function was verified in a non-metabolic PCOS mouse model induced by dehydroepiandrosterone (DHEA) and rosiglitazone, as well as granulosa cell -specific STAT3 knockout (Fshrcre+Stat3f/f) mice (10 groups totally and n = 5 per group). Mice were maintained under controlled temperature and lighting conditions with free access to food and water in a specific pathogen-free (SPF) facility. Secondary follicles separated from Fshrcre+Stat3f/f mice were cultured in vitro with DHEA to mimic the hyperandrogenic environment in PCOS ovaries (4 groups and n = 7 per group) and then were treated with IL-22 to investigate the specific role of IL-22 on ovarian function. RESULTS: We developed a non-metabolic mice model with rosiglitazone superimposed on DHEA. This model has normal metabolic function as evidenced by normal glucose tolerance without insulin resistance and PCOS-like ovarian function as evidenced by irregular estrous cycle, polycystic ovarian morphology (PCOM), abnormalities in sex hormone level. Supplementation with IL-22 improved these ovarian functions in non-metabolic PCOS mice. Application of DHEA in an in vitro follicular culture system to simulate PCOS follicular developmental block and ovulation impairment. Follicles from Fshrcre+Stat3f/f did not show improvement in POCS follicle development with the addition of IL-22. In DHEA-induced PCOS mice, selective ablation of STAT3 in granulosa cells significantly reversed the ameliorative effect of IL-22 on ovarian function. CONCLUSION: IL-22 can improve non-metabolic PCOS mice ovarian function. Granulosa cells deficient in STAT3 reverses the role of IL-22 in alleviating ovary dysfunction in non-metabolic PCOS mice.

Obesity and polycystic ovary syndrome influence on intestinal permeability at fasting, and modify the effect of diverse macronutrients on the gut barrier.

Women with the extremely prevalent polycystic ovary syndromegather multiple cardiovascular risk factors and chronic subclinical inflammation. Interactions between diet, adiposity, and gut microbiota modulate intestinal permeabilityand bacterial product translocation, and may contribute to the chronic inflammation process associated with the polycystic ovary syndrome. In the present study, we aimed to address the effects of obesity, functional hyperandrogenism, and diverse oral macronutrients on intestinal permeabilityby measuring circulating markers of gut barrier dysfunction and endotoxemia. Participants included 17 non-hyperandrogenic control women, 17 women with polycystic ovary syndrome, and 19 men that were submitted to glucose, lipid, and protein oral loads. Lipopolysaccharide-binding protein, plasma soluble CD14, succinate, zonulin family peptide, and glucagon-like peptide-2 were determined at fasting and after oral challenges. Macronutrient challenges induced diverse changes on circulating intestinal permeabilitybiomarkers in the acute postprancial period, with lipids and proteins showing the most unfavorable and favorable effects, respectively. Particularly, lipopolysaccharide-binding protein, zonulin family peptide, and glucagon-like peptide-2 responses were deregulated by the presence of obesity after glucose and lipid challenges. Obese subjects showed higher fasting intestinal permeabilitybiomarkers levels than non-obese individuals, except for plasma soluble CD14. The polycystic ovary syndromeexacerbated the effect of obesity further increasing fasting glucagon-like peptide-2, lipopolysaccharide-binding protein, and succinate concentrations. We observed specific interactions of the polycystic ovary syndromewith obesity in the postprandial response of succinate, zonulin family peptide, and glucagon-like peptide-2. In summary, obesity and polycystic ovary syndromemodify the effect of diverse macronutrients on the gut barrier, and alsoinfluence intestinal permeabilityat fasting,contributing to the morbidity of functional hyperandrogenism by inducing endotoxemia and subclinical chronic inflammation.

The impact of androgen levels on serum metabolic profiles in patients with polycystic ovary syndrome.

OBJECTIVE: This study aimed to investigate the impact of serum androgen levels on metabolic profiles in patients with polycystic ovary syndrome (PCOS). METHODS: We included 216 patients with PCOS and 216 healthy individuals selected as the control group. According to the measured serum androgen levels, patients with PCOS were divided into the hyperandrogenism group and non-hyperandrogenism group. Clinical metabolic indicators were assessed and compared between the two groups. Additionally, we assessed the correlation between androgen levels and clinical metabolic indicators. RESULTS: The body mass index, waist-to-hip ratio, mF-G score, and acne score, as well as T, LH, LSH/FSH, FPG, Cr, UA, TG, TC, and LDL-C levels were significantly higher in the PCOS group than in the control group. The incidence of hyperandrogenism and clinical hyperandrogenism in the PCOS group was significantly higher than that in the control group. Regarding clinical hyperandrogenism, hirsutism, acne, and acanthosis nigricans were significantly more common in the PCOS group than in the control group. Serum androgen levels were significantly correlated with the mF-G score, acne score, FSH, glucose concentration at 30 min, glucose concentration at 60 min, glucose concentration at 120 min, FINS, N120, HOMA-IR, HbA1c, AUCG, UA, TG, and hHDL-Clevels. CONCLUSION: Elevated serum androgen levels are commonly observed in patients with PCOS and are associated with multiple metabolic abnormalities. Therefore, it is recommended to regularly monitor glucose and lipid metabolism-related indicators in patients with PCOS who have elevated androgen levels.

Hyperandrogenic environment regulates the function of ovarian granulosa cells by modulating macrophage polarization in PCOS.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder characterized by oligo-anovulation, hyperandrogenism, and polycystic ovaries, with hyperandrogenism being the most prominent feature of PCOS patients. However, whether excessive androgens also exist in the ovarian microenvironment of patients with PCOS, and their modulatory role on ovarian immune homeostasis and ovarian function, is not clear. METHODS: Follicular fluid samples from patients participating in their first in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment were collected. Androgen concentration of follicular fluid was assayed by chemiluminescence, and the macrophage M1:M2 ratio was detected by flow cytometry. In an in vitro model, we examined the regulatory effects of different concentrations of androgen on macrophage differentiation and glucose metabolism levels using qRT-PCR, Simple Western and multi-factor flow cytometry assay. In a co-culture model, we assessed the effect of a hyperandrogenic environment in the presence or absence of macrophages on the function of granulosa cells using qRT-PCR, Simple Western, EdU assay, cell cycle assay, and multi-factor flow cytometry assay. RESULTS: The results showed that a significantly higher androgen level and M1:M2 ratio in the follicular fluid of PCOS patients with hyperandrogenism. The hyperandrogenic environment promoted the expression of pro-inflammatory and glycolysis-related molecules and inhibited the expression of anti-inflammatory and oxidative phosphorylation-related molecules in macrophages. In the presence of macrophages, a hyperandrogenic environment significantly downregulated the function of granulosa cells. CONCLUSION: There is a hyperandrogenic microenvironment in the ovary of PCOS patients with hyperandrogenism. Hyperandrogenic microenvironment can promote the activation of ovarian macrophages to M1, which may be associated with the reprogramming of macrophage glucose metabolism. The increased secretion of pro-inflammatory cytokines by macrophages in the hyperandrogenic microenvironment would impair the normal function of granulosa cells and interfere with normal ovarian follicle growth and development.

Metabolic landscape and pathogenic insights: a comprehensive analysis of high ovarian response in infertile women undergoing in vitro fertilization.

BACKGROUND: In the realm of assisted reproduction, a subset of infertile patients demonstrates high ovarian response following controlled ovarian stimulation (COS), with approximately 29.7% facing the risk of Ovarian Hyperstimulation Syndrome (OHSS). Management of OHSS risk often necessitates embryo transfer cancellation, leading to delayed prospects of successful pregnancy and significant psychological distress. Regrettably, these patients have received limited research attention, particularly regarding their metabolic profile. In this study, we aim to utilize gas chromatography-mass spectrometry (GC-MS) to reveal these patients' unique serum metabolic profiles and provide insights into the disease's pathogenesis. METHODS: We categorized 145 infertile women into two main groups: the CON infertility group from tubal infertility patients and the Polycystic Ovary Syndrome (PCOS) infertility group. Within these groups, we further subdivided them into four categories: patients with normal ovarian response (CON-NOR group), patients with high ovarian response and at risk for OHSS (CON-HOR group) within the CON group, as well as patients with normal ovarian response (PCOS-NOR group) and patients with high ovarian response and at risk for OHSS (PCOS-HOR group) within the PCOS group. Serum metabolic profiles were analyzed using GC-MS. The risk criteria for OHSS were: the number of developing follicles > 20, peak Estradiol (E2) > 4000pg/mL, and Anti-Müllerian Hormone (AMH) levels > 4.5ng/mL. RESULTS: The serum metabolomics analysis revealed four different metabolites within the CON group and 14 within the PCOS group. Remarkably, 10-pentadecenoic acid emerged as a discernible risk metabolite for the CON-HOR, also found to be a differential metabolite between CON-NOR and PCOS groups. cysteine and 5-methoxytryptamine were also identified as risk metabolites for the PCOS-HOR. Furthermore, KEGG analysis unveiled significant enrichment of the aminoacyl-tRNA biosynthesis pathway among the metabolites differing between PCOS-NOR and PCOS-HOR. CONCLUSION: Our study highlights significant metabolite differences between patients with normal ovarian response and those with high ovarian response and at risk for OHSS within both the tubal infertility control group and PCOS infertility group. Importantly, we observe metabolic similarities between patients with PCOS and those with a high ovarian response but without PCOS, suggesting potential parallels in their underlying causes.

Correlation between anti-mullerian hormone with insulin resistance in polycystic ovarian syndrome: a systematic review and meta-analysis.

BACKGROUND: Epidemiological studies regarding the correlation between anti-Müllerian hormone (AMH) and insulin resistance (IR) in polycystic ovarian syndrome (PCOS) remain inconsistent. The primary aim of this study was to determine the correlations between AMH and IR in patients with PCOS and to explore the selected factors that influence the correlations. METHODS: We conducted systemic searches of online databases (PubMed, Science Direct, Taylor and Francis, Scopus, and ProQuest) from inception to December 20, 2023 and manual searches of the associated bibliographies to identify relevant studies. We then performed subgroup and sensitivity analyses to explore the sources of heterogeneity, followed by a publication bias risk assessment of the included studies using the Joanna Briggs Institute critical appraisal tool. We used a random-effects model to estimate the pooled correlations between AMH and the homeostatic model assessment for insulin resistance (HOMA-IR) in patients with polycystic ovarian syndrome (PCOS). RESULTS: Of the 4835 articles identified, 22 eligible relevant studies from three regions were included and identified as low risk of bias. The random-effects pooled correlation estimate was 0.089 (95% confidence interval [CI]: -0.040, 0.215), with substantial heterogeneity (I2 = 87%; τ2 = 0.0475, p < .001). Subgroup analyses showed that the study region did not influence the correlation estimates, and sensitivity analysis showed no significant alteration in the pooled correlation estimate or 95% CI values. No publication bias was observed. CONCLUSION: There was a weak, statistically insignificant correlation between AMH and HOMA-IR in patients with PCOS. The correlation estimates did not vary according to the study participants' regions.

Apelin receptor modulation mitigates letrozole-induced polycystic ovarian pathogenesis in mice.

AIMS: Polycystic ovarian syndrome (PCOS) is one of the most common (about 5-20%) reproductive disorders in women of reproductive age; it is characterized by polycystic ovaries, hyperandrogenism, and oligo/ anovulation. The levels and expression of ovarian adipokines are deregulated in the PCOS. Apelin is an adipokine that acts through its receptor (APJ) and is known to express in the various tissues including the ovary. It has also been suggested that apelin and APJ could be targeted as therapeutic adjuncts for the management of PCOS. However, no study has been conducted on the management of PCOS by targeting the apelin system. Thus, we aimed to evaluate its impact on combating PCOS-associated ovarian pathogenesis. METHODS: The current work employed a letrozole-induced-hyperandrogenism PCOS-like mice model to investigate the effects of apelin13 and APJ, antagonist ML221. The PCOS model was induced by oral administration of letrozole (1 mg/kg) for 21 days. A total of four experimental groups were made, control, PCOS control, PCOS + aplein13, and PCOS + ML221. The treatment of apelin13 and ML221 was given from day 22 for two weeks. KEY FINDINGS: The letrozole-induced PCOS-like features such as hyperandrogenism, cystic follicle, decreased corpus luteum, elevated levels of LH/FSH ratio, and up-regulation of ovarian AR expression were ameliorated by apelin13 and ML221 treatment. However, the PCOS-augmented oxidative stress and apoptosis were suppressed by apelin 13 treatments only. ML221 treatment still showed elevated oxidative stress and stimulated apoptosis as reflected by decreased antioxidant enzymes and increased active caspase3 and Bax expression. The expression of ERs was elevated in all groups except control. Furthermore, the PCOS model showed elevated expression of APJ and apelin13 treatment down-regulated its own receptor. Overall, observing the ovarian histology, corpus luteum formation, and decreased androgen levels by both apelin13 and ML221 showed ameliorative effects on the cystic ovary. SIGNIFICANCE: Despite the similar morphological observation of ovarian histology, apelin13 and ML221 exhibited opposite effects on oxidative stress and apoptosis. Therefore, apelin13 (which down-regulates APJ) and ML221 (an APJ antagonist) may have suppressed APJ signalling, which would account for our findings on the mitigation of polycystic ovarian syndrome. In conclusion, both apelin13 and ML221 mediated mitigation have different mechanisms, which need further investigation.

A Cross-Sectional Study of Glomerular Hyperfiltration in Polycystic Ovary Syndrome.

Glomerular hyperfiltration (GH) has been reported to be higher in women with polycystic ovary syndrome (PCOS) and is an independent risk factor for renal function deterioration, metabolic, and cardiovascular disease. The aim of this study was to determine GH in type A PCOS subjects and to identify whether inflammatory markers, markers of CKD, renal tubule injury markers, and complement system proteins were associated. In addition, a secondary cohort study was performed to determine if the eGFR had altered over time. In this comparative cross-sectional analysis, demographic, metabolic, and proteomic data from Caucasian women aged 18-40 years from a PCOS Biobank (137 with PCOS, 97 controls) was analyzed. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was undertaken for inflammatory proteins, serum markers of chronic kidney disease (CKD), tubular renal injury markers, and complement system proteins. A total of 44.5% of the PCOS cohort had GH (eGFR ≥ 126 mL/min/1.73 m2 (n = 55)), and 12% (n = 17) eGFR ≥ 142 mL/min/1.73 m2 (super-GH(SGH)). PCOS-GH women were younger and had lower creatinine and urea versus PCOS-nonGH. C-reactive protein (CRP), white cell count (WCC), and systolic blood pressure (SBP) were higher in PCOS versus controls, but CRP correlated only with PCOS-SGH alone. Complement protein changes were seen between controls and PCOS-nonGH, and decay-accelerator factor (DAF) was decreased between PCOS-nonGH and PCOS-GSGH (p < 0.05). CRP correlated with eGFR in the PCOS-SGH group, but not with other inflammatory or complement parameters. Cystatin-c (a marker of CKD) was reduced between PCOS-nonGH and PCOS-GSGH (p < 0.05). No differences in tubular renal injury markers were found. A secondary cohort notes review of the biobank subjects 8.2-9.6 years later showed a reduction in eGFR: controls -6.4 ± 12.6 mL/min/1.73 m2 (-5.3 ± 11.5%; decrease 0.65%/year); PCOS-nonGH -11.3 ± 13.7 mL/min/1.73 m2 (-9.7 ± 12.2%; p < 0.05, decrease 1%/year); PCOS-GH (eGFR 126-140 mL/min/17.3 m2) -27.1 ± 12.8 mL/min/1.73 m2 (-19.1 ± 8.7%; p < 0.0001, decrease 2%/year); PCOS-SGH (eGFR ≥ 142 mL/min/17.3 m2) -33.7 ± 8.9 mL/min/17.3 m2 (-22.8 ± 6.0%; p < 0.0001, decrease 3.5%/year); PCOS-nonGH eGFR versus PCOS-GH and PCOS-SGH, p < 0.001; no difference PCOS-GH versus PCOS-SGH. GH was associated with PCOS and did not appear mediated through tubular renal injury; however, cystatin-c and DAF were decreased, and CRP correlated positively with PCOS-SGH, suggesting inflammation may be involved at higher GH. There were progressive eGFR decrements for PCOS-nonGH, PCOS-GH, and PCOS-SGH in the follow-up period which, in the presence of additional factors affecting renal function, may be clinically important in the development of CKD in PCOS.

Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients.

Decidualisation, the process whereby endometrial stromal cells undergo morphological and functional transformation in preparation for trophoblast invasion, is often disrupted in women with polycystic ovary syndrome (PCOS) resulting in complications with pregnancy and/or infertility. The transcription factor Wilms tumour suppressor 1 (WT1) is a key regulator of the decidualization process, which is reduced in patients with PCOS, a complex condition characterized by increased expression of androgen receptor in endometrial cells and high presence of circulating androgens. Using genome-wide chromatin immunoprecipitation approaches on primary human endometrial stromal cells, we identify key genes regulated by WT1 during decidualization, including homeobox transcription factors which are important for regulating cell differentiation. Furthermore, we found that AR in PCOS patients binds to the same DNA regions as WT1 in samples from healthy endometrium, suggesting dysregulation of genes important to decidualisation pathways in PCOS endometrium due to competitive binding between WT1 and AR. Integrating RNA-seq and H3K4me3 and H3K27ac ChIP-seq metadata with our WT1/AR data, we identified a number of key genes involved in immune response and angiogenesis pathways that are dysregulated in PCOS patients. This is likely due to epigenetic alterations at distal enhancer regions allowing AR to recruit cofactors such as MAGEA11, and demonstrates the consequences of AR disruption of WT1 in PCOS endometrium.

Acetate ameliorates ovarian mitochondrial dysfunction in letrozole-induced polycystic ovarian syndrome rat model by improving mitofusin-2.

Androgen excess and metabolic abnormality largely contribute to the pathogenesis of polycystic ovarian syndrome (PCOS), which primarily precipitates ovarian dysfunction and infertility in reproductive-age women. Impaired mitochondrial function and epigenetic alteration have been linked to the development of PCOS. However, it is unknown whether acetate would exert a therapeutic effect on ovarian mitochondrial dysfunction in PCOS. Herein, the study hypothesized that acetate reverses ovarian mitochondrial dysfunction in experimental PCOS rat model, possibly through modulation of mitofusin-2 (MFn2). Eight-week-old female Wistar rats were randomized into four groups (n = 5). Induction of PCOS was performed by 1 mg/kg letrozole (p.o.), administered for 21 days. Thereafter, the rats were treated with acetate (200 mg/kg; p.o.) for 6 weeks. The PCOS rats demonstrated androgen excess, multiple ovarian cysts, elevated anti-mullerian hormone and leptin and decreased SHBG, adiponectin and 17-ß estradiol with corresponding increase in ovarian transforming growth factor-ß1. Additionally, inflammation (tumor growth factor and nuclear factor-kB), elevated caspase-6, decreased hypoxia-inducible factor-1α and elevated histone deacetylase-2 (HDAC2) were observed in the ovaries of PCOS rats, while mitochondrial abnormality with evidence of decreased adenosine triphosphate synthase and MFn2 was observed in rats with PCOS. Treatment with acetate reversed the alterations. The present results collectively suggest that acetate ameliorates ovarian mitochondrial abnormality, a beneficial effect that is accompanied by MFn2 with consequent normalization of reproductive-endocrine profile and ovarian function. Perhaps, the present data provide hope for PCOS individuals that suffer infertility.

Assessing the clinical diagnostic value of anti-Müllerian hormone in polycystic ovarian syndrome and its correlation with clinical and metabolism indicators.

BACKGROUND: This study investigated the association between Anti-Müllerian Hormone (AMH) and relevant metabolic parameters and assessed its predictive value in the clinical diagnosis of polycystic ovarian syndrome (PCOS). METHODS: A total of 421 women aged 20-37 years were allocated to the PCOS (n = 168) and control (n = 253) groups, and their metabolic and hormonal parameters were compared. Spearman correlation analysis was conducted to investigate associations, binary logistic regression was used to determine PCOS risk factors, and receiver operating characteristic (ROC) curves were generated to evaluate the predictive value of AMH in diagnosing PCOS. RESULTS: The PCOS group demonstrated significantly higher blood lipid, luteinizing hormone (LH), and AMH levels than the control group. Glucose and lipid metabolism and hormonal disorders in the PCOS group were more significant than in the control group among individuals with and without obesity. LH, TSTO, and AMH were identified as independent risk factors for PCOS. AMH along with LH, and antral follicle count demonstrated a high predictive value for diagnosing PCOS. CONCLUSION: AMH exhibited robust diagnostic use for identifying PCOS and could be considered a marker for screening PCOS to improve PCOS diagnostic accuracy. Attention should be paid to the effect of glucose and lipid metabolism on the hormonal and related parameters of PCOS populations.

Validation of mitochondrial biomarkers and immune dynamics in polycystic ovary syndrome.

PROBLEM: Polycystic ovary syndrome (PCOS), a prevalent endocrine-metabolic disorder, presents considerable therapeutic challenges due to its complex and elusive pathophysiology. METHOD OF STUDY: We employed three machine learning algorithms to identify potential biomarkers within a training dataset, comprising GSE138518, GSE155489, and GSE193123. The diagnostic accuracy of these biomarkers was rigorously evaluated using a validation dataset using area under the curve (AUC) metrics. Further validation in clinical samples was conducted using PCR and immunofluorescence techniques. Additionally, we investigate the complex interplay among immune cells in PCOS using CIBERSORT to uncover the relationships between the identified biomarkers and various immune cell types. RESULTS: Our analysis identified ACSS2, LPIN1, and NR4A1 as key mitochondria-related biomarkers associated with PCOS. A notable difference was observed in the immune microenvironment between PCOS patients and healthy controls. In particular, LPIN1 exhibited a positive correlation with resting mast cells, whereas NR4A1 demonstrated a negative correlation with monocytes in PCOS patients. CONCLUSION: ACSS2, LPIN1, and NR4A1 emerge as PCOS-related diagnostic biomarkers and potential intervention targets, opening new avenues for the diagnosis and management of PCOS.

Evaluating the therapeutic potential of moxibustion on polycystic ovary syndrome: a rat model study on gut microbiota and metabolite interaction.

Polycystic ovary syndrome (PCOS) is a common systemic disorder related to endocrine disorders, affecting the fertility of women of childbearing age. It is associated with glucose and lipid metabolism disorders, altered gut microbiota, and insulin resistance. Modern treatments like pioglitazone, metformin, and spironolactone target specific symptoms of PCOS, while in Chinese medicine, moxibustion is a common treatment. This study explores moxibustion's impact on PCOS by establishing a dehydroepiandrosterone (DHEA)-induced PCOS rat model. Thirty-six specific pathogen-free female Sprague-Dawley rats were divided into four groups: a normal control group (CTRL), a PCOS model group (PCOS), a moxibustion treatment group (MBT), and a metformin treatment group (MET). The MBT rats received moxibustion, and the MET rats underwent metformin gavage for two weeks. We evaluated ovarian tissue changes, serum testosterone, fasting blood glucose (FBG), and fasting insulin levels. Additionally, we calculated the insulin sensitivity index (ISI) and the homeostasis model assessment of insulin resistance index (HOMA-IR). We used 16S rDNA sequencing for assessing the gut microbiota, 1H NMR spectroscopy for evaluating metabolic changes, and Spearman correlation analysis for investigating the associations between metabolites and gut microbiota composition. The results indicate that moxibustion therapy significantly ameliorated ovarian dysfunction and insulin resistance in DHEA-induced PCOS rats. We observed marked differences in the composition of gut microbiota and the spectrum of fecal metabolic products between CTRL and PCOS rats. Intriguingly, following moxibustion intervention, these differences were largely diminished, demonstrating the regulatory effect of moxibustion on gut microbiota. Specifically, moxibustion altered the gut microbiota by increasing the abundance of UCG-005 and Turicibacter, as well as decreasing the abundance of Desulfovibrio. Concurrently, we also noted that moxibustion promoted an increase in levels of short-chain fatty acids (including acetate, propionate, and butyrate) associated with the gut microbiota of PCOS rats, further emphasizing its positive impact on gut microbes. Additionally, moxibustion also exhibited effects in lowering FBG, testosterone, and fasting insulin levels, which are key biochemical indicators associated with PCOS and insulin resistance. Therefore, these findings suggest that moxibustion could alleviate DHEA-induced PCOS by regulating metabolic levels, restoring balance in gut microbiota, and modulating interactions between gut microbiota and host metabolites.

Fuzzy machine learning logic utilization on hormonal imbalance dataset.

In this research work, a novel fuzzy data transformation technique has been proposed and applied to the hormonal imbalance dataset. Hormonal imbalance is ubiquitously found principally in females of reproductive age which ultimately leads to numerous related medical conditions. Polycystic Ovary Syndrome (PCOS) is one of them. Treatment along with adopting a healthy lifestyle is advised to mitigate its consequences on the quality of life. The biological dataset of hormonal imbalance "PCOS" provides limited results that is whether the syndrome is present or not. Also, there are input variables that contain binary responses only, to deal with this conundrum, a novel fuzzy data transformation technique has been developed and applied to them thus leading to their fuzzy transformation which provides a broader spectrum to diagnose PCOS. Due to this, the output variable has also been transformed. Hence, a novel fuzzy transformation technique has been employed due to the limitation of the dataset leading to the transition of binary classification output into three classes. An adaptive fuzzy machine learning logic model is developed in which the inference of the transformed biological dataset is performed by the machine learning techniques that provide the fuzzy output. Machine learning techniques have also been applied to the untransformed biological dataset. Both implementations have been compared by computation of the relevant metrics. Machine learning employment on untransformed biological dataset provides limited results whether the syndrome is present or absent however machine learning on fuzzy transformed biological dataset provides a broader spectrum of diagnosis consisting of a third class depicting that PCOS might be present which would ultimately alert a patient to take preventive measures to minimize the chances of syndrome development in future.

Assessment of the Effect of Leonurine Hydrochloride in a Mouse Model of PCOS by Gene Expression Profiling.

Polycystic ovary syndrome (PCOS) is an endocrine disease commonly associated with metabolic disorders in females. Leonurine hydrochloride (Leo) plays an important role in regulating immunity, tumours, uterine smooth muscle, and ovarian function. However, the effect of Leo on PCOS has not been reported. Here, we used dehydroepiandrosterone to establish a mouse model of PCOS, and some mice were then treated with Leo by gavage. We found that Leo could improve the irregular oestros cycle of PCOS mice, reverse the significantly greater serum testosterone (T) and luteinising hormone (LH) levels, significantly reduce the follicle-stimulating hormone (FSH) level, and significantly increase the LH/FSH ratio of PCOS mice. Leo could also change the phenomenon of ovaries in PCOS mice presented with cystic follicular multiplication and a lacking corpus luteum. Transcriptome analysis identified 177 differentially expressed genes related to follicular development between the model and Leo groups. Notably, the cAMP signalling pathway, neuroactive ligand-receptor interactions, the calcium signalling pathway, the ovarian steroidogenesis pathway, and the Lhcgr, Star, Cyp11a, Hsd17b7, Camk2b, Calml4, and Phkg1 genes may be most related to improvements in hormone levels and the numbers of ovarian cystic follicles and corpora lutea in PCOS mice treated by Leo, which provides a reference for further study of the mechanism of Leo.

Effects of quercetin on polycystic ovary syndrome in animal models: a systematic review and meta-analysis.

BACKGROUND: Metformin is an insulin sensitizer that is widely used for the treatment of insulin resistance in polycystic ovary syndrome patients. However, metformin can cause gastrointestinal side effects. PURPOSE: This study showed that the effects of quercetin are comparable to those of metformin. Therefore, this study aimed to systematically evaluate the efficacy of quercetin in treating PCOS. METHODS: The present systematic search of the Chinese National Knowledge Infrastructure (CNKI), Wanfang Data Information Site, Chinese Scientific Journals Database (VIP), SinoMed, Web of Science, and PubMed databases was performed from inception until February 2024. The methodological quality was then assessed by SYRCLE's risk of bias tool, and the data were analyzed by RevMan 5.3 software. RESULTS: Ten studies were included in the meta-analysis. Compared with those in the model group, quercetin in the PCOS group had significant effects on reducing fasting insulin serum (FIS) levels (P = 0.0004), fasting blood glucose (FBG) levels (P = 0.01), HOMA-IR levels (P < 0.00001), cholesterol levels (P < 0.0001), triglyceride levels (P = 0.001), testosterone (T) levels (P < 0.00001), luteinizing hormone (LH) levels (P = 0.0003), the luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio (P = 0.01), vascular endothelial growth factor (VEGF) levels (P < 0.00001), malondialdehyde (MDA) levels (P = 0.03), superoxide dismutase (SOD) levels (P = 0.01) and GLUT4 mRNA expression (P < 0.00001). CONCLUSION: This meta-analysis suggested that quercetin has positive effects on PCOS treatment. Quercetin can systematically reduce insulin, blood glucose, cholesterol, and triglyceride levels in metabolic pathways. In the endocrine pathway, quercetin can regulate the function of the pituitary-ovarian axis, reduce testosterone and luteinizing hormone (LH) levels, and lower the ratio of LH to follicle-stimulating hormone (FSH). Quercetin can regulate the expression of the GLUT4 gene and has antioxidative effects at the molecular level.

Circulating levels of irisin and Meteorin-like protein in PCOS and its correlation with metabolic parameters.

INTRODUCTION: Research on obesity, which results from excessive food consumption and sedentary lifestyle, has focused on increasing energy expenditure. Recently, muscle tissue is being investigated as an endocrine active organ, secreting molecules called myokines. Multiple studies have been performed to assess myokine levels in various disorders, including polycystic ovary syndrome (PCOS) and metabolic syndrome. Irisin and Meteorin-like protein (Metrnl) are particles which, among others, are suggested to play an important role in adipose tissue browning and improving insulin sensitivity. MATERIAL AND METHODS: The study population consisted of 31 women with PCOS and 18 healthy individuals. PCOS was diagnosed based on revised 2003 Rotterdam criteria. Multiple anthropometrical, hormonal, and biochemical parameters were assessed, including oral glucose tolerance test and body composition with dual energy X-ray absorptiometry. Serum levels of irisin and Metrnl were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: There were no differences between the PCOS and control groups according to age, body mass index (BMI), waist-to-hip ratio (WHR), fasting glucose, homeostasis model assessment of insulin resistance (HOMA-IR), or body mass composition. Assessment of Metrnl and irisin concentrations revealed no significant differences between PCOS and healthy women. The irisin level was negatively correlated with BMI, body fat mass, fasting glucose, and insulin concentrations. No relationship between Metrnl level and metabolic parameters was found. CONCLUSIONS: Although irisin seems to be a promising biomarker, inconsistent research limits its value in clinical use in the assessment or treatment of obesity. Metrnl level was not affected in the study population, but it might be connected to the severity of metabolic disturbances.

Tenascin C activates the toll­like receptor 4/NF­κB signaling pathway to promote the development of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a globally prevalent gynecological disorder among women of childbearing age. The present study aimed to investigate the role of tenascin C (TNC) in PCOS and its potential mechanisms. Fasting blood glucose and serum insulin, the homeostasis model assessment of insulin resistance and the serum hormone levels were determined in PCOS rats. In addition, H&E staining was used for assessing pathology. In addition, the effects of TNC on oxidative stress and inflammation response in PCOS rat and cell models was assessed. Furthermore, the roles of TNC on KGN cell proliferation and apoptosis were determined employing EdU assay and flow cytometry. TLR4/NF­κB pathway­related proteins were measured using western blotting, immunofluorescence and immunohistochemistry. It was found that the mRNA and protein expression was upregulated in PCOS rats and in KGN cells induced by dihydrotestosterone (DHT). Knockdown of TNC relieved the pathological characteristics and the endocrine abnormalities of PCOS rats. Knockdown of TNC inhibited ovarian cell apoptosis, oxidative stress and inflammation in PCOS rats. Knockdown of TNC reversed the DHT­induced reduction in cell proliferation and increase in apoptosis in KGN cells. Furthermore, knockdown of TNC alleviated oxidative stress and inflammatory responses induced by DHT in KGN cells. Additionally, knockdown of TNC inhibited the toll­like receptor 4 (TLR4)/NF­κB signaling pathway in PCOS rats and DHT­treated KGN cells. In conclusion, knockdown of TNC could ameliorate PCOS in both rats and a cell model by inhibiting cell apoptosis, oxidative stress and inflammation via the suppression of the TLR4/NF­κB signaling pathway.