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Polycystic ovary syndrome (PCOS), a common endocrine and metabolic disorder affecting women in their reproductive years. Emerging evidence suggests that the maternal-fetal immune system is crucial for proper pregnancy. However, whether immune function is altered at the end of pregnancy in PCOS women and the underlying molecular mechanisms is currently unexplored. Herein, the basic maternal immune system was investigated (n = 136 in the control group; n = 103 in the PCOS group), and whole-transcriptome sequencing was carried out to quantify the mRNAs, miRNAs, and lncRNAs expression levels in fetal side placental tissue of women with PCOS. GO, KEGG, and GSEA analysis were employed for functional enrichment analysis. The process of identifying hub genes was conducted utilizing the protein-protein interaction network. CIBERSORT and Connectivity Map were deployed to determine immune cell infiltration and predict potential drugs, respectively. A network of mRNA-miRNA-lncRNA was constructed and then validated by qRT-PCR. First, red blood cell count, neutrophil count, lymphocyte count, hypersensitive C-reactive protein, and procalcitonin were significantly elevated, while placental growth factor was hindered in PCOS women. We identified 308 DEmRNAs, 77 DEmiRNAs, and 332 DElncRNAs in PCOS samples. Functional enrichment analysis revealed that there were significant changes observed in terms of the immune system, especially the chemokine pathway. Eight genes, including FOS, JUN, EGR1, CXCL10, CXCR1, CXCR2, CXCL11, and CXCL8, were considered as hub genes. Furthermore, the degree of infiltration of neutrophils was dramatically decreased in PCOS tissues. In total, 57 ceRNA events were finally obtained, and immune-related ceRNA networks were validated. Some potential drug candidates, such as enalapril and RS-100329, could have a function in PCOS therapy. This study represents the inaugural attempt to evaluate the immune system at the end of pregnancy and placental ceRNA networks in PCOS, indicating alterations in the chemokine pathway, which may impact fetal and placental growth, and provides new therapy targets., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Xie et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Polycystic ovary syndrome (PCOS), as a common endocrine disease in reproductive-age women, which is characterized by both reproductive and metabolic disorders. Cang-Fu-Dao-Tan Formula (CFDTF) is an effective and relatively safe treatment for PCOS. However, the underlying mechanism is poorly understood., Purpose: To explore the effective compounds and mechanisms of CFDTF in treating PCOS based on UPLC/Q-TOF-MS/MS, network pharmacology and molecular experiments., Methods: The UPLC/Q-TOF-MS/MS and TCMSP, SwissTargetPrediction databases were used to identify the active ingredients of CFDTF. Then GeneCards, Disgenet, Drugbank databases were used to obtain the PCOS related targets. Based above, the Drug-component-target (D-C-T) network and protein-protein-interaction (PPI) network were built to analysis the key targets. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis were performed to find the potential mechanisms. Finally, molecular docking analysis, molecular dynamics (MD) simulations and molecular experiments were used to confirm the interactions among the active compounds, targets and explore the potential mechanisms., Results: A total of 20 compounds were identified by UPLC/Q-TOF-MS/MS, and 136 active compounds by TCMSP from CFDTF. After removing the duplicate results, there were 370 targets related to both CFDTF and PCOS, among which, MAPK3, AKT1, RELA, EGF, TP53 and MYC were proved to have high interactions with the components. The mechanisms of CFDTF against PCOS were related to PI3K-Akt, mTOR, MAPK signaling pathways, and the in vitro experiments proved that the CFDTF positively regulated the cell proliferation and inhibited the apoptosis levels in PCOS cell model., Conclusions: The combination of UPLC/Q-TOF-MS/MS, systematic network pharmacology and molecular experiments identified that the quercetin, hesperidin, and glycyrrhizin disaccharide are the TOP 3 effective compounds of CFDTF in treating PCOS and the potential mechanisms may involve in regulating proliferation and apoptosis of granulosa cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Polycystic ovary syndrome (PCOS) is a common gynecological endocrine and metabolic disorder. Chinese herbal medicine has some advantages in the treatment of PCOS with its unique theoretical system and rich clinical practice experiences., Aim of the Study: The present study was to investigate the potential mechanisms of Bu-Shen-Jian-Pi Formula (BSJPF) on the treatment of PCOS., Material and Methods: The combination of ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS/MS) rapid analysis, network pharmacology, molecular docking analysis and bio-experiments were firstly conducted to identify the main effective components of BSJPF, and to predict the potential mechanisms. The ovarian granulosa cell line (KGN) was treated with testosterone to construct the PCOS model in vitro, and the cells were further treated with the lyophilized powder of BSJPF. The levels of proliferation, autophagy and apoptosis were detected to explore the mechanisms of BSJPF on treating PCOS., Results: Firstly, thirty-six active compounds were identified in BSJPF and thirty-one potential targets on PCOS were found. Then, PI3K and PDK1 were verified to have good binding activity with the active compounds through molecular docking analysis. In bio-experiments, BSJPF significantly alleviated the arrested proliferation of KGN cells in G0/G1 phase and reduced the active levels of autophagy and apoptosis of KGN cells induced by testosterone. Additionally, the inhibition of autophagy diminished apoptosis, while the repression apoptosis enhanced autophagy. Finally, BSJPF significantly decreased the FOXO1 expression levels induced by testosterone, especially for nuclear FOXO1, and significantly activated the PI3K/AKT pathway., Conclusions: BSJPF significantly alleviated the activated autophagy and apoptosis in KGN induced by testosterone through PI3K/AKT1/FOXO1pathway, which is an effective treatment for PCOS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: To compare the clinical characteristics of pregnant women with polycystic ovary syndrome (PCOS) and perinatal outcomes with or without preeclampsia (PE) and to factors that are potentially associated with the onset of PE., Material and Methods: This was a retrospective study of pregnant women diagnosed with PCOS from January 2017 to December 2021. Eligible patients were divided into two groups based on the presence or absence of preeclampsia: a PE group and a non-PE group. Demographics, clinical characteristics, maternal and perinatal outcomes, and potential factors linked to disease recurrence were analyzed., Results: In total, 616 patients were enrolled and respectively classified into the PE group (n = 51) and the non-PE group (n = 565). The incidence of PE in pregnant women with PCOS was 8.28%; this was significantly higher than that in non-PCOS pregnant women (3.22%, p < 0.001). Logistic regression analysis of the predictive factors for PE in women with PCOS revealed that the combination of maternal hyperandrogenism, a pre-pregnancy BMI ≥ 24 kg/m², and a family history of cardiovascular disease (CVD) and assisted reproductive techniques (ART) exhibited the steepest receiver-operating characteristic (ROC) curve value at 0.797 [95% confidence interval (CI): 0.733-0.862]., Conclusions: Patients with PCOS have a higher incidence of PE. We identified a series of significant and independent factors associated with PE in PCOS: maternal hyperandrogenism, a pre-pregnancy BMI ≥ 24 kg/m², and a family history of CVD and ART.

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Objective: As one of the most common endocrine disorders in women of reproductive age, polycystic ovary syndrome (PCOS) is highly heterogeneous with varied clinical features and diverse gestational complications among individuals. The patients with PCOS have 2-fold higher risk of preterm labor which is associated with substantial infant morbidity and mortality and great socioeconomic cost. The study was designated to identify molecular subtypes and the related hub genes to facilitate the susceptibility assessment of preterm labor in women with PCOS., Methods: Four mRNA datasets (GSE84958, GSE5090, GSE43264 and GSE98421) were obtained from Gene Expression Omnibus database. Twenty-eight candidate genes related to preterm labor or labor were yielded from the researches and our unpublished data. Then, we utilized unsupervised clustering to identify molecular subtypes in PCOS based on the expression of above candidate genes. Key modules were generated with weighted gene co-expression network analysis R package, and their hub genes were generated with CytoHubba. The probable biological function and mechanism were explored through Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis. In addition, STRING and Cytoscape software were used to identify the protein-protein interaction (PPI) network, and the molecular complex detection (MCODE) was used to identify the hub genes. Then the overlapping hub genes were predicted., Results: Two molecular subtypes were found in women with PCOS based on the expression similarity of preterm labor or labor-related genes, in which two modules were highlighted. The key modules and PPI network have five overlapping five hub genes, two of which, GTF2F2 and MYO6 gene, were further confirmed by the comparison between clustering subgroups according to the expression of hub genes., Conclusions: Distinct PCOS molecular subtypes were identified with preterm labor or labor-related genes, which might uncover the potential mechanism underlying heterogeneity of clinical pregnancy complications in women with PCOS., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among women, and the curative effects of its current management are not satisfactory. A formula of Chinese herbal medicine (CHM), called Bu-Shen-Tian-Jing Formula (BSTJF), has clinically shown beneficial effects in treating PCOS., Purpose: This study aimed to investigate the mechanism underlying BSTJF for treatment of PCOS., Methods: Whole blood samples were collected from women with PCOS treated and not treated with BSTJF (n = 5 per group). Whole transcriptome sequencing of leukocytes and untargeted metabonomic analysis of the plasma were performed. Three groups of 18 female Sprague-Dawley rats were randomly selected: control, PCOS, and BSTJF. A PCOS rat model was established using testosterone propionate. The estrous cycle; glucose tolerance; ovarian morphology; serum markers of oxidative stress; and expression of Sirtuin 3 (SIRT3), phospho-p38 mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI3K), and phospho-protein kinase B in the ovary were measured. Palmitate was initially applied to KGN cells, followed by freeze-dried BSTJF powder. The glucose uptake, reactive oxygen species (ROS) production, and protein levels of SIRT3, PI3K, and glucose transporter type 4 (GLUT4) were detected in KGN cells., Results: The transcriptomic and metabolomic profiles showed alterations in 572 genes and 73 metabolites in women with PCOS treated with BSTJF. The enriched pathways in women with PCOS treated with BSTJF were mainly involved in inflammation, insulin resistance, glucose and lipid metabolism, and neuro and associated signaling pathways. In PCOS rat models, BSTJF improved the estrous cycle, glucose tolerance, and ovarian morphology; relieved oxidative stress; increased ovarian SIRT3 expression; inhibited p38 MAPK activation; and promoted the activation of PI3K/AKT signaling in the ovary. In the in-vitro study with KGN cells, BSTJF rescued the palmitate-induced impaired glucose uptake and SIRT3 expression, reduced mitochondrial ROS production mediated by SIRT3, and restored the impaired insulin-induced PI3K/AKT signaling pathway., Conclusion: BSTJF effectively alleviated the pathogenesis of PCOS by improving oxidative stress and glucose metabolism via mitochondrial SIRT3 and the following insulin signaling pathway. This study innovatively revealed the action mechanism of CHM in treating PCOS., Competing Interests: Conflict of interest All authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

The association between polycystic ovary syndrome (PCOS) and metabolic syndrome (MetS) is not widely recognized or properly assessed in adolescents. The aim of this study was to conduct a systematic review and meta-analysis to provide reliable results concerning MetS development in adolescents with PCOS. We searched studies published in PubMed, Medline, and Web of Science from January 2010 to December 2020. The quality of studies was assessed by the Newcastle-Ottawa Scale (NOS), and the data analysis was performed with Stata 14.0. Twelve articles were finally included in the systematic review and meta-analysis. The results suggested that adolescents with PCOS have more than three times the odds of having MetS than controls (OR 3.32, 95% CI [2.14, 5.14]). Obese adolescents with PCOS also had a higher risk of MetS than those with obesity but without PCOS (OR 3.97, 95% CI [1.49, 10.53]). Compared to those without PCOS, systolic blood pressure was higher in adolescents with PCOS (weighted mean difference (WMD) 3.85, 95% CI [1.73, 5.97]), while diastolic blood pressure was higher only in girls with PCOS who had a normal weight (WMD 3.52, 95% CI [1.57, 5.48]). The levels of triglycerides were higher in obese adolescents with PCOS than in those with obesity but without PCOS (WMD 27.84, 95% CI [10.16, 45.51]). PCOS could increase the frequency of MetS by influencing blood pressure and lipid metabolism independent of obesity as early as the adolescent period. Thus, clinicians should perform early interventions in adolescents with PCOS and follow up the relevant indicators of MetS to decrease the risk of poor long-term prognosis., (© 2022. The Author(s).)

Background: Intrahepatic cholestasis of pregnancy (ICP) is a common gestational complication characterized by pruritus and elevated bile acids, usually occurring in the third trimester when the serum estrogen and progesterone levels are highest. Hyperandrogenism during pregnancy is a pathological state that is mostly induced by polycystic ovary syndrome (PCOS) but rarely by concomitant androgen-secreting ovarian tumours. To date, no correlation has been drawn between ICP and hyperandrogenism., Case Presentation: Here, we present a rare case of early-onset severe ICP in a PCOS patient conceived via in vitro fertilization-embryo transfer, with worsening hirsutism and acne due to high levels of testosterone and dehydroepiandrosterone sulphate, both of which were produced by a fast-growing ovarian Sertoli-Leydig cell tumour. Her serum estradiol was also very high, which was speculated to be converted from the circulating androgens by the placenta. She had preterm premature rupture of membranes and delivered at 30 weeks, followed by a rapid remission of ICP as her serum estradiol dropped. However, the excessive androgens did not retreat until the large ovarian tumour was surgically removed., Conclusion: This unusual case highlights the concurrence of original hyperandrogenism and subsequent hyperestrogenism during pregnancy and the resultant confounding manifestations. Obstetricians should be aware of the potential association between androgen excess and ICP via placental aromatization., (© 2022. The Author(s).)

Mitochondrial function and glucose metabolism play important roles in bidirectional signaling between granulosa cells (GCs) and oocytes. However, the factors associated with mitochondrial function and glucose metabolism of GCs in polycystic ovary syndrome (PCOS) are poorly understood, and their potential downstream effects on oocyte quality are still unknown. The aim of this study was to investigate whether there are alterations in mitochondrial-related functions and glucose metabolism in ovarian GCs of women with PCOS and the role of Sirtuin 3 (SIRT3) in this process. Here, we demonstrated that women with PCOS undergoing in vitro fertilization and embryo transfer had significantly lower rates of metaphase II oocytes, two-pronuclear fertilization, cleavage, and day 3 good-quality embryos. Germinal vesicle- and metaphase I-stage oocytes from women with PCOS exhibited increased mitochondrial reactive oxygen species (ROS), decreased mitochondrial membrane potential, and downregulation of glucose-6-phosphate dehydrogenase. GCs from women with PCOS presented significant alterations in mitochondrial morphology, amount, and localization, decreased membrane potential, reduced adenosine triphosphate (ATP) synthesis, increased mitochondrial ROS and oxidative stress, and insufficient oxidative phosphorylation (OXPHOS) together with decreased glycolysis. SIRT3 expression was significantly decreased in GCs of PCOS patients, and knockdown of SIRT3 in KGN cells could mimic the alterations in mitochondrial functions and glucose metabolism in PCOS GCs. SIRT3 knockdown changed the acetylation status of NDUFS1, which might induce altered mitochondrial OXPHOS, the generation of mitochondrial ROS, and eventually defects in the cellular insulin signaling pathway. These findings suggest that SIRT3 deficiency in GCs of PCOS patients may contribute to mitochondrial dysfunction, elevated oxidative stress, and defects in glucose metabolism, which potentially induce impaired oocytes in PCOS., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To investigate whether maternal PCOS could impact growth and development in offspring at an early age through continuous observation from age 3 months to 6 years., Methods: This prospective study was conducted in 198 children born to mothers with PCOS and 227 children born to healthy mothers in Ningbo (Zhejiang Province, China) between October 2012 and July 2015. Measurements of offspring height, weight, head circumference, and teething were examined by trained professionals through age 6 years. Height, weight, and body mass index (BMI) were analysed using repeated measures analysis of variance between the PCOS and control groups., Results: Offspring born to women with PCOS showed significantly higher BMI at age 12, 18, and 30 months and 5 years (P = 0.040, P = 0.000, P = 0.000, and P = 0.023, respectively). Female offspring born to women with PCOS showed significantly increased body weight at 3, 8, 12, 18, and 30 months, and 3 and 6 years (P = 0.027, P = 0.008, P = 0.010, P = 0.034, P = 0.047, P = 0.040, and P = 0.035, respectively) and significantly higher BMI at 3, 8, 12, 18, and 30 months (P = 0.009, P = 0.016, P = 0.029, P = 0.000, and P = 0.000, respectively). After adjusting for maternal, paternal, and pregnancy confounders, PCOS status presented significant associations with weight at age 3, 8, and 12 months and 3 years (P = 0.005, P = 0.004, P = 0.021, P = 0.035 respectively), and with BMI at age 3 and 8 months (P = 0.011 and P = 0.014) in female offspring., Conclusions: Maternal PCOS is associated with an increased risk of developing obesity in female offspring., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: 1) To explore the associations between autistic traits and sex hormone changes in patients with polycystic ovary syndrome (PCOS); 2) To explore the influence of PCOS parental autistic traits and related sex hormone changes on autistic traits in their offspring., Method: This is a case-control study that recruited two groups: polycystic ovarian syndrome-induced infertile subjects as the observation group and fallopian tube factor-induced infertility subjects as the control group. Both cohorts were patients undergoing infertility treatment in the Productive Medicine Center, Peking University People's Hospital. Two types of questionnaires were completed by patients between May 1 st , 2015, and May 1 st , 2016: 1. The autism-spectrum quotient (AQ) 2. Repetitive behavior scale-revised (RBS-r). Levels of sex hormones in serum were measured in patients. The correlations between the levels of these biochemical factors and scores of the autistic traits were analysed. From July 1 st , 2020 to September 1 st , 2021, these patients were followed up by telephone and asked to fill out a questionnaire online. The questionnaire included date of delivery, complications, medicine used and negative events during pregnancy (e.g., death of relatives, divorce, etc.), delivery condition, breastfeeding, AQ scale and Autism Behavior Checklist (ABC) of their children., Results: The patients in the PCOS group had significantly higher AQ scores than those in the control group. Levels of luteinizing hormone and testosterone were also higher in the PCOS group. No significant differences were found between the two groups in RBS-r levels, follicle-stimulating hormone, estradiol or progesterone. In the two combined groups, there were significantly positive correlations between the AQ scores and the luteinizing hormone concentration, as well as between scores of RBS-r and testosterone concentration. Moreover, there was a significantly negative correlation between the level of progesterone and the RBS-r score. According to the follow-up data, the AQ scores of offspring were positively correlated with the RBS-r scores of their mothers. The ABC scores of offspring were positively correlated with the RBS-r scores and the childbearing age of their mothers. No significant difference was found between the two groups in age of delivery, complications, special medication used, negative events during pregnancy, delivery situation, postpartum breastfeeding, age of children, or AQ scores or ABC scores of children. There were no significant correlations between the scale scores of children and the related sex hormone levels of mothers. This could indicate that the higher levels of luteinizing hormone and testosterone and the lower level of progesterone accompanied more pronounced autistic traits in PCOS. Furthermore, the higher delivery age and RBS-r score in mothers accompanied the higher AQ and ABC scores in children., Conclusion: Compared with the control group, PCOS patients had more autistic traits (especially social dysfunction). The autistic traits in PCOS patients might be related to the elevation in testosterone concentration and luteinizing hormone levels and the decline in progesterone level. Moreover, the autistic traits in the offspring of PCOS patients might be related to the parental high delivery age and high tendency to autism traits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiang, Tian, Yuan, Xu, Qu, Zhang and Wang.)

Objective: To evaluate the body mass index and neurologic development of 1-2 years offspring born to mothers with polycystic ovary syndrome., Study Design: A case-control study., Place and Duration of Study: Dongyang Women and Children's Hospital, Zhejiang Province, China, between June 2018 and January 2019., Methodology: A total of 145 children were included in the final analysis, including 16 daughters of mothers with PCOS, 13 sons of mothers with PCOS, 55 daughters of mothers without PCOS and 61 sons of mothers without PCOS. Developmental assessments for each child were conducted, including anthropometric measurements and ability developments using the Denver developmental screening test., Results: The body mass index of children was significantly lower in polycystic ovary syndrome group than control group (p=0.022). Children of mothers with polycystic ovary syndrome and control group had no significant differences in the outcomes of the Denver developmental screening test (all p >0.05)., Conclusion: Maternal polycystic ovary syndrome may affect body mass index of offspring aged 1-2 years and had no negative effects on neurologic development. However, this conclusion may be limited due to the small sample size. Key Words: Neurologic development, Polycystic ovary syndrome, Offspring, Denver development screening test, Body mass index.

Background: Maternal polycystic ovary syndrome (PCOS) has potential detrimental effects on the neurodevelopment of offspring. This study aimed to evaluate the brain metrics in fetuses of women with PCOS based on fetal magnetic resonance imaging (MRI)., Methods: This retrospective study included 60 pregnant women with PCOS (PCOS group) and 120 pregnant non-PCOS women (control group). Fetal MRI was performed followed an ultrasound and for numerous clinical indications including known or suspected fetal pathology, history of fetal abnormality in previous pregnancy or in a family member. Fetal brain biometry and apparent diffusion coefficient (ADC) value were analysed., Results: After adjusting for potential confounders, fetuses in the PCOS group showed the following characteristics compared to fetuses in the control group: (1) smaller cerebral fronto-occipital diameter (FOD), vermian height (VH) and anteroposterior diameter of the pons (APDP) (evident before 32 weeks; P = 0.042, P = 0.002 and P = 0.016, respectively); (2) larger left and right biparietal index (evident before 32 weeks; P = 0.048 and P = 0.025, respectively); (3) smaller left lateral ventricle (LV) (evident after 32 weeks; P = 0.005); (4) larger anteroposterior diameter of the vermis (APDV) and hippocampal infolding angle (HIA) (evident after 32 weeks; P = 0.003 and P < 0.001, respectively); (5) higher ADC value in frontal white matter (FWM) and in basal ganglia (BG) (evident before and after 32 weeks; all P < 0.05)., Conclusions: There exist a different pattern of brain metrics in PCOS offspring in utero., (© 2021. The Author(s).)

Objective: To explore the association of circadian rhythm disruption with polycystic ovary syndrome (PCOS) and the potential underlying mechanism in ovarian granulosa cells (GCs)., Design: Multicenter questionnaire-based survey, in vivo and ex vivo studies., Setting: Twelve hospitals in China, animal research center, and research laboratory of a women's hospital., Patients/animals: A total of 436 PCOS case subjects and 715 control subjects were recruited for the survey. In vivo and ex vivo studies were conducted in PCOS-model rats and on ovarian GCs collected from women with PCOS and control subjects., Intervention(s): The PCOS rat model was established with the use of testosterone propionate., Main Outcome Measure(s): Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), RNA sequencing, rhythmicity analysis, functional enrichment analysis., Result(s): There was a significant correlation between night shift work and PCOS. PCOS-model rats presented distinct differences in the circadian variation of corticotropin-releasing hormone, adrenocorticotropic hormone, prolactin, and a 4-h phase delay in thyrotropic hormone levels. The motif enrichment analysis of ATAC-seq revealed the absence of clock-related transcription factors in specific peaks of PCOS group, and RNA sequencing ex vivo at various time points over 24 hours demonstrated the differential rhythmic expression patterns of women with PCOS. Kyoto Encyclopedia of Genes and Genomes analysis further highlighted metabolic dysfunction, including both carbohydrate and amino acid metabolism and the tricarboxylic acid cycle., Conclusion(s): There is a significant association of night shift work with PCOS, and genome-wide chronodisruption exists in ovarian GCs., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age with the prevalence from 5% to 15%, and the prevalence of PCOS in adolescents with obesity seems even higher. The weight status is significantly associated with the quality of life in adolescents with PCOS., Objective: This review aims to summarize the latest findings of pathogenesis, diagnosis, comorbidity, and management in PCOS adolescents with obesity., Methods: This is a narrative review of articles published in PubMed from June 2013 to June 2020 Data were searched using the key words of "polycystic ovary syndrome" AND "adolescent" AND "obesity.", Results: Pubertal obesity, particularly central obesity, could have a negative impact on the pathophysiology of PCOS. In adolescents with obesity, a review of medical history and a long-term follow-up for PCOS symptoms are essential to avoid misdiagnosis. There is a link between obesity and comorbidities of PCOS in adolescents. Holistic treatment and concern for related comorbidities should ideally begin as early as possible in obese adolescents once the diagnosis of PCOS is confirmed., Conclusion: Adolescents with PCOS and obesity need more attention from physicians and researchers, and the effective interventions in the early stage are critical to improve their life quality.

Objective: Polycystic ovary syndrome (PCOS), a common endocrine-metabolic dysfunction in reproductive-aged women, may be involved in compromised pregnancy and offspring outcomes. This study aimed to investigate whether maternal PCOS affects fetal growth, fetal development, and placental features., Methods: This retrospective case-control study included 60 pregnant women with PCOS (PCOS group) and 120 healthy pregnant women without PCOS (control group). Fetal magnetic resonance imaging (MRI) was performed followed by an ultrasound examination and indications for imaging, including known or suspected fetal pathology, history of fetal abnormality in previous pregnancy or in a family member, and concern for placenta accreta. Fetal MRI images were analyzed for head circumference (HC), abdomen circumference (AC), lung-to-liver signal intensity ratio (LLSIR, a prenatal marker of fetal lung maturity), lengths of liver and kidney diameters in fetuses, and placental relative signal intensity on T2-weighted single-shot fast spin echo (SSFSE) imaging (rSI SSFSE ), and placental relative apparent diffusion coefficient value (rADC). Data on height and weight of offspring were collected through telephone follow-up., Results: Compared to the control group, the PCOS group showed the following characteristics: (1) smaller biparietal diameter and femur length in fetuses (P=0.026 and P=0.005, respectively), (2) smaller HC in fetuses (evident after 32 weeks; P=0.044), (3) lower LLSIR and smaller dorsoventral length of liver in fetuses (evident before 32 weeks; P=0.005 and P=0.019, respectively), and (4) smaller placental thickness (evident before 32 weeks; P=0.017). No significant differences in placental rSI SSFSE or rADC were observed between the groups (all P>0.05). No significant differences in height and weight of offspring during childhood existed between the groups (all P>0.05)., Conclusions: There exist alterations of fetal growth, fetal development, and placental features from women with PCOS.

Background: This study explored the mechanisms underlying altered neurobehavioural development of female offspring born to mothers with polycystic ovary syndrome (PCOS)., Methods: In total, 20 women with PCOS and 32 healthy women who underwent caesarean deliveries with a single female foetus were recruited. Infants were assessed with Dubowitz scoring. Swan71 cell line with stable FOS overexpression was used to verify the regulatory effects of FOS on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) expression. Learning and memory in female first-generation (F1) and second-generation (F2) offspring in a rat model of PCOS was tested using the Morris water maze at puberty and adulthood. Transcriptome analysis of pubertal hippocampi and hypothalami of female F1 offspring was conducted., Findings: Total score and behaviour subscales of Dubowitz scoring were significantly lower in female infants of women with PCOS. FOS and NGF protein levels were downregulated in placental villi of the PCOS group. FOS played a key role in BDNF inhibition and enhancing NGF in Swan71 cells. PCOS female F1 rats exhibited lower target crossing times during puberty when compared to controls. Transcriptome analysis revealed significant changes in hippocampal and hypothalamic neuronal pathways in female F1 rats at puberty., Interpretation: FOS regulation of neurotrophins in the placenta negatively affects neurobehavioural development of female offspring of PCOS mothers., Funding: This study was funded by the National Key R&D Program of China (2018YFC1004900 to F.Q. and F.W.) and the National Natural Science Foundation of China (81874480 to F.Q.; 81873837 to F.W.)., Competing Interests: Declaration of Competing Interests The authors have no conflict of interest to declare., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Polycystic ovary syndrome (PCOS) is one of the most common metabolic and reproductive endocrinopathies. However, few studies have tried to develop a diagnostic model based on gene biomarkers. In this study, we applied a computational method by combining two machine learning algorithms, including random forest (RF) and artificial neural network (ANN), to identify gene biomarkers and construct diagnostic model. We collected gene expression data from Gene Expression Omnibus (GEO) database containing 76 PCOS samples and 57 normal samples; five datasets were utilized, including one dataset for screening differentially expressed genes (DEGs), two training datasets, and two validation datasets. Firstly, based on RF, 12 key genes in 264 DEGs were identified to be vital for classification of PCOS and normal samples. Moreover, the weights of these key genes were calculated using ANN with microarray and RNA-seq training dataset, respectively. Furthermore, the diagnostic models for two types of datasets were developed and named neuralPCOS. Finally, two validation datasets were used to test and compare the performance of neuralPCOS with other two set of marker genes by area under curve (AUC). Our model achieved an AUC of 0.7273 in microarray dataset, and 0.6488 in RNA-seq dataset. To conclude, we uncovered gene biomarkers and developed a novel diagnostic model of PCOS, which would be helpful for diagnosis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Ning-Ning Xie et al.)

Polycystic ovary syndrome (PCOS) is the most common metabolic and endocrine disorder in women. However, there is no agreement concerning how to diagnose and treat PCOS worldwide. Three practice guidelines or consensuses, including consensus from the European Society of Human Reproduction and Embryology (ESHRE)/the American Society for Reproductive Medicine (ASRM) in Rotterdam, diagnosis criteria and consensus in China, and clinical practice guideline from the Endocrine Society (ES) in the United States are widely recognized. The present paper may provide some guidance for clinical practice based on a comparative analysis of the above three practice guidelines or consensuses.

Background: Polycystic ovary syndrome (PCOS), whose etiology remains uncertain, is a highly heterogenous and genetically complex endocrine disorder. The aim of this study was to identify differentially expressed genes (DEGs) in granulosa cells (GCs) from PCOS patients and make epigenetic insights into the pathogenesis of PCOS., Results: Included in this study were 110 women with PCOS and 119 women with normal ovulatory cycles undergoing in vitro fertilization acting as the control group. RNA-seq identified 92 DEGs unique to PCOS GCs in comparison with the control group. Bioinformatic analysis indicated that synthesis of lipids and steroids was activated in PCOS GCs. 5-Methylcytosine analysis demonstrated that there was an approximate 25% reduction in global DNA methylation of GCs in PCOS women (4.44 ± 0.65%) compared with the controls (6.07 ± 0.72%; P  < 0.05). Using MassArray EpiTYPER quantitative DNA methylation analysis, we also found hypomethylation of several gene promoters related to lipid and steroid synthesis, which might result in the aberrant expression of these genes., Conclusions: Our results suggest that hypomethylated genes related to the synthesis of lipid and steroid may dysregulate expression of these genes and promote synthesis of steroid hormones including androgen, which could partially explain mechanisms of hyperandrogenism in PCOS., Competing Interests: Ethical approval (no.20120034) for this project was granted by the Ethics Committee of the School of Medicine, Zhejiang University, and informed consents were obtained from all participants.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Polycystic ovary syndrome (PCOS) is an endocrine disorder with reproductive dysfunction and abnormal metabolic syndrome. However, its etiology is unknown yet. Androgen hypersecretion is one of the main features of PCOS. It has been found that PCOS has various effects on the offspring in reproductive, metabolic and nervous systems, including:increasing secretion of gonadotropin-releasing hormone and luteinizing hormone, ovarian morphological changes and abnormal secretion of sex hormones, leading to disorders of lipid and glucose metabolism, and increasing the risks of depression and autism. However, there is still lack of direct evidence, and more studies should be conducted on the underlying mechanism in future.

Objective: To provide guidance for future randomized controlled trials (RCTs) based on a review concerning acupuncture for treating polycystic ovary syndrome (PCOS)., Methods: A comprehensive literature search was conducted in October 2015 using MEDLINE, EMBASE, SCISEARCH, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Menstrual Disorders and Subfertility Group trials register, Allied and Complementary Medicine (AMED), China National Knowledge Infrastructure (CNKI), and the Wanfang databases. RCTs comparing either acupuncture with no/sham/pharmacological intervention or a combination of acupuncture and conventional therapy with conventional therapy in the treatment of PCOS were included in this review. A quality evaluation was performed for each of the included studies., Results: Thirty-one RCTs were included in the review and were divided into four categories according to the type of intervention used in the comparator or control group. Menstrual frequency, hormones, anthropometrics, insulin sensitivity, blood lipids, and fertility were used as the main measurements to assess the effects of acupuncture on the patients with PCOS. Thirty trials, except for one, showed an improvement in at least one of the indicators of PCOS after acupuncture treatment. However, normalizing the methodological and reporting format remains an issue., Conclusions: Based upon this review of current clinical trials concerning acupuncture for treating PCOS, we provide guidelines for better clinical trial design in the future.

Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders and a leading cause of female subfertility. The mechanism underlying the pathophysiology of PCOS remains to be illustrated. Here, we identify two alternative splice variants (ASVs) of the androgen receptor (AR), insertion and deletion isoforms, in granulosa cells (GCs) in ∼62% of patients with PCOS. AR ASVs are strongly associated with remarkable hyperandrogenism and abnormalities in folliculogenesis, and are absent from all control subjects without PCOS. Alternative splicing dramatically alters genome-wide AR recruitment and androgen-induced expression of genes related to androgen metabolism and folliculogenesis in human GCs. These findings establish alternative splicing of AR in GCs as the major pathogenic mechanism for hyperandrogenism and abnormal folliculogenesis in PCOS.

The objective of this study was to explore whether hyperandrogenism induces epigenetic alterations of peroxisome proliferator-activated receptor gamma 1 (PPARG1), nuclear corepressor 1 (NCOR1), and histone deacetylase 3 (HDAC3) genes in granulosa cells (GCs) of polycystic ovary syndrome (PCOS) women and whether these alterations are involved in the ovarian dysfunction induced by hyperandrogenism. Thirty-two infertile PCOS women and 147 infertile women with tubal blockage were recruited. PCOS women were divided into the hyperandrogenism (HA) PCOS group (n = 13) and nonhyperandrogenism (N-HA) PCOS group (n = 19). Sixty female Sprague-Dawley rats were used for PCOS model establishment. In GCs of HA PCOS women, PPARG1 mRNA expression was lower, whereas NCOR1 and HDAC3 mRNA expression were higher than N-HA PCOS women and controls (P < 0.05). When all women were divided into successful and failed pregnancy subgroups according to the following clinical pregnancy outcome, we found lower PPARG1 mRNA levels and higher NCOR1 and HDAC3 mRNA levels in the failed subgroup of HA PCOS (P < 0.05). Two hypermethylated CpG sites in the PPARG1 promoter and five hypomethylated CpG sites in the NCOR1 promoter were observed only in HA PCOS women (P < 0.01 to P < 0.0005). The acetylation levels of histone H3 at lysine 9 and p21 mRNA expression were decreased in human GCs treated with dihydrotestosterone in vitro (P < 0.05). PCOS rat models also showed alterations of PPARG1, NCOR1, and HDAC3 mRNA expression and methylation changes of PPARG1 and NCOR1, consistent with the results from humans. Hyperandrogenism induces the epigenetic alterations of PPARG1, NCOR1, and HDAC3 in GCs, which are involved in the ovarian dysfunction of HA PCOS.

We explored the effects of combination of acupuncture and Chinese medicinal herbs in treating model rats with polycystic ovarian syndrome (PCOS) and to explore whether acupuncture has positive effects on the absorption of salvianolic acid B in the extracts of a Chinese medicine formula when treating the model rats. 60 female Sprague-Dawley (SD) rats were randomly divided into Groups A, B, C, D, E and F, with ten rats in each group. Except Group F, all of the other rats were induced to PCOS with oral administration of letrozole. The rats in Group F served as normal controls. Group A was treated with acupuncture. Group B was treated with oral administration of the extracts of the Chinese medicine formula. Group C was treated with a combination of oral administration of the extracts of Chinese medicine and acupuncture. Group D received western medicine as positive controls. After treatment, the serum levels of follicle stimulating hormone (FSH), luteinizing hormone(LH) and testosterone (T) in each group were detected with the Enzyme-Linked ImmunoSorbent Assay (ELISA) and the serum concentration of salvianolic acid B were determined using High Performance Liquid Chromatography (HPLC). The serum levels of T and the ratio of LH/FSH in Group A, B. C, D, and F were significantly lower than those of Group E, indicating the model rats with PCOS were successfully established. Compared with Groups A, B, D and E, the serum levels of T and the ratio of LH/FSH in Group C were significantly lower respectively, indicating combination of acupuncture and Chinese medicinal herbs can significantly enhance curative effects in treating model rats with PCOS. The concentration of serum salvianolic acid Group C was significantly higher than Group B, indicating that acupuncture might improve the absorption of salvianolic acid B from the extracts of Salvia miltiorrhiza Bunge in the Chinese medicine formula. Combination of acupuncture and Chinese medicinal herbs significantly enhance curative effects in treating model rats with PCOS and acupuncture has positive effects in improving the absorption of salvianolic acid B in the extracts of the Chinese medicine formula when treating the model rats with PCOS.

Background: The present study was designed to evaluate whether the alteration of aquaporin-9 (AQP-9) expression in granulosa cells (GCs) of patients with polycystic ovary syndrome (PCOS) was associated with the hyperandrogenism in follicular fluid (FF)., Methods: We recruited infertile women with PCOS (n = 14) and infertile women with tubal blockage (controls, n = 31) for this study. We examined total testosterone (TT), free androgen index (FAI), sex hormone-binding globulin (SHBG), FSH, LH and estradiol in FF. Real-time PCR and western blotting were performed to assess AQP-9 expression in GCs, including effects of dihydrotestosterone (DHT) in vitro., Results: AQP-9 protein was localized in the nucleus, cytoplasm and cell membrane of the human GCs. The TT, FAI and LH levels were all higher, and SHBG levels lower, in the FF of women with PCOS versus controls (P = 0.0145, 0.0001, 0.0191, 0.0001, respectively). AQP-9 mRNA level in GCs of patients with PCOS was tightly correlated with the TT, SHBG levels and FAI in FF (P = 0.0020, 0.0001, 0.0020, respectively). In vitro, DHT (10(-9) mol/l) decreased AQP-9 mRNA (lowest at 12 h) and protein levels in control GCs (P = 0.0005, 0.0247, respectively). The inhibitory effect of DHT on AQP-9 mRNA was attenuated by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor (P = 0.0013). Fifty micromolar 4-(hydroxymercuri) benzoic acid sodium salt (PMB) and 10(-9) mol/l DHT blunted the swelling of GCs in hypotonic medium, respectively (P = 0.0350, 0.0027)., Conclusion: Hyperandrogenism in FF of women with PCOS inhibited AQP-9 in GCs through the PI3K pathway.

Background: Chinese herbal medicine (CHM) has significant effects that improve the reproductive functions of patients with polycystic ovary syndrome (PCOS). However, the intergenerational effects of CHM on offspring and the underlying mechanism of CHM remain unclear. This study aimed to explore the effects and the underlying mechanism of CHM, specifically the Bu-Shen-Tian-Jing formula (BSTJF), on model rats with polycystic ovary syndrome (PCOS) and the neurobehavioral alterations of female offspring born to PCOS rats administered BSTJF. Methods: High-performance liquid chromatography-mass spectrometry (HPLC–MS) and network pharmacology analysis were performed to identify the active ingredients and potential targets of BSTJF. Moreover, PCOS model rats were used to validate the role of BSTJF in reproduction and progeny neural development and to confirm the network pharmacological targets. Results: A total of 91 constituents were characterized from BSTJF. The 20 most significant KEGG pathways and the high-frequency genes of these pathways were predicted to be putative targets of these molecules. The rat experiment showed that the downregulation of FOS protein expression in the ovarian granulosa cells of the PCOS group was reversed by BSTJF. The target residence time of the 5-week-old female offspring of the BSTJF group was higher than that of the PCOS group in the water maze experiment. Compared to the PCOS group, the changes in dendritic spine density, ultrastructure of neurons and synapses, and Gabrb1 and Grin2b protein expression levels in the hippocampus of female offspring were partially reversed in the BSTJF group. Conclusions: BSTJF can effectively improve ovarian follicle development in PCOS rats and has positive effects on pubertal neurobehavioral alterations in the female offspring of these rats by reversing dendritic spine density, the ultrastructure of neurons and synapses, and the Gabrb1 and Grin2b protein expression levels in the hippocampus. [ABSTRACT FROM AUTHOR]

• Pregnancy outcomes of women with polycystic ovary syndrome (PCOS) remain unsatisfactory. • Chinese herbal medicine is widely used for treating gynecological endocrine disorders. • Bu-Shen-Jian-Pi Formula (BSJPF) can improve fertility potential among PCOS population. • BSJPF significantly enhanced bone morphogenetic protein 15 levels in follicular fluids. Chinese herbal medicine is widely used for treating polycystic ovary syndrome (PCOS). The present study aimed to explore the effects of Bu-Shen-Jian-Pi Formula, a Chinese herbal medicine formula, on the pregnancy outcomes of women with PCOS undergoing in vitro fertilization and embryo transfer (IVF-ET) based on a retrospective cohort study. One hundred and forty-six females with PCOS undergoing IVF-ET were included in the study from Women's Hospital, School of Medicine, Zhejiang University between July 2016 and June 2021, of whom 73 patients received Bu-Shen-Jian-Pi Formula treatment for 12 weeks before IVF-ET, while the other 73 did not. The clinical data were collected from the medical records of the included patients. Bone morphogenetic protein 15 (BMP15) and leukemia inhibitory factor levels in the follicular fluids were detected. After the treatment of Bu-Shen-Jian-Pi Formula, women with PCOS undergoing IVF-ET exhibited significant improvement in the fertilization (P<0.05), good-quality embryo (P<0.01), clinical pregnancy (P<0.01), and live birth (P<0.01) rates, and single birthweight in newborns (P<0.05). The expression levels of BMP15 in the follicular fluids of the women with PCOS were significantly increased after Bu-Shen-Jian-Pi Formula treatment (P<0.05). This study provided preliminary evidence of a significant association of Bu-Shen-Jian-Pi Formula treatment with improved pregnancy outcomes in women with PCOS undergoing IVF-ET, partly through increasing BMP15 levels in the follicular fluids. [ABSTRACT FROM AUTHOR]

Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The original article can be found online at https://doi.org/10.1007/s10815-021-02378-9. The article note "Fangfang Zhang and Liying Ying contributed equally to the present study" was incorrectly placed in the Keyword section and Fan Qu should be the only corresponding author. [Extracted from the article]

Abstract: Twelve water channels (aquaporins) are expressed in mammalian reproductive systems, and play very important roles in maintaining water homeostasis in reproductive cells. Impairment of their functions can result in attenuated male and female fertility. Alteration of AQPs expression is also found in reproductive tissues of the patients with polycystic ovarian syndrome, endometriosis or endometrium carcinoma. A lot of data have increased understanding of the functions and mechanisms of regulation of aquaporins at both the molecular and the clinical level. Researches have also focused on aquaporins as therapeutic targets. This review discusses recent advances in uncovering the physiological and pathophysiological roles of aquaporins in the reproductive systems. [Copyright &y& Elsevier]