Mendelian randomization analyses for PCOS: evidence, opportunities, and challenges.

Identifying etiological risk factors is significant for preventing and treating patients with polycystic ovary syndrome (PCOS). Through genetic variation, Mendelian randomization (MR) assesses causal associations between PCOS risk and related exposure factors. This emerging technology has provided evidence of causal associations of anti-Müllerian hormone (AMH) levels, sex hormone-binding globulin (SHBG) levels, menopause age, adiposity, insulin resistance (IR), depression, breast cancer, ovarian cancer, obsessive-compulsive disorder (OCD), and forced vital capacity (FVC) with PCOS, while lacking associations of type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), stroke, anxiety disorder (AD), schizophrenia (SCZ), bipolar disorder (BIP), and offspring birth weight with PCOS. In this review, we briefly introduce the concept and methodology of MR in terms of the opportunities and challenges in this field based on recent results obtained from MR analyses involving PCOS.

Elevated serum uric acid level is associated with adverse reproductive outcomes in women with polycystic ovary syndrome undergoing in vitro fertilization or intracytoplasmic sperm injection embryo transfer cycles: a retrospective cohort study.

BACKGROUND: Serum uric acid levels are elevated in polycystic ovary syndrome, however, the relationship between serum uric acid level and reproductive outcomes in women with polycystic ovary syndrome remains unclear. OBJECTIVE: This study aimed to investigate the association between serum uric acid level and the reproductive outcomes in women with polycystic ovary syndrome undergoing in vitro fertilization or intracytoplasmic sperm injection embryo transfer cycles. STUDY DESIGN: This was a retrospective cohort study performed at a university-affiliated reproductive medicine center. A total of 1903 women with polycystic ovary syndrome undergoing their first in vitro fertilization or intracytoplasmic sperm injection embryo transfer cycles between January 2010 and January 2021 were initially included. The trends for reproductive outcomes in polycystic ovary syndrome across quartiles of serum uric acid levels were assessed. A logistic regression analysis was performed to obtain the odds ratios for in vitro fertilization outcomes based on the quartiles of serum uric acid with or without adjusting for potential confounding variables. Using generalized additive models, serum uric acid was further treated as its original continuous property to visualize its nonlinear relationship with in vitro fertilization outcomes. The live birth rate was the main outcome. RESULTS: After exclusions, a total of 883 women with polycystic ovary syndrome with their first fresh-embryo transfer cycles were included. In quartiles of serum uric acid levels, there was a significant decreasing trend in the live birth rate from the lowest quartile (Q1: 61.8%) to the highest (Q4: 45.9%) (Ptrend=.002). The percentage of low birthweight increased from Q1 (22.3%) to Q4 (31.7%) (Ptrend=.049). Compared with those in Q1, women in Q4 showed a significant lower probability of live birth and clinical pregnancy and a higher risk for low birthweight (all P<.05). Both the unadjusted and adjusted generalized additive models indicated that as the serum uric acid level increased, the probability of clinical pregnancy and the live birth rate exhibited an overall decreasing profile, and the risk for low birthweight showed an increasing profile. CONCLUSION: An elevated serum uric acid level is associated with decreased probabilities of live birth and clinical pregnancy and an increased risk for low birthweight in women with polycystic ovary syndrome. However, these associations may be confounded by other factors and more well-designed studies are needed to confirm these findings in the future.

Advances in clinical applications of kisspeptin-GnRH pathway in female reproduction.

BACKGROUND: 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. MAIN TEXT: 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. CONCLUSION: 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.

Non-coding RNAs in polycystic ovary syndrome: a systematic review and meta-analysis.

BACKGROUND: Genetic, environmental and epigenetical factors may play important roles in the pathogenesis of polycystic ovary syndrome (PCOS), however the etiology of PCOS remains unclear. Studies indicated that non-coding RNAs (ncRNAs) were involved in the occurrence and development of PCOS. Thus, we aim to perform a systematic review and meta-analysis to investigate the presence and dysregulated expression of ncRNAs in human PCOS. METHODS: We searched in PubMed, Medline, Web of Science and Embase until July 2019 and summarized all eligible publications focusing on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and small interfering RNAs (siRNAs) in PCOS. RESULTS: Sixty-seven articles were included in our systematic review and 9 articles were included in meta-analysis. There is little overlap between studies when comparing miRNA profiles. Sensitivity analysis showed that the expression of miR-93 was upregulated in PCOS patients (WMD 0.75, P < 0.00001), without heterogeneity among remaining studies (I2 = 0%). CONCLUSION: A large number of ncRNAs with altered levels were observed in plasma, serum, follicular fluid, granulosa cells or other issues from PCOS patients. Aberrant ncRNAs expression in PCOS may lead to aberrant steroidogenesis, adipocyte dysfunction, altered ovarian cell proliferation and/or apoptosis and have the potential to be used as diagnostic biomarkers.

Uric acid participating in female reproductive disorders: a review.

Uric acid (UA) is the end metabolic product of purine metabolism. Early on, UA was considered to be a metabolite with a certain antioxidant capacity. As research has progressed, other properties of UA have been explored, and its association with many diseases has been found. The association between UA and kidney disease and cardiovascular disease is well established; however, there is still a paucity of reviews on the association between UA and the female reproductive system. An increasing number of epidemiological studies have shown elevated serum UA levels in patients with polycystic ovary syndrome (PCOS), endometriosis, etc. Additionally, serum UA can be used as a predictor of pregnancy complications and adverse foetal outcomes. An increasing number of animal experiments and clinical studies have revealed possible mechanisms related to the involvement of UA in certain female reproductive disorders: oxidative stress, chronic inflammation, mitochondrial dysfunction, etc. This article reviews the current mainstream mechanisms regarding the pathogenesis of UA and the role of UA in certain specific female reproductive disorders (direct involvement in the development of certain diseases or enhancement of other risk factors) in the hope of contributing to clinical prevention, diagnosis, treatment and improvement in prognosis.

MATERNAL THYROID-STIMULATING HORMONE LEVEL IN THE FIRST TRIMESTER AND SEX RATIO AT BIRTH.

Objective: Few studies have explored the influence of thyroid status on sex ratio at birth, and conclusions are inconsistent. The aim of this study was to determine if there is an association between serum thyroid-stimulating hormone (TSH) level in first trimester and sex ratio at birth. Methods: The study was a retrospective cohort study performed at a tertiary care center. From March 2014 to February 2017, a total of 4,822 women who had thyroid function testing during the first trimester were included. Study population was divided into five groups according to quintile of TSH level (≤0.60 mIU/L; 0.61 to 1.02 mIU/L; 1.03 to 1.44 mIU/L; 1.45 to 2.13 mIU/L; and ≥2.14 mIU/L). Logistic regression analysis was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of the percentage of male infants across the quintiles, with the lowest quintile as the reference category. Results: Median level of TSH was 1.27 mIU/L in women who delivered a boy, which was significantly higher than that in women who delivered a girl (1.15 mIU/L). After adjusting for age, gravidity, and parity, multivariate logistic analysis found that women in quintiles 3, 4, and 5 all showed significantly higher ORs for delivering a boy than those in quintile 1. In addition, after adjusting for age, gravidity, and parity, serum TSH was significantly associated with likelihood of having a boy (OR, 1.08; 95% CI, 1.03 to 1.13). Conclusion: Maternal TSH level in the first trimester is positively associated with the probability of delivering a male newborn. Abbreviations: CI = confidence interval; FT3 = free triiodothyronine; FT4 = free thyroxine; OR = odd ratio; SRB = sex ratio at birth; TBG = thyroxin-binding globulin; TSH = thyroid-stimulating hormone.

Insulin resistance and ß-cell dysfunction and the relationship with cardio-metabolic disorders among women with polycystic ovary syndrome.

OBJECTIVE: To investigate both independent and combined effects of insulin resistance and ß-cell dysfunction on cardio-metabolic abnormalities in polycystic ovary syndrome (PCOS). DESIGN: A national epidemiologic survey was performed in reproductive aged females in China from October 2007 to September 2011. METHODS: A total of 824 PCOS and 2715 non-PCOS were included. The Rotterdam Criteria were applied for PCOS diagnosis. We used the homeostasis model assessment of insulin resistance (HOMA-IR) and HOMA of ß-cell function (HOMA-ß) to evaluate insulin resistance and ß-cell dysfunction, respectively. RESULTS: Compared with non-PCOS, PCOS showed a higher index of HOMA-IR and HOMA-ß, and a higher prevalence of obesity, central obesity, and dyslipidaemia. High HOMA-IR was independently related to a high prevalence of obesity, central obesity, dyslipidaemia, and high blood glucose in PCOS. In contrast, a low index of HOMA-ß index was independently correlated with a low prevalence of obesity, and central obesity, but negatively correlated with an elevated prevalence of high blood glucose in PCOS. In addition, proportion of insulin resistance was higher than that of ß-cell dysfunction in PCOS with cardio-metabolic disorders. ß-cell dysfunction was negatively correlated with the prevalence of central obesity and obesity. CONCLUSIONS: Insulin resistance and ß-cell dysfunction independently affected cardio-metabolic abnormalities in PCOS, while insulin resistance was correlated with a higher prevalence of cardio-metabolic abnormalities than that of ß-cell dysfunction. Moreover, ß-cell dysfunction and insulin resistance showed divergent correlations with obesity in PCOS.

Association between the prevalence of hyperuricemia and reproductive hormones in polycystic ovary syndrome.

BACKGROUND: The prevalecne of hyperuricemia in polycystic ovary syndrome (PCOS) is still uncertain. We aimed to investigate the prevalence of hyperuricemia in PCOS and to determine the influence of reproductive hormones on uric acid concentration. METHODS: This retrospective cross-sectional study was performed at a large reproductive medicine center. Between March 2007 and October 2016, a total of 1,183 women with PCOS and 10,772 women without PCOS were included. PCOS was diagnosed according to the Rotterdam criteria. Anthropometric parameters, blood pressure, uric acid, reproductive hormones, glucose and lipids were measured in all subjects. RESULTS: The serum uric acid (SUA) level was higher in women with PCOS than in women without PCOS. The prevalence of hyperuricemia in women with PCOS (25.48%) was significantly higher than that in women without PCOS (8.74%). Analysis stratified for age and body mass index (BMI) showed that both the SUA level and the prevalence of hyperuricemia were higher in women with PCOS of different age and BMI groups than in women without PCOS. After adjusting for age, BMI and estimated glomerular filtration rate (eGFR), logistic regression analysis revealed that the luteinizing/follicle-stimulating hormone (LH/FSH) ratio (odds ratio (OR) = 1.20, 95% CI = 1.01-1.43) and testosterone level (OR = 1.56, 95% CI = 1.27-1.90) were positively associated with the prevalence of hyperuricemia in females with PCOS. CONCLUSIONS: The serum uric acid (SUA) level and the prevalence of hyperuricemia markedly increased in women with PCOS. The testosterone level was positively associated with the SUA level and the prevalence of hyperuricemia in females with PCOS.

Metabolic characteristics of normal weight central obesity phenotype polycystic ovary syndrome women: a large-scale national epidemiological survey.

RESEARCH QUESTION: The aim was to investigate the metabolic profiles of women with normal weight but central obesity in polycystic ovary syndrome (PCOS). DESIGN: In total, 727 women with PCOS from a large-scale epidemiological survey were included. Diagnosis of PCOS was based on Rotterdam criteria. Subjects were categorized into four subgroups: (i) normal weight non-central obesity (NWNCO): body mass index (BMI) ≤18.5 kg/m2 to <25 kg/m2 and waist-to-hip ratio (WHR) <0.85; (ii) normal weight central obesity (NWCO): BMI ≤18.5 kg/m2 to <25 kg/m2 and WHR ≥0.85; (iii) obese non-central obesity (ONCO): BMI ≥25 kg/m2 and WHR <0.85; and (iv) obese central obesity (OCO): BMI ≥25 kg/m2 and WHR ≥0.85. BMI, WHR, blood pressure, glucose and lipid profiles were measured. RESULTS: NWCO subjects had significantly higher percentages of insulin resistance, high triglycerides and low high-density lipoprotein cholesterol (HDL-C) than NWNCO subjects (all P < 0.05), and similar percentages compared with ONCO subjects. Compared with the NWNCO group, the NWCO group had higher age-adjusted risks of insulin resistance, high triglycerides and low HDL-C (odds ratio [OR] = 3.83, 95% confidence interval [CI] = 2.23-6.58; OR = 1.66, 95% CI = 1.00-2.77, OR = 1.60, 95% CI = 1.11-2.30, respectively). CONCLUSIONS: PCOS women with normal weight but central obesity had increased risks of insulin resistance and dyslipidaemia compared with normal weight PCOS women without central obesity, suggesting that combining BMI with measurement of central obesity may provide better adiposity-related metabolic risk factor stratification in clinical practice than either method alone.

Intensive insulin therapy combined with metformin is associated with reduction in both glucose variability and nocturnal hypoglycaemia in patients with type 2 diabetes.

BACKGROUND: The effect on glucose variability in patients with intensive insulin therapy has not been fully understood. This observational study investigated the different glucose variability and hypoglycaemia patterns in type 2 diabetes patients treated with continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI) with or without metformin administration. METHODS: During hospitalization, a total of 501 patients with poor glycaemic control and in initial treatment with either CSII alone (n = 187), CSII + Metformin (n = 81), MDI alone (n = 146), or MDI + Metformin (n = 87) were involved in the final analysis. Data obtained from continuous glucose monitoring were used to assess blood glucose fluctuation and nocturnal hypoglycaemia. RESULTS: Among the 4 groups, no difference was found in mean blood glucose levels. Results in parameters reflecting glucose fluctuation: continuous overlapping net glycaemic action in CSII + Metformin and mean amplitude of glycaemic excursions in MDI + Metformin were significantly lower than those in either CSII alone or MDI alone, respectively, even after adjustment (P = .031 and .006). Frequency of nocturnal hypoglycaemia was significantly decreased in CSII + Metformin as compared with CSII alone (0.6% vs 1.8%) and in MDI + Metformin as compared with MDI alone (1.6% vs 2.3%), with the highest frequency observed in MDI alone and the lowest in CSII + Metformin (all between group P < .001). Consistent results were obtained in between-group comparisons for hypoglycaemia duration. Subgroup analysis matched with baseline body mass index, and glycated haemoglobin and fasting blood glucose further confirmed these findings. CONCLUSION: Metformin added to initial CSII or MDI therapy is associated with a reduction in both glucose fluctuation and nocturnal hypoglycaemic risk in patients with type 2 diabetes.

Role of Ketotifen on metabolic profiles, inflammation and oxidative stress in diabetic rats.

We aim to explore effects of Ketotifen on metabolic profiles, inflammation and oxidative stress. Sprague Dawley (SD) male rats were randomly divided into normal control group (NC) and experimental groups, and experimental group rats were fed with high-sugar and fat diet for 6 weeks. Then, experimental group rats were divided into diabetes group (DM) and ketotifen treatment group (KT). KT group was given ketotifen via Intragastric for 8 weeks with the dosage of 0.09 mg/kg/d. Fasting plasma glucose (FPG) was measured using glucose oxidase-phenol amino phenazone method. Fasting insulin (FINS), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were tested by enzyme-linked immunosorbent assay. Malondialdehyde (MDA) and superoxide dismutase (SOD) were quantified by spectrophotometer method. Before Ketotifen administration, compared with NC group, DM and KT groups showed significantly high levels of body weight, FPG, FINS, HOMA-IR, TC, TG, LDL, IL-6, TNF-α and MDA, and lower levels of HDL and SOD (All p <0.05). After 4 weeks of Ketotifen administration, levels of body weight, FPG, FINS, HOMA-IR, TC, TG, LDL, IL-6, TNF-α in KT group decreased significantly, and levels of HDL and SOD elevated significantly (All p <0.05). After 8 weeks of Ketotifen administration, levels of body weight, FPG, FINS, HOMA-IR, TC, TG, LDL, IL-6, TNF-α and MDA in KT group decreased more obviously, and levels of HDL and SOD elevated significantly further (All p <0.05). Ketotifen improved metabolic profiles, and ameliorated status of inflammation and oxidative stress.

Aberrant SERPINE1 DNA methylation is involved in carboplatin induced epithelial-mesenchymal transition in epithelial ovarian cancer.

AIM: Resistance to platinum-based therapeutic agents is the major contributor to epithelial ovarian cancer (EOC) mortality. There is an urgent need to better understand the underlying mechanisms. Here we investigated the role of serpins in EOC chemoresistance and related mechanisms, and found that SERPINE1 played an important role in chemoresistance in A2780cp cells. MATERIALS AND METHODS: A2780cp and A2780s cells were used in our study. Microarray screening was used to identify the gene expression change under carboplatin treatment. A cell-counting kit-8 was used to detect the sensitivity of ovarian cancer cells after treatment. The expression of SERPINE1 was silenced by siRNA. The levels of SERPINE1 and epithelial-mesenchymal transition (EMT)-related proteins were confirmed by Western blot. MassArray EpiTYPER quantitative DNA methylation analysis was introduced to evaluate the methylation of the promoter of SERPINE1. RESULTS: Microarray data showed that SERPINE1 and SERPINE2 increased most dramatically under carboplatin treatment in A2780cp cells. Carboplatin treatment could significantly increase the expression of SERPINE1 and induce the EMT process, with decreased expression of E-cadherin and increased expression of Vimentin, Snail and Twist. Knockdown of SERPINE1, but not SERPINE2, in A2780cp cells could inhibit the EMT process. We also found that hypomethylation in the promoter of SERPINE1 might result in the increased expression of SERPINE1 and subsequent EMT process in A2780cp cells. CONCLUSION: Our study suggested that SERPINE1 may be a promising therapeutic target for chemoresistance.

Genetic and Epigenetic Landscape for Drug Development in Polycystic Ovary Syndrome.

The treatment of polycystic ovary syndrome (PCOS) faces challenges as all known treatments are merely symptomatic. The U.S. Food and Drug Administration (FDA) has not approved any drug specifically for treating PCOS. As the significance of genetics and epigenetics rises in drug development, their pivotal insights have greatly enhanced the efficacy and success of drug target discovery and validation, offering promise for guiding the advancement of PCOS treatments. In this context, we outline the genetic and epigenetic advancement in PCOS, which provide novel insights into the pathogenesis of this complex disease. We also delve into the prospective method for harnessing genetic and epigenetic strategies to identify potential drug targets and ensure target safety. Additionally, we shed light on the preliminary evidence and distinctive challenges associated with gene and epigenetic therapies in the context of PCOS.

Association of serum uric acid with women's ovarian reserve: observational study and Mendelian randomization analyses.

OBJECTIVE: To investigate the association between serum uric acid and women's ovarian reserve. DESIGN: Retrospective observational study and Mendelian randomization study. SETTING: University-affiliated in vitro fertilization center. PATIENTS: Observational analyses were undertaken using data from 8,257 women with infertility who finished their first in vitro fertilization treatments between May 2017 and December 2021. Mendelian randomization analyses were based on genome-wide association summary statistics from several biobanks of predominantly European ancestries. INTERVENTIONS: Observational study involved testing log2 transformed serum uric acid levels (for linear, negative regression, and logistic regression analyses); original uric acid levels (for nonlinear association analyses). Mendelian randomization study involved testing genetically predicted uric acid levels. MAIN OUTCOME MEASURES: Biomarkers including antimüllerian hormone, basal antral follicle count, follicle-stimulating hormone, luteinizing hormone, ratio of follicle-stimulating hormone to luteinizing hormone, estradiol; indices of ovarian response to stimulation including poor ovarian response according to different criteria and oocyte yield. RESULTS: In retrospective observational study, all ovarian reserve-related outcomes demonstrated significant differences across serum uric acid quartiles. A two-fold uric acid increase was associated with increased antimüllerian hormone (adjusted ß = 0.69; 95% confidence interval [CI], 0.43-0.95), antral follicle count (adjusted incidence rate ratio = 1.10, 95% CI, 1.05-1.14), luteinizing hormone (adjusted ß = 0.53, 95% CI, 0.28-0.78), decreased risks of Bologna poor ovarian response (adjusted odds ratio = 0.97; 95% CI, 0.95-0.99) and groups 2-4 Poseidon poor ovarian response (group 2: 0.63, 0.56-0.71; group 3: 0.71, 0.65-0.78; group 4: 0.50, 0.46-0.55), whereas an increased risk of group 1 (1.26, 1.13-1.41). Nonlinear analyses showed a common inflection point at 320-340 µmol/L of uric acid. Interactions between uric acid and antimüllerian hormone and antral follicle count were presented in association with oocyte yield. Mendelian randomization results suggested a significant association between genetically predicted uric acid levels and antimüllerian hormone levels (ß = 0.08; 95% CI, 0.04-0.12) but none for uric acid in relation to polycystic ovarian syndrome or other related hormones. CONCLUSION: Higher uric acid levels were associated with better ovarian reserve and increased levels of antimüllerian hormone albeit an increased risk of unexpected poor ovarian response.

Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction.

Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.

Circulating Inflammatory Cytokines and Female Reproductive Diseases: A Mendelian Randomization Analysis.

CONTEXT: Extensive studies have provided considerable evidence suggesting the role of inflammation in the development of female reproductive diseases. However, causality has not been established. OBJECTIVE: To explore whether genetically determined circulating levels of cytokines are causally associated with female reproductive diseases and discover potential novel drug targets for these diseases. METHODS: Instrumental variables (IVs) for 47 circulating cytokines were obtained from a genome-wide association study (GWAS) meta-analysis of 31 112 European individuals. Protein quantitative trait loci and expression quantitative trait loci close to genes served as our IVs. Summary data of 9 female reproductive diseases were mainly derived from GWAS meta-analysis of the UK biobank and FinnGen. We elevated the association using the Wald ratio or inverse variance-weighted Mendelian randomization (MR) with subsequent assessments for MR assumptions in several sensitivity and colocalization analyses. We consider a false discovery rate <0.05 as statistical significance in MR analyses. Replication studies were conducted for further validation, and phenome-wide association studies were designed to explore potential side effects. RESULTS: Our results indicated that high levels of macrophage colony-stimulating factor (MCSF), growth-regulated oncogene-alpha (GROα), and soluble intercellular adhesion molecule-1 were associated with increased risks of endometriosis, female infertility, and pre-eclampsia, respectively. High platelet-derived growth factor-BB (PDGF-BB) levels that reduced the risk of ovarian aging were also supported. Replication analysis supported the relationship between GROα and female infertility, and between MCSF and endometriosis. CONCLUSION: We identified 4 correlated pairs that implied potential protein drug targets. Notably, we preferred highlighting the value of PDGF-BB as a drug target for ovarian aging, and MCSF as a drug target for endometriosis.

Multi-channel electrohysterography enabled uterine contraction characterization and its effect in delivery assessment.

Uterine contractions are routinely monitored by tocodynamometer (TOCO) at late stage of pregnancy to predict the onset of labor. However, TOCO reveals no information on the synchrony and coherence of contractions, which are important contributors to a successful delivery. The electrohysterography (EHG) is a recording of the electrical activities that trigger the local muscles to contract. The spatial-temporal information embedded in multiple channel EHG signals make them ideal for characterizing the synchrony and coherence of uterine contraction. To proceed, contractile time-windows are identified from TOCO signals and are then used to segment out the simultaneously recorded EHG signals of different channels. We construct sample entropy SamEn and Concordance Correlation based feature ψ from these EHG segments to quantify the synchrony and coherence of contraction. To test the effectiveness of the proposed method, 122 EHG recordings in the Icelandic EHG database were divided into two groups according to the time difference between the gestational ages at recording and at delivery (TTD). Both SamEn and ψ show clear difference in the two groups (p<10-5) even when measurements were made 120 h before delivery. Receiver operating characteristic curve analysis of these two features gave AUC values of 0.834 and 0.726 for discriminating imminent labor defined with TTD ≤ 24 h. The SamEn was significantly smaller in women (0.1433) of imminent labor group than in women (0.3774) of the pregnancy group. Using an optimal cutoff value of SamEn to identify imminent labor gives sensitivity, specificity, and accuracy as high as 0.909, 0.712 and 0.743, respectively. These results demonstrate superiority in comparing to the existing SOTA methods. This study is the first research work focusing on characterizing the synchrony property of contractions from the electrohysterography signals. Despite the very limited dataset used in the validation process, the promising results open a new direction to the use of electrohysterography in obstetrics.

PPM1K-regulated impaired catabolism of branched-chain amino acids orchestrates polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common diseases with the coexistence of reproductive malfunction and metabolic disorders. Previous studies have found increased branched chain amino acid (BCAA) levels in women with PCOS. However, it remains unclear whether BCAA metabolism is causally associated with the risk of PCOS. METHODS: The changes of BCAA levels in the plasma and follicular fluids of PCOS women were detected. Mendelian randomization (MR) approaches were used to explore the potential causal association between BCAA levels and the risk of PCOS. The function of the gene coding the protein phosphatase Mg2+/Mn2+-dependent 1K (PPM1K) was further explored by using Ppm1k-deficient mouse model and PPM1K down-regulated human ovarian granulosa cells. FINDINGS: BCAA levels were significantly elevated in both plasma and follicular fluids of PCOS women. Based on MR, a potential direct, causal role for BCAA metabolism was revealed in the pathogenesis of PCOS, and PPM1K was detected as a vital driver. Ppm1k-deficient female mice had increased BCAA levels and exhibited PCOS-like traits, including hyperandrogenemia and abnormal follicle development. A reduction in dietary BCAA intake significantly improved the endocrine and ovarian dysfunction of Ppm1k-/- female mice. Knockdown of PPM1K promoted the conversion of glycolysis to pentose phosphate pathway and inhibited mitochondrial oxidative phosphorylation in human granulosa cells. INTERPRETATION: Ppm1k deficiency-impaired BCAA catabolism causes the occurrence and development of PCOS. PPM1K suppression disturbed energy metabolism homeostasis in the follicular microenvironment, which provided an underlying mechanism of abnormal follicle development. FUNDING: This study was supported by the National Key Research and Development Program of China (2021YFC2700402, 2019YFA0802503), the National Natural Science Foundation of China (81871139, 82001503, 92057107), the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-001), Key Clinical Projects of Peking University Third Hospital (BYSY2022043), the China Postdoctoral Science Foundation (2021T140600), and the Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01).

Abnormal Activation of Tryptophan-Kynurenine Pathway in Women With Polycystic Ovary Syndrome.

Background: Women with polycystic ovary syndrome (PCOS) suffer from dysfunctional metabolism and studies have reported increased levels of tryptophan in patients with PCOS. However, the changes of downstream metabolites in tryptophan catabolism pathways remain unclear. Methods: This is a cross-sectional study that included 200 PCOS patients and 200 control women who were recruited from the Reproductive Medicine Center of Peking University Third Hospital from October 2017 to June 2019. The PCOS patients and the control group were further divided into subtypes of normal weight and overweight/obesity. Fasting blood samples from all subjects were collected on days 2~3 of a natural menstrual cycle or when amenorrhea for over 40 days with follicle diameter not exceeding 10 mm. The plasma levels of tryptophan metabolites were quantitatively determined by the liquid chromatograph mass spectrometer, including tryptophan, serotonin, kynurenine, kynurenic acid, 3-hydroxykynurenine, and quinolinic acid. Results: The tryptophan-kynurenine pathway was dysregulated in women with PCOS, along with significantly elevated levels of tryptophan, serotonin, kynurenine, kynurenic acid, and quinolinic acid. Moreover, levels of tryptophan, kynurenine, and kynurenic acid were positively correlated with luteinizing hormone, anti-Müllerian hormone, fasting insulin, HOMA-IR. tryptophan, and kynurenine and quinolinic acid had an obvious association with C-reactive protein levels. Furthermore, logistic regression showed that tryptophan, serotonin, kynurenine, kynurenic acid and quinolinic acid were all associated significantly with the increased risk of PCOS with the adjustment for potential confounding factors. Additionally, tryptophan, kynurenine, and kynurenic acid had good diagnostic performances for PCOS, and their combination exhibited higher sensitivity and specificity to diagnostic efficiency, with the area under the ROC curve of 0.824 (95% CI 0.777-0.871), which was comparable to the endocrine indicators. Conclusion s: The tryptophan-kynurenine pathway was abnormally activated in PCOS patients.

Elevated Levels of Follicular Fatty Acids Induce Ovarian Inflammation via ERK1/2 and Inflammasome Activation in PCOS.

CONTEXT: Polycystic ovary syndrome (PCOS) is accompanied by chronic inflammation and metabolic disorders. Whether metabolic abnormalities affect inflammation in PCOS or not, the underlying mechanism remains to be clarified. OBJECTIVE: We aimed to investigate changes in fatty acids and their effects on inflammatory response in the follicular niche of PCOS patients. METHODS: This study recruited 50 PCOS patients and 50 age-matched controls for follicular fluids and ovarian mural granulosa cells collection. The human ovarian granulosa cell line KGN was used for evaluating the effect of oleic acid (OA) stimulation. The levels of follicular fatty acids were measured by liquid chromatography-tandem mass spectrometry. The concentrations of inflammatory cytokines were detected by electrochemiluminescence and enzyme-linked immunosorbent assays. The regulation of inflammation-related genes was confirmed by quantitative polymerase chain reaction and Western blotting after OA stimuli. RESULTS: Three saturated fatty acids and 8 unsaturated fatty acids were significantly elevated in follicular fluids of PCOS patients compared to those in controls. The concentrations of follicular interleukin (IL)-6, IL-8, and mature IL-18 were significantly higher in the PCOS group and were positively correlated with the levels of fatty acids. Moreover, OA stimulation upregulated the transcription levels of IL-6 and IL-8 via extracellularly regulated kinase 1/2 signaling pathways in KGN cells. Furthermore, OA treatment induced reactive oxygen species production and inflammasome activation, which is manifested by enhanced caspase-1 activity and mature IL-18 protein level. CONCLUSION: Fatty acid metabolism was significantly altered in the follicular niche of PCOS patients. Elevated levels of fatty acids could induce ovarian inflammation both at the transcriptional level and in posttranslational processing.