Circular RNAs: Emerging Modulators in the Pathophysiology of Polycystic Ovary Syndrome and their Clinical Implications.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine/metabolic disorder in women of reproductive age. PCOS is characterized by hyperandrogenism, polycystic ovary morphology, and ovulatory dysfunction/anovulation. It involves multiple effects in patients, including granulosa/theca cell hyperplasia, menstrual disturbances, infertility, acne, obesity, insulin resistance, and cardiovascular disorders. Biochemical analyses and the results of RNA sequencing studies in recent years have shown a type of non-coding RNAs as a splicing product known as circular RNAs (circRNAs). Several biological functions have been identified in relation to circRNAs, including a role in miRNA sponge, protein sequestration, increased parental gene expression, and translation leading to polypeptides. These circular molecules are more plentiful and specialized than other types of RNAs. For this reason, they are referred to as potential biomarkers in different diseases. Evidence suggests that circRNAs may have regulatory potentials through different signaling pathways, such as the miRNA network. Probably most experts in the field of obstetricians are not aware of circRNAs as a useful biomarker. Therefore, this review focused on the researches that have been done on the involvement of circRNAs in PCOS and summarized recent supportive evidence, and evaluated the circRNA association and mechanisms involved in PCOS.

Granulosa cells from immature follicles exhibit restricted glycolysis and reduced energy production: a dominant problem in polycystic ovary syndrome.

PURPOSE: We hypothesized that immature oocytes are associated with impaired energy production in surrounding granulosa cells (GCs) in polycystic ovary syndrome (PCOS). Thus, this study investigated mitochondrial function, determined expression of glycolytic regulatory enzymes, and measured ATP levels in GCs of PCOS patients. METHODS: GCs were isolated from forty-five PCOS patients and 45 control women. Intracellular concentration of reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), the rate of glycolysis, total antioxidant capacity (TAC), activities of catalase (CAT) and superoxide dismutase (SOD), and ATP level were measured in GCs. The gene expression and protein levels of glycolytic enzymes (hexokinase, muscular phosphofructokinase, platelet derived phosphofructokinase, and muscular pyruvate kinase) were determined. Association of GC energy level with oocyte maturation was further validated by measuring glycolysis rate and ATP level in GCs isolated from mature and immature follicles from new set of fifteen PCOS patients and 15 controls. RESULTS: PCOS patients showed higher ROS level, decreased TAC, reduced CAT and SOD activities, and lower Δψm together with reduced expression of key glycolytic enzymes. ATP concentration and biochemical pregnancy were lower in PCOS compared with control group. ATP levels were found to be significantly correlated with ROS and Δψm (r = - 0.624 and r = 0.487, respectively). GCs isolated from immature follicles had significantly lower ATP levels and rate of glycolysis compared with the GCs separated from mature follicles in both PCOS patients and control. CONCLUSION: Declined energy due to the mitochondrial dysfunction and restrained glycolysis in GCs is associated with the immature oocytes and lower biochemical pregnancy in PCOS.

Association of glutamate cystein ligase (GCL) activity Peroxiredoxin 4 (prxR4) and apelin levels in women with preeclampsia.

INTRODUCTION: Preeclampsia is a common disease of pregnancy that is characterized by symptoms such as high blood pressure and proteinuria. Peroxiredoxin 4 (Prx4), is a protein with antioxidant properties which is produced in placenta and protects it from antioxidant stress and recurrent miscarriage. For regeneration of Peroxiredoxin 4 need to glutathione (GSH) and Glutamate-cysteine ligase (GCL) enzyme controls the pathway of glutathione regeneration. Apelin is a paired internal ligand with a G protein coupled receptor and is associated with angiotensin receptor (AT1) as a blood pressure regulator. This study was designed to evaluate GCL enzyme activity and Peroxiredoxin 4, glutathione and apelin levels in serum of women with preeclampsia. MATERIAL AND METHODS: Thirty pregnant women with preeclampsia and 30 healthy pregnant women were enrolled in this study. All participants were diagnosed by clinical examination and confirmation by Obstetrician-Gynecologist. The GCL enzyme activity and concentration of Prx4 and apelin in serum samples were measured using ready-to-use non-competitive ELISA methods while glutathione level was determined using Ellman's reagent. RESULTS: The GCL enzyme activity and Prx4 level were significantly lower in preeclampsia compared with control group (p < 0.05). In addition, marked reductions were observed in the concentrations of glutathione and apelin in preeclampsia compared to the healthy pregnant women (p < 0.05). CONCLUSION: This study identified the role of the GCL and Prx4 system in preeclampsia disorder and may be one of the ways to prevent and reduce the risks of preeclampsia in high-risk women using diet control and stress reduction.

Preliminary study showing no association between G238A (rs361525) tumor necrosis factor-α (TNF-α) gene polymorphism and its serum level, hormonal and biochemical aspects of polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the main cause of female infertility. Interactions among genetic, biochemical, and immunological factors can affect the pathogenesis of PCOS. As a proinflammatory cytokine, tumor necrosis factor-α (TNF-α) plays an important role in this regard. The present study aimed to evaluate the association of the rs361525 gene single-nucleotide polymorphism (SNP) and TNF-α serum levels with the hormonal and biochemical characteristics of PCOS in Iranian individuals. METHODS: The SNP rs361525 in the TNF-α gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in a total of 111 PCOS patients and 105 healthy females. Serum levels of TNF-α, lipid and hormone profiles, and biochemical factors were measured using enzyme-linked immunosorbent assay (ELISA) and calorimetric methods, as appropriate. RESULTS: The TNF-α serum level was higher in women with PCOS compared with the control group (p <  0.0001), and it was significantly correlated with the homeostasis model assessment (HOMA) factor (r = 0.138, p <  0.05). No significant differences were found in the genotype and allelic frequencies between the two groups (p >  0.05). Higher levels and significant differences were found for the HOMA factor, luteinizing hormone/follicle-stimulating hormone (LH/FSH), testosterone, and body mass index (BMI) in the PCOS group compared with the control group (p <  0.0001). High LH/FSH ratios (odds ratio [OR] = 1.98, 95% confidence interval [CI] = 1.20-3.28, p <  0.01), and high HOMA factor (OR = 5.04, 95% CI = 2.82-9.01, p <  0.001) were significantly associated with an increased risk of PCOS. CONCLUSIONS: Despite the lack of significant difference between rs361525 polymorphism of the TNF-α gene and PCOS, the serum level of TNF-α was increased in PCOS patients and positively correlated with the HOMA factor. Elevation of the LH/FSH ratio and HOMA for insulin resistance (HOMA-IR) increased the risk of PCOS. Therefore, TNF-α could indirectly contribute to PCOS progression.

Serum magnesium concentrations in polycystic ovary syndrome and its association with insulin resistance.

OBJECTIVE: It has been revealed that low serum magnesium (Mg) is often associated with insulin resistance (IR), cardiovascular problems, diabetes mellitus, and hypertension. Patients with polycystic ovary syndrome (PCOS) are known to have a high incidence of insulin resistance. This study was designed to determine whether women with PCOS exhibit serum magnesium deficiency and its potential association with IR. SUBJECTS AND METHODS: In this cross-sectional study, 103 cases with PCOS and 103 normal women who were matched for their age and body mass index (BMI) were included. Blood samples were collected after an overnight fast and concentrations of calcium, magnesium, testosterone, dehydroepianderosterone sulfate, insulin, fasting plasma glucose (FPG), triglyceride, total cholesterol, and HDL-cholesterol were measured. RESULTS: The risk of PCOS for subjects with Mg deficiency was 19 times greater than those who had normal serum Mg concentrations (p ≤ 0.0001). No correlation was found between Mg and insulin sensitivity or secretion, FPG, dyslipidemias, and also androgen concentrations. After adjustment for calcium concentration the role of magnesium to predict PCOS attenuated and became non-significant (ß:-1.9, p: 0.7). CONCLUSION: The present study provides the first evidence showing that magnesium deficiency is not associated with IR in PCOS. According the evidences of this study, serum calcium concentration is more potent predictor of PCOS than serum Mg and only calcium, not Mg, is related to insulin resistance in PCOS.

Decreased adiponectin levels in polycystic ovary syndrome, independent of body mass index.

BACKGROUND: Insulin resistance has been shown to have an association with polycystic ovary syndrome (PCOS). This study was designed to evaluate the potential role of adiponectin, which is linked with insulin resistance, in the etiology of PCOS and its relationship to obesity. METHODS: This case-control study consisted of 103 newly diagnosed PCOS cases and 73 female controls seen at a referral university hospital in Zanjan, Iran. Serum adiponectin, insulin, plasma fasting glucose, and lipid levels were measured. The homeostasis model assessment index was used to determine the level of insulin resistance. Women were classified as follows: Group I (normal nonlean women); group II (normal lean women); group III (nonlean women with PCOS); and group IV (lean women with PCOS) RESULTS: Adiponectin levels were decreased in women with PCOS (8.4 +/- 2.7 ng/mL vs. 13.6 +/- 5 ng/mL in the control group, P < 0.001). There was no significant difference between the adiponectin concentrations of women in group III and that in group IV (8.1 +/- 2.8 ng/mL vs. 9.2 +/- 2.6 ng/mL, respectively, P = 0.1). Adiponectin levels were significantly lower in group I compared with group II. A weak but significant negative correlation was found between adiponectin and insulin levels in all the subjects. Multiple regression analyses showed that the presence of PCOS was the only significant determinant of serum adiponectin levels. CONCLUSIONS: Adiponectin levels were reduced in all the women with PCOS. There seemed to be an interaction between adiponectin and PCOS pathogenesis that was independent of body mass index.