Pathology Of Polycystic Ovary Syndrome Research Articles

Sodium oligomannate's amelioration of reproductive and metabolic phenotypes in a letrozole-induced PCOS-like mouse model depends on the gut microbiome†.

It has been well established that there is a connection between polycystic ovary syndrome pathology and gut microbiome dysbiosis. A marine-derived oligosaccharide, GV-971, has been reported to alter gut microbiota and alleviate Aβ amyloidosis. In this study, the effects of GV-971 on polycystic ovary syndrome-like mice were explored. Mice were randomly assigned into four groups: control, letrozole, letrozole + GV-971, and control + GV-971. Glucose metabolism in polycystic ovary syndrome-like mice was ameliorated by GV-971, while the reproductive endocrine disorder of polycystic ovary syndrome-like mice was partially reversed. The messenger ribonucleic acid levels of steroidogenic enzymes in ovaries of polycystic ovary syndrome-like mice were improved. GV-971 restored the fertility of polycystic ovary syndrome-like mice and significantly increase the number of litters. Furthermore, GV-971 treatment effectively mitigated abnormal bile acid metabolism. Notably, after GV-971 intervention, gut microbiota alpha-diversity was considerably raised and the relative abundance of Firmicutes was reduced. In conclusion, the hyperinsulinemia and hyperandrogenemia of polycystic ovary syndrome-like mice were alleviated by GV-971 intervention, which was associated with mitigating bile acid metabolism and modulating gut microbiota.

Cellular senescence of granulosa cells in the pathogenesis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, but its pathology has not been fully characterized and the optimal treatment strategy remains unclear. Cellular senescence is a permanent state of cell-cycle arrest that can be induced by multiple stresses. Senescent cells contribute to the pathogenesis of various diseases, owing to an alteration in secretory profile, termed 'senescence-associated secretory phenotype' (SASP), including with respect to pro-inflammatory cytokines. Senolytics, a class of drugs that selectively eliminate senescent cells, are now being used clinically, and a combination of dasatinib and quercetin (DQ) has been extensively used as a senolytic. We aimed to investigate whether cellular senescence is involved in the pathology of PCOS and whether DQ treatment has beneficial effects in patients with PCOS. We obtained ovaries from patients with or without PCOS, and established a mouse model of PCOS by injecting dehydroepiandrosterone. The expression of the senescence markers p16INK4a, p21, p53, γH2AX, and senescence-associated β-galactosidase and the SASP-related factor interleukin-6 was significantly higher in the ovaries of patients with PCOS and PCOS mice than in controls. To evaluate the effects of hyperandrogenism and DQ on cellular senescence in vitro, we stimulated cultured human granulosa cells (GCs) with testosterone and treated them with DQ. The expression of markers of senescence and a SASP-related factor was increased by testosterone, and DQ reduced this increase. DQ reduced the expression of markers of senescence and a SASP-related factor in the ovaries of PCOS mice and improved their morphology. These results indicate that cellular senescence occurs in PCOS. Hyperandrogenism causes cellular senescence in GCs in PCOS, and senolytic treatment reduces the accumulation of senescent GCs and improves ovarian morphology under hyperandrogenism. Thus, DQ might represent a novel therapy for PCOS.

SAT355 Single-Cell RNA Sequencing Pipeline for the Human Ovary Using IVF Tissue

Abstract Disclosure: A.J. Hanson: None. S. Shah: None. C. Wai: None. R. Bauer: None. C. Boots: None. M. Urbanek: None. Objective: Polycystic Ovary Syndrome (PCOS) is the most common endocrinopathy of reproductive aged women, affecting 6-15% of women in this age group. Defined by hyperandrogenism and irregular menses, PCOS is a complex trait with a strong genetic component; its underlying cause remains poorly understood. To understand the molecular pathogenesis of PCOS, an appropriate experimental model of the human ovary is needed. The ovary is the primary source of androgen production and an essential regulator of ovulation and menstruation, the key processes disrupted in PCOS. Discard tissue from oocyte retrievals as part of assisted reproduction treatment (ART) is a plentiful source of human ovarian tissue, requires no additional risk to the patient, and is enriched for subjects with PCOS. Therefore, we developed a pipeline using discard ovarian aspirate tissue from reproductively healthy women and women with PCOS undergoing oocyte retrievals for ART to generate a single-cell (sc) transcriptomic atlas of human ovaries. We will use those maps to define the differences in gene expression between the two groups and determine the impact of genetic variation on human ovary function in women with PCOS. Materials and Methods: Our pipeline consists of i. harvesting oocyte retrieval discard tissue including follicular fluid, pieces of ovary, and blood from reproductively healthy women and women with PCOS ii. generating a sc suspension of ovarian cells, iii. constructing and sequencing a scRNA sequencing library, iv. building a transcriptomic atlas of the ovary, and v. identifying differences in cell abundance and expression between reproductively healthy women and women with PCOS. Results: We have processed samples from seven reproductively healthy women and eight women with PCOS using this scRNA sequencing pipeline. The sc isolation protocol resulted in a sc suspension with high viability (95%) and yield (19.6 x106 cells/mL), demonstrating that we can generate a large quantity of high-quality sc suspensions. The sequenced single cells were clustered into distinct groups based on their transcriptomes including cell types predicted to be affected by PCOS including theca, granulosa, and immune cells. Conclusions: We successfully created a scRNA sequencing pipeline from discard oocyte retrieval tissue and generated transcriptomic maps of the human ovary of reproductively healthy women and women with PCOS, demonstrating the feasibility of our approach. Impact Statement: By integrating our transcriptomic data with whole exome sequencing (WES) data to assess the impact of genomic variation on ovarian cellular composition and transcriptional profiles, we will, for the first time, evaluate the impact of an individual woman’s genetic variation on their ovarian functional profile, a critical first step towards understanding the underlying pathology of PCOS and personalized medicine. Presentation Date: Saturday, June 17, 2023

FRI457 Protein-coding Genetic Variation In Polycystic Ovary Syndrome

Abstract Disclosure: C. Parker: None. R. Bauer: None. C.K. Welt: None. R.S. Legro: None. M.G. Hayes: None. M. Urbanek: None. Background: Polycystic ovary syndrome (PCOS) is a multisystem endocrine disorder and is the most common form of anovulatory infertility of reproductive aged women (6-15%). PCOS is characterized by the presence of hyperandrogenemia, irregular menses, and polycystic ovarian morphology. A previous twin study has shown PCOS to be highly heritable (h2=0.72). Thus, we hypothesize that genetic variation is a major contributor to the etiology of PCOS. Objective: Our goal is to identify the genetic factors that contribute to the PCOS phenotype and how they define phenotypic subtypes of PCOS with the aim of better understanding PCOS pathology and optimizing treatment strategies for individual women. Methodology: We are performing whole exome sequencing (WES) supplemented with genomic regions mapping to PCOS GWAS loci on 772 subjects with PCOS and 300 age and ancestry-matched controls to generate a comprehensive catalog of PCOS-associated protein coding variants. We will use prediction tools to identify likely-to-be deleterious variants and in silico evidence of epigenetic modification to identify PCOS associated genes/pathways. We will then prioritize variants for molecular follow-up creating a comprehensive catalog of protein coding variants associated with PCOS. We expect the variants identified by WES to map to multiple genes and pathways including novel genes/pathways which have not previously been implicated in PCOS as well as genes/pathways that have previously been shown or predicted to play a major role in the etiology of PCOS by us or other groups. Results: To date we have obtained high quality sequencing data on 772 women with PCOS. Sequencing of 300 age and ancestry matched reproductively heathy women is being started. We have identified 81 rare protein coding genetic variants using targeted re-sequencing in three distinct pathways in an independent PCOS cohort. These genes are associated with insulin resistance, the gonadotropin signaling pathway and the Anti-Müllerian Hormone (AMH) signaling pathway. We identified 37 functionally validated deleterious variants in genes that encode AMH or its cognate receptor AMHR2, 7 rare variants that encode LMNA, 11 rare (MAF <0.1) variants that encode the insulin receptor, and 26 coding variants for the genes encoding the beta subunit of gonadotropins, LH and FSH, and their receptors, FSHR and LHCGR. Conclusion: We have identified 81 rare protein altering genetic variants in pathways that are predicted to be impaired in individuals with PCOS supporting a critical role for genetics in the etiology of PCOS. Our WES screen will allow us to generate a comprehensive catalog of likely to be deleterious PCOS associated variants. This catalog of variants will identify the genes/pathways that are mutated in PCOS leading to improved personalized phenotyping and treatment of PCOS. Presentation Date: Friday, June 16, 2023

Assessment of chemokines MIP-1α and MIP-1 βin Iraqi women with polycystic ovarian syndrome

Polycystic ovary syndrome (PCOS) is reproductive, endocrine, and metabolic disorder affecting females. The pathology of PCOS is complicated and associated to chronic low-grade inflammation, this includes a disruption in pro-inflammatory factor production, leukocytosis, and endothelial cell dysfunction, also associated with high level of pro-inflammatory cytokines, chemokines and leukocyte count. In addition, PCOS is characterized by hormonal and immunological dysfunction. Inflammation of the ovary affects ovulation and induces or aggravates systemic inflammation. Macrophage inflammatory protein-1 (MIP-1), a pro-inflammatory chemokine, is crucial in the recruitment of inflammatory and immunological cells to the place of inflammation or infection, T- and B-lymphocytes, neutrophils, macrophages, mast cells, dendritic cells and natural killer cells are all capable of producing large amounts of MIP-1. The current study aimed to investigate the role of MIP-1α and MIP-1β in Iraqi patients with PCOS and their correlation with obesity and other demographic parameters. This study included two groups, 60 women with PCOS and 30 control women, conducted during the period from October 2022 to January 2023. The diagnosis of PCOS women was based on two out of three of the following diagnostic criteria (hyperandrogenism – oligo or anovulation – polycystic ovaries). MIP-1 alpha and Beta levels were determined by ELISA. The outcomes revealed that the group with PCOS showed significant increase in the level of MIP-1α (635.28 ±20.58) than in the control women, (571.20 ±25.92), (p<0.05). Although there was an increase the level of MIP-1β in women with PCOS (191.85 ±17.54) than in the control group (165.31 ±11.01), the difference did not reach statistical significance. In conclusion, based on our findings, that MIP-1α and MIP-1β increased in PCOS cases, this may indicate that PCOS is low grade chronic inflammation.

The role of B cells in immune cell activation in polycystic ovary syndrome.

Variations in B cell numbers are associated with polycystic ovary syndrome (PCOS) through unknown mechanisms. Here we demonstrate that B cells are not central mediators of PCOS pathology and that their frequencies are altered as a direct effect of androgen receptor activation. Hyperandrogenic women with PCOS have increased frequencies of age-associated double-negative B memory cells and increased levels of circulating immunoglobulin M (IgM). However, the transfer of serum IgG from women into wild-type female mice induces only an increase in body weight. Furthermore, RAG1 knock-out mice, which lack mature T- and B cells, fail to develop any PCOS-like phenotype. In wild-type mice, co-treatment with flutamide, an androgen receptor antagonist, prevents not only the development of a PCOS-like phenotype but also alterations of B cell frequencies induced by dihydrotestosterone (DHT). Finally, B cell-deficient mice, when exposed to DHT, are not protected from developing a PCOS-like phenotype. These results urge further studies on B cell functions and their effects on autoimmune comorbidities highly prevalent among women with PCOS.

P-735 Are there any differences in preimplantation blastocyst chromosomal abnormalities between polycystic ovary syndrome patients and controls? A multi-center retrospective cohort study

Abstract Study question Are there possible differences in the preimplantation blastocyst chromosome aberrations between polycystic ovary syndrome (PCOS) patients and controls? Summary answer PCOS lowers aneuploidy risk but increases mosaicism risk in preimplantation embryos, and PCOS-related insulin resistance should be investigated as a potential cause. What is known already PCOS is thought to alter granulosa cell functions and effects on oocyte development, potentially leading to chromosomal abnormalities and increasing the risk of pregnancy loss. However, few studies have compared the chromosomal status of preimplantation embryos from PCOS patients to those from healthy controls. Study design, size, duration This was a multi-center retrospective cohort study conducted at 3 IVF centers. A total of 707 blastocysts from 147 PCOS patients and 3006 blastocysts from 821 control women receiving preimplantation genetic testing (PGT) between 2015 and 2021. Participants/materials, setting, methods PGT was performed using next-generation sequencing (NGS). Differences in the chromosome aberrations were compared. Multivariate and subgroup analyses were conducted to control for confounders. Influences of insulin resistance and PCOS phenotype on the risks of specific chromosomal abnormalities were also examined. Main results and the role of chance Compared to controls, blastocysts from PCOS patients demonstrated lower aneuploidy rate (14.7% vs. 25.4%, P < 0.001) but greater mosaicism rate (16.5% vs. 8.7%, P < 0.001). Multivariable analysis adjusting for age, IVF center, body mass index (BMI), total gonadotropin (Gn) dose, and peak serum estradiol (E2) on trigger day, identified PCOS as an independent protective factor against embryonic aneuploidy (adjusted OR = 0.56, 95% CI, 0.42–0.76, P<0.001) but a risk factor for embryonic mosaicism (adjusted OR = 2.05, 95% CI 1.48–2.85, P<0.001). These differences in chromosomal spectrum were also observed in subgroups stratified by age, IVF center and BMI. Further multivariate analysis suggested that insulin resistance could be responsible for the increased risk of embryonic mosaicism among PCOS patients (OR = 1.89, 95% CI, 1.06–3.34, P=0.03). Limitations, reasons for caution The main limitation is the retrospective design. Besides, methodological uncertainties still exist in detecting mosaicism in current reproductive medicine. A longer-term, multiple-center prospective study with greater methodological standardization is warranted to confirm the present results. Wider implications of the findings These results suggest that PCOS pathology may increase the risk of mitosis errors but not the risk of meiosis errors during oocyte development, and PCOS-related insulin resistance should be investigated as a potential cause. Trial registration number 2020[325]

Transcriptomic survey of key reproductive and metabolic tissues in mouse models of polycystic ovary syndrome

Excessive androgen production and obesity are key to polycystic ovary syndrome (PCOS) pathogenesis. Prenatal androgenized (PNA), peripubertal androgenized, and overexpression of nerve growth factor in theca cells (17NF) are commonly used PCOS-like mouse models and diet-induced maternal obesity model is often included for comparsion. To reveal the molecular features of these models, we have performed transcriptome survey of the hypothalamus, adipose tissue, ovary and metaphase II (MII) oocytes. The largest number of differentially expressed genes (DEGs) is found in the ovaries of 17NF and in the adipose tissues of peripubertal androgenized models. In contrast, hypothalamus is most affected in PNA and maternal obesity models suggesting fetal programming effects. The Ms4a6e gene, membrane-spanning 4-domains subfamily A member 6E, a DEG identified in the adipose tissue in all mouse models is also differently expressed in adipose tissue of women with PCOS, highlighting a conserved disease function. Our comprehensive transcriptomic profiling of key target tissues involved in PCOS pathology highlights the effects of developmental windows for androgen exposure and maternal obesity, and provides unique resource to investigate molecular mechanisms underlying PCOS pathogenesis.

The E3 Ubiquitin Ligase SYVN1 Plays an Antiapoptotic Role in Polycystic Ovary Syndrome by Regulating Mitochondrial Fission.

Polycystic ovary syndrome (PCOS) is one of the most common hormonal disorders among premenopausal women. PCOS is accompanied by many other reproductive, endocrinal, and metabolic disorders thus amassing the difficulties encountered by the women affected. However, there is limited information on its molecular etiology. Synoviolin (SYVN1) is an E3 ubiquitin ligase that is thought to participate in the pathology of PCOS. However, the expression and function of SYVN1 in PCOS are unknown. In this study, we found that downregulation of SYVN1 expression was followed by increased apoptosis in the granulosa cells (GCs) of patients with PCOS. Subsequent in vitro experiments indicated that the overexpression of SYVN1 inhibited apoptosis and mitochondrial fission. Furthermore, using immunoprecipitation and western blotting, we identified that SYVN1 promoted the degradation of Drp1 via the proteasome-dependent pathway. Additionally, we generated a PCOS model in female Sprague Dawley rats and treated them with an SYVN1 inhibitor, LS-102. We observed that the inhibition of SYVN1 increased Drp1 levels and exacerbated the degeneration of GCs in the PCOS rat model. Finally, in vitro and in vivo experiments showed that SYVN1 inhibits apoptosis and mitochondrial fission by promoting Drp1 degradation in GCs. These results highlight the function of SYVN1 in PCOS and provide a potential target for the clinical treatment of PCOS.

Association of insertion/deletion polymorphism of angiotensin converting enzyme gene with metabolic components of polycystic ovary syndrome

Background: Polycystic ovary syndrome (PCOS) has taken the prime position as an endocrine disease in women of reproductive age and is estimated to affect 2.2–22.5% worldwide and in Indian women it ranges from 9% to 12%. The primary defects that cause PCOS still remains unknown. A lot of genetic factors not excluding polymorphisms and mutations of multiple genes have been linked with PCOS, exact mechanisms which might be the cause of PCOS are yet unknown. Angiotensin converting enzyme (ACE) and its yields are related with angiogenesis of ovarian epithelium, restoration of meiosis, steroidogenesis, and follicular growth. Aims and Objectives: The present study was aimed to establish the association of ACE insertion/deletion (I/D) polymorphism in PCOS patients and to assess the influence of this polymorphism on the metabolic components of PCOS. Materials and Methods: Genomic DNA was extracted from blood obtained from 100 patients with PCOS and 100 healthy controls following ethical guidelines. DNA was amplified by polymerase chain reaction (PCR) using I/D distinct allele primers. PCR products were assessed after being exposed to gel electrophoresis. Results were analyzed in respect to biochemical parameters. Results: The allelic frequency and genotypic distribution of the ACE gene polymorphism is associated with PCOS in women. The concentrations of testosterones as well as luteinizing hormone/follicle stimulating hormone ratio among the distinct genotypes were significantly different. The presence of “D” allele in a population more likely to be associated with formation of polycystic ovary and hyperandrogenism was observed. Conclusion: The data suggest that ACE I/D polymorphism and PCOS pathology are unassociated. However, aggravation of clinical symptoms of PCOS can be linked to the steroidogenesis which, in turn, is associated with the polymorphism.

The interplay between PCOS pathology and diet on gut microbiota in a mouse model

ABSTRACT The gut microbiome has been implicated in polycystic ovary syndrome (PCOS) pathophysiology. PCOS is a disorder with reproductive, endocrine and metabolic irregularities, and several studies report that PCOS is associated with a decrease in microbial diversity and composition. Diet is an important regulator of the gut microbiome, as alterations in macronutrient composition impact the balance of gut microbial communities. This study investigated the interplay between macronutrient balance and PCOS on the gut microbiome of control and dihydrotestosterone (DHT)-induced PCOS-like mice exposed to diets that varied in protein (P), carbohydrate (C) and fat (F) content. The amount of dietary P, C and F consumed significantly altered alpha (α) and beta (β) diversity of the gut microbiota of control and PCOS-like mice. However, α-diversity between control and PCOS-like mice on the same diet did not differ significantly. In contrast, β-diversity was significantly altered by PCOS pathology. Further analysis identified an operational taxonomic unit (OTU) within Bacteroides (OTU3) with 99.2% similarity to Bacteroides acidifaciens, which is inversely associated with obesity, to be significantly decreased in PCOS-like mice. Additionally, this study investigated the role of the gut microbiome in the development of PCOS traits, whereby PCOS-like mice were transplanted with healthy fecal microbiota from control mice. Although the PCOS gut microbiome shifted toward that of control mice, PCOS traits were not ameliorated. Overall, these findings demonstrate that while diet exerts a stronger influence over gut microbiota diversity than PCOS pathology, overall gut microbiota composition is affected by PCOS pathology.

Unusual suspects: Glial cells in fertility regulation and their suspected role in polycystic ovary syndrome.

Gonadotropin‐releasing‐hormone (GnRH) neurons sitting within the hypothalamus control the production of gametes and sex steroids by the gonads, therefore ensuring survival of species. As orchestrators of reproductive function, GnRH neurons integrate information from external and internal cues. This occurs through an extensively studied neuronal network known as the “GnRH neuronal network.” However, the brain is not simply composed of neurons. Evidence suggests a role for glial cells in controlling GnRH neuron activity, secretion and fertility outcomes, although numerous questions remain. Glial cells have historically been seen as support cells for neurons. This idea has been challenged by the discovery that some neurological diseases originate from glial dysfunction. The prevalence of infertility disorders is increasing worldwide, with one in four couples being affected; therefore, it remains essential to understand the mechanisms by which the brain controls fertility. The “GnRH glial network” could be a major player in infertility disorders and represent a potential therapeutic target. In polycystic ovary syndrome (PCOS), the most common infertility disorder of reproductive aged women worldwide, the brain is considered a prime suspect. Recent studies have demonstrated pathological neuronal wiring of the “GnRH neuronal network” in PCOS‐like animal models. However, the role of the “GnRH glial network” remains to be elucidated. In this review, I aim to propose glial cells as unusual suspects in infertility disorders such as PCOS. In the first part, I state our current knowledge about the role of glia in the regulation of GnRH neurons and fertility. In the second part, based on our recent findings, I discuss how glial cells could be implicated in PCOS pathology.

Polycystic Ovary Syndrome and the Neuroendocrine Consequences of Androgen Excess.

Polycystic ovary syndrome (PCOS) is a major endocrine disorder strongly associated with androgen excess and frequently leading to female infertility. Although classically considered an ovarian disease, altered neuroendocrine control of gonadotropin-releasing hormone (GnRH) neurons in the brain and abnormal gonadotropin secretion may underpin PCOS presentation. Defective regulation of GnRH pulse generation in PCOS promotes high luteinizing hormone (LH) pulsatile secretion, which in turn overstimulates ovarian androgen production. Early and emerging evidence from preclinical models suggests that maternal androgen excess programs abnormalities in developing neuroendocrine circuits that are associated with PCOS pathology, and that these abnormalities are sustained by postpubertal elevation of endogenous androgen levels. This article will discuss experimental evidence, from the clinic and in preclinical animal models, that has significantly contributed to our understanding of how androgen excess influences the assembly and maintenance of neuroendocrine impairments in the female brain. Abnormal central gamma-aminobutyric acid (GABA) signaling has been identified in both patients and preclinical models as a possible link between androgen excess and elevated GnRH/LH secretion. Enhanced GABAergic innervation and drive to GnRH neurons is suspected to contribute to the pathogenesis and early manifestation of neuroendocrine derangement in PCOS. Accordingly, this article also provides an overview of GABA regulation of GnRH neuron function from prenatal development to adulthood to discuss possible avenues for future discovery research and therapeutic interventions. © 2022 American Physiological Society. Compr Physiol 12:3347-3369, 2022.

The role of gonadotropin-releasing hormone neurons in polycystic ovary syndrome.

Given the critical central role of gonadotropin‐releasing hormone (GnRH) neurons in fertility, it is not surprising that the GnRH neural network is implicated in the pathology of polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility. Although many symptoms of PCOS relate most proximately to ovarian dysfunction, the central reproductive neuroendocrine system ultimately drives ovarian function through its regulation of anterior pituitary gonadotropin release. The typical cyclical changes in frequency of GnRH release are often absent in women with PCOS, resulting in a persistent high‐frequency drive promoting gonadotropin changes (i.e., relatively high luteinizing hormone and relatively low follicle‐stimulating hormone concentrations) that contribute to ovarian hyperandrogenemia and ovulatory dysfunction. However, the specific mechanisms underpinning GnRH neuron dysfunction in PCOS remain unclear. Here, we summarize several preclinical and clinical studies that explore the causes of aberrant GnRH secretion in PCOS and the role of disordered GnRH secretion in PCOS pathophysiology.

Pathophysiology of polycystic ovary syndrome revisited: Current understanding and perspectives regarding future research.

BackgroundPolycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive‐age women and has lifelong effects on health.MethodsIn this review, I discuss the pathophysiology of PCOS. First, I summarize our current understanding of the etiology and pathology of PCOS, then, discuss details of two representative environmental factors involved in the pathogenesis of PCOS. Finally, I present perspectives regarding the directions of future research.Main findingsThe pathophysiology of PCOS is heterogeneous and shaped by the interaction of reproductive dysfunction and metabolic disorders. Hyperandrogenism and insulin resistance exacerbate one another during the development of PCOS, which is also affected by dysfunction of the hypothalamus‐pituitary‐ovarian axis. PCOS is a highly heritable disorder, and exposure to certain environmental factors causes individuals with predisposing genetic factors to develop PCOS. The environmental factors that drive the development of PCOS pathophysiology make a larger contribution than the genetic factors, and may include the intrauterine environment during the prenatal period, the follicular microenvironment, and lifestyle after birth.ConclusionOn the basis of this current understanding, three areas are proposed to be subjects for future research, with the ultimate goals of developing therapeutic and preventive strategies and providing appropriate lifelong management, including preconception care.

Evaluating the Differential Expression of miR-146a, miR-222, and miR-9 in Matched Serum and Follicular Fluid of Polycystic Ovary Syndrome Patients: Profiling and Predictive Value.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder of women in reproductive age with significant effects on reproductive and metabolic functions. Many molecular players may be involved in PCOS pathology; however, miRNAs possess great ability in gene expression control in normal ovarian function and folliculogenesis. We appraised the relative expression of miR-146a, miR-222, miR-9, and miR-224 in serum and follicular fluid (FF) of PCOS patients compared to control subjects. PCOS (n = 35) and control (n = 30) subjects were recruited in the study during their enrolment in IVF cycles. Serum and FF of human subjects were collected and stored. Total RNA was isolated from samples and cDNA was synthesized using miRNA-specific stem-loop RT primers. Quantitative real-time PCR was used to evaluate the expression of miRNAs relative to U6 expression. The predictive value of miRNAs' expression for discrimination of PCOS patients from control subjects was evaluated by receiver-operating characteristic (ROC) curve analysis. miR-224 was not detected in serum and FF samples. Significantly, higher levels of miR-146a and miR-9 in serum of PCOS group were detected. In contrast, relative expression of miR-146a and miR-9 significantly decreased in FF. In PCOS group, relative expression of all detected miRNAs was elevated in serum in comparison to FF, whereas in control group no change was noticed. Combination of FF miRNAs showed improved predictive value with area under the ROC curve (AUC) of 0.84, 93.8% sensitivity, and 83.3% specificity. Contradicting alternations of miRNAs in serum and FF are indicative of different sources of miRNAs in body fluids. Presumptive target genes of studied miRNAs in signalling pathways may show the potential role of these miRNA in folliculogenesis.

Contribution of high-fat diet-induced PCSK9 upregulation to a mouse model of PCOS is mediated partly by SREBP2.

The incidence of polycystic ovary syndrome (PCOS) due to high-fat diet (HFD) consumption has been increasing significantly. However, the mechanism by which a HFD contributes to the pathogenesis of PCOS has not been elucidated. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein that regulates cholesterol metabolism. Our previous study revealed abnormally high PCSK9 levels in serum from patients with PCOS and in serum and hepatic and ovarian tissues from PCOS model mice, suggesting that PCSK9 is involved in the pathogenesis of PCOS. However, the factor that induces high PCSK9 expression in PCOS remains unclear. In this study, Pcsk9 knockout mice were used to further explore the role of PCSK9 in PCOS. We also studied the effects of a HFD on the expression of PCSK9 and sterol regulatory element-binding protein 2 (SREBP2), a regulator of cholesterol homeostasis and a key transcription factor that regulates the expression of PCSK9, and the roles of these proteins in PCOS pathology. Our results indicated HFD may play an important role by inducing abnormally high PCSK9 expression via SREBP2 upregulation. We further investigated the effects of an effective SREBP inhibitor, fatostain, and found that it could reduce HFD-induced PCSK9 expression, ameliorate hyperlipidemia and improve follicular development in PCOS model mice. Our study thus further elucidates the important role of an HFD in the pathogenesis of PCOS and provides a new clue in the prevention and treatment of this disorder.

Increased miR-188-3p in Ovarian Granulosa Cells of Patients with Polycystic Ovary Syndrome.

MicroRNA-target networks are often dysregulated in diseases. Our purpose is to investigate this dysregulation of polycystic ovary syndrome (PCOS). Through the bioinformatics reanalysis of the public RNAseq dataset, we found that miR-188-3p was the miRNA with the highest induction rate, and indicated that miR-188-3p might have a rare function of upregulating its targeted expression. This discovery will increase our understanding of the pathology of PCOS and provide new targets for treatment strategies.

Circulating resistin and follistatin levels in obese and non-obese women with polycystic ovary syndrome: A systematic review and meta-analysis.

This meta-analysis was performed to resolve the inconsistencies regarding resistin and follistatin levels in women with polycystic ovary syndrome (PCOS) by pooling the available evidence. A systematic literature search using PubMed and Scopus was carried out through November 2020 to obtain all pertinent studies. Weighted mean differences (WMDs) with corresponding 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between the levels of resistin and follistatin with PCOS in the overall and stratified analysis by obesity status. A total of 47 publications, 38 for resistin (2424 cases; 1906 controls) and 9 studies for follistatin (815 cases; 328 controls), were included in the meta-analysis. Resistin levels were significantly higher in PCOS women compared with non-PCOS controls (WMD = 1.96 ng/ml; 95%CI = 1.25-2.67, P≤0.001) as well as in obese PCOS women vs. obese controls, and in non-obese PCOS women compared with non-obese controls, but not in obese PCOS vs. non-obese PCOS patients,. A significantly increased circulating follistatin was found in PCOS patients compared with the controls (WMD = 0.44 ng/ml; 95%CI = 0.30-0.58, P≤0.001) and in non-obese PCOS women compared with non-obese controls and in obese PCOS women vs. obese controls, but, no significant difference in follistatin level was observed in obese PCOS compared with non-obese PCOS women. Significant heterogeneity and publication bias was evident for some analyses. Circulating levels of resistin and follistatin, independent of obesity status, are higher in women with PCOS compared with controls, showing that these adipokines may contribute to the pathology of PCOS.

Induction of aryl hydrocarbon receptor in granulosa cells by endoplasmic reticulum stress contributes to pathology of polycystic ovary syndrome.

Recent studies have uncovered the critical role of aryl hydrocarbon receptor (AHR) in various diseases, including obesity and cancer progression, independent of its previously identified role as a receptor for endocrine-disrupting chemicals (EDCs). We previously showed that endoplasmic reticulum (ER) stress, a newly recognized local factor in the follicular microenvironment, is activated in granulosa cells from patients with polycystic ovary syndrome (PCOS) and a mouse model of the disease. By affecting diverse functions of granulosa cells, ER stress contributes to PCOS pathology. We hypothesized that expression of AHR and activation of its downstream signaling were upregulated by ER stress in granulosa cells, irrespective of the presence of EDCs, thereby promoting PCOS pathogenesis. In this study, we found that AHR, AHR nuclear translocator (ARNT), and AHR target gene cytochrome P450 1B1 (CYP1B1) were upregulated in the granulosa cells of PCOS patients and model mice. We examined CYP1B1 as a representative AHR target gene. AHR and ARNT were upregulated by ER stress in human granulosa-lutein cells (GLCs), resulting in an increase in the expression and activity of CYP1B1. Administration of the AHR antagonist CH223191 to PCOS mice restored estrous cycling and decreased the number of atretic antral follicles, concomitant with downregulation of AHR and CYP1B1 in granulosa cells. Taken together, our findings indicate that AHR activated by ER stress in the follicular microenvironment contributes to PCOS pathology, and that AHR represents a novel therapeutic target for PCOS.