Beneficial Effects of Curcumin on Rats with Polycystic Ovary Syndrome: Evaluation of the Gene Expression of GLUT4, Erα and Insulin Resistance

Abstract Context Inflammation and insulin resistance are often present in polycystic ovary syndrome (PCOS). Objective We determined the effect of saturated fat ingestion on mononuclear cell (MNC) nuclear factor-κB (NFκB) activation; NFκB, inhibitory-κBα (IκBα), and tumor necrosis factor-α (TNFα) gene expression; and circulating C-reactive protein (CRP) in women with PCOS. Design Cross-sectional study. Setting Academic medical center. Patients Twenty reproductive-age women with PCOS (10 lean, 10 with obesity) and 20 ovulatory controls (10 lean, 10 with obesity). Main Outcome Measures Activated NFκB, NFκB heterodimer subunits, IκBα and TNFα messenger ribonucleic acid content and NFκB p65 and IκBα protein content were quantified in mononuclear cells (MNC), and CRP was measured in plasma from blood drawn fasting and 2, 3, and 5 h after saturated fat ingestion. Insulin sensitivity was derived from oral glucose tolerance testing (ISOGTT). Androgen secretion was assessed from blood drawn fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration. Results In response to saturated fat ingestion, women with PCOS regardless of weight class exhibited lipid-induced increases in activated NFκB, NFκB, and TNFα gene expression and plasma CRP and decreases in IκBα protein compared with lean control subjects. Both PCOS groups exhibited lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. Lipid-stimulated NFκB activation was negatively correlated with ISOGTT, and positively correlated with HCG-stimulated androgen secretion. Conclusion In PCOS, increases in NFκB activation and circulating CRP and decreases in IκBα protein following saturated fat ingestion are independent of obesity. Circulating MNC and excess adipose tissue are separate and distinct contributors to inflammation in this disorder.

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Expression of the CD11c gene in subcutaneous adipose tissue is associated with cytokine level and insulin resistance in women with polycystic ovary syndrome

Acta Endocrinologica ◽

10.1530/eje-12-0340 ◽

2012 ◽

Vol 167 (5) ◽

pp. 705-713 ◽

Cited By ~ 11

Author(s):

Tao Tao ◽

Shengxian Li ◽

Aimin Zhao ◽

Yanyun Zhang ◽

Wei Liu

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Adipose Tissue ◽

Polycystic Ovary Syndrome ◽

Subcutaneous Adipose Tissue ◽

Polycystic Ovary ◽

Mrna Abundance ◽

Model Assessment ◽

Ovary Syndrome ◽

Subcutaneous Adipose

Objective Alterations in the phenotypes of macrophages in adipose tissue play a key role in inflammation and insulin resistance (IR). The phenotypes of macrophages in subcutaneous adipose tissue (SAT) and the relationship between proinflammation markers and IR in women with polycystic ovary syndrome (PCOS) remain unclear. The objectives of this study are to characterize the gene expression of macrophage markers and cytokines in the SAT of PCOS women and to estimate their relationships with circulating levels of cytokines and IR. Methods The cross-sectional study involves 16 PCOS women and 18 normal control women. Cytokines and macrophage markers in the circulation and SAT were determined using ELISA, quantitative PCR, or immunofluorescence staining. IR was estimated using the homeostasis model assessment (HOMA-IR). Results The gene expression levels of CD11c along with TNF α and leptin in SAT remained significantly higher in PCOS women than in normal women (P<0.05). However, no significant differences were found in CD68 mRNA expression in SAT between women with and without PCOS (P>0.05). Furthermore, CD11c mRNA abundance provided a stronger contribution to models predicting serum levels of TNFα (sTNFα) than did CD68 mRNA abundance. Lastly, increased sTNFα was associated with increased HOMA-IR in PCOS women, and this association was independent of both overall and visceral adiposity. Conclusion The high expression level of CD11c mRNA in SAT was proved to be an important feature in PCOS women. Furthermore, CD11c mRNA abundance made a stronger contribution to models predicting sTNFα in which existing proinflammatory properties might significantly contribute to the pathogenesis of IR in PCOS women.

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Ovarian angiogenesis in polycystic ovary syndrome

Reproduction ◽

10.1530/rep-17-0597 ◽

2018 ◽

Vol 155 (5) ◽

pp. R199-R209 ◽

Cited By ~ 10

Author(s):

Mariana Di Pietro ◽

Natalia Pascuali ◽

Fernanda Parborell ◽

Dalhia Abramovich

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Corpus Luteum ◽

Polycystic Ovary ◽

Follicular Development ◽

Reproductive Age ◽

Ovarian Cysts ◽

Therapeutic Approaches ◽

Ovary Syndrome ◽

Beneficial Effects

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine pathology among women in reproductive age. Its main symptoms are oligo or amenorrhea, hyperandrogenism and the presence of ovarian cysts. It is also associated with infertility, obesity and insulin resistance. Mainly due to its heterogeneity, PCOS treatments are directed to manage its symptoms and to prevent associated diseases. The correct formation and regression of blood vessels during each ovarian cycle is indispensable for proper follicular development, ovulation and corpus luteum formation. The importance of these processes opened a new and promising field: ovarian angiogenesis. Vascular alterations characterize numerous pathologies, either with increased, decreased or abnormal angiogenesis. In the last years, several anomalies of ovarian angiogenesis have been described in women with PCOS. Therefore, it has been suggested that these alterations may be associated with the decreased – or lack of – ovulation rates and for the formation of cysts in the PCOS ovaries. Restoration of a proper vessel formation in the ovaries may lead to improved follicular development and ovulation in these patients. In the present review, we attempt to summarize the alterations in ovarian angiogenesis that have been described in women with PCOS. We also discuss the therapeutic approaches aimed to correct these alterations and their beneficial effects on the treatment of infertility in PCOS.

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Amelioration by quercetin of insulin resistance and uterine GLUT4 and ERα gene expression in rats with polycystic ovary syndrome (PCOS)

Reproduction Fertility and Development ◽

10.1071/rd18222 ◽

2019 ◽

Vol 31 (2) ◽

pp. 315 ◽

Cited By ~ 10

Author(s):

Asma Neisy ◽

Fatemeh Zal ◽

Atefeh Seghatoleslam ◽

Sanaz Alaee

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Glucose Transporter ◽

Specific Activity ◽

Polycystic Ovary ◽

Fasting Blood Glucose ◽

Model Assessment ◽

Ovary Syndrome ◽

Metabolic Systems

Insulin resistance (IR) and infertility are two major complications of polycystic ovary syndrome (PCOS), which are the results of changes in certain parts of the reproductive and metabolic systems. We aimed to observe the effect of quercetin on dehydroepiandrosterone (DHEA)-induced PCOS and insulin resistance in rats. All animals were divided into five groups and DHEA was used to induce PCOS. Bodyweight and ovarian morphology of all groups were observed. Fasting blood glucose and insulin levels were analysed. The homeostasis model assessment of insulin resistance (HOMA-IR) method was used for IR level determination. The expression of oestrogen receptor α (ERα) and glucose transporter 4 (GLUT4) genes in the uterus was examined by real-time polymerase chain reaction. Liver hexokinase (HK) and glucokinase (GK) activity was determined using spectrophotometry. Quercetin significantly improved the IR state in PCOS rats. PCOS resulted in a decrease in liver GK and an increase in liver HK specific activity, whereas quercetin increased both liver HK and GK activity. Our data also showed a significant reduction in uterine ERα and GLUT4 expression in the PCOS group, which was increased by quercetin. A remarkable effect of quercetin was the intensive reduction of PCOS-IR and significant induction of uterine GLUT4 and ERα gene expression; it could thus be a possible effective treatment for PCOS and its complications, IR and infertility.

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Current aspects of polycystic ovary syndrome II: treatment of hyperandrogenism, insulin resistance and infertility

Bulletin of Medical Sciences ◽

10.2478/orvtudert-2019-0016 ◽

2019 ◽

Vol 92 (2) ◽

pp. 89-104

Author(s):

Kun Imre Zoltán ◽

Kun Ildikó ◽

Kolcsár Melinda

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Cyproterone Acetate ◽

Polycystic Ovary ◽

Clomiphene Citrate ◽

Clinical Manifestations ◽

Primary Therapy ◽

Ovary Syndrome ◽

Beneficial Effects ◽

Causal Therapy

Abstract This work is a continuation of an earlier article published in this journal (no. 91/1: “Current aspects of polycystic ovary syndrome I: definition, pathophysiology, clinical manifestations, diagnosis and complications”). As the pathology of polycystic ovary syndrome is not fully known, the treatments used do not constitute a causal therapy, only pathogenetical interventions to break the vicious circles of pathological events. It does not currently have a universal therapeutic procedure or an approved specific drug. Treatment may be aimed at reducing hyperandrogenism, inducing ovulation and preventing complications. The patient’s complaints and desire for becoming pregnant should also be taken into account. In mild cases, an appropriate lifestyle (prevention/treatment of obesity) is sufficient, i.e. a 5-10% reduction in body weight can already result in significant improvement and also serves to prevent late complications (diabetes, hypertension, cardiovascular disease, hyperlipidemia). Oral contraceptives and antiandrogens are mainly used to treat hyperandrogenism (hirsutism, acne, and alopecia). A contraceptive whose progestogen component has antiandrogenic properties, or at least is androgen-neutral, is preferred, such as third-generation contraceptives. However, combined contraceptives (containing gestodene, desogestrel, drospirenone and cyproterone acetate) may increase the risk of venous thromboembolism and are therefore contraindicated in case of hypercoagulability. Antiandrogens (cyproterone acetate, spironolactone, finasteride, etc.) can also be used independently, but only with effective contraception (as these can cause feminization of the male fetus). Insulin resistance plays a crucial role in the development of this disease. Metformin is used as primary therapy, as it also has many other beneficial effects (e.g. cardiovascular and anti-cancer) described in recent years. These pleiotropic effects and their subtle mechanisms are discussed in detail. We highlight the possibilities of avoiding side effects and the current interpretation of rare contraindications (acidosis, hypoxic conditions, renal damage). Insulin resistance lowering agents include thiazolidinediones, acarbose, GLP-1 agonists, vitamin D, resveratrol, octreotide, but the beneficial effects of myoinositol and D-chiro-inositol are also mentioned. In the last part of the paper, the treatment options for infertility are discussed, highlighting the efficacy of clomiphene citrate, gonadotropins (“step-up”, “step- down” methods), IVF techniques, and ovarian drilling used for ovulation induction. We detail the importance and possibilities of the prevention of ovarian hyperstimulation syndrome and multiple pregnancies.

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Transcriptional and Epigenetic Changes Influencing Skeletal Muscle Metabolism in Women With Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-00935 ◽

2018 ◽

Vol 103 (12) ◽

pp. 4465-4477 ◽

Cited By ~ 18

Author(s):

Emma Nilsson ◽

Anna Benrick ◽

Milana Kokosar ◽

Anna Krook ◽

Eva Lindgren ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Dna Methylation ◽

Polycystic Ovary Syndrome ◽

Mrna Expression ◽

Polycystic Ovary ◽

Differentially Expressed ◽

Ovary Syndrome ◽

Cpg Sites

Abstract Context Insulin resistance in skeletal muscle is a major risk factor for the development of type 2 diabetes in women with polycystic ovary syndrome (PCOS). Despite this, the mechanisms underlying insulin resistance in PCOS are largely unknown. Objective To investigate the genome-wide DNA methylation and gene expression patterns in skeletal muscle from women with PCOS and controls and relate them to phenotypic variations. Design/Participants In a case-control study, skeletal muscle biopsies from women with PCOS (n = 17) and age-, weight-, and body mass index‒matched controls (n = 14) were analyzed by array-based DNA methylation and mRNA expression profiling. Results Eighty-five unique transcripts were differentially expressed in muscle from women with PCOS vs controls, including DYRK1A, SYNPO2, SCP2, and NAMPT. Furthermore, women with PCOS had reduced expression of genes involved in immune system pathways. Two CpG sites showed differential DNA methylation after correction for multiple testing. However, an mRNA expression of ∼30% of the differentially expressed genes correlated with DNA methylation levels of CpG sites in or near the gene. Functional follow-up studies demonstrated that KLF10 is under transcriptional control of insulin, where insulin promotes glycogen accumulation in myotubes of human muscle cells. Testosterone downregulates the expression levels of COL1A1 and MAP2K6. Conclusion PCOS is associated with aberrant skeletal muscle gene expression with dysregulated pathways. Furthermore, we identified specific changes in muscle DNA methylation that may affect gene expression. This study showed that women with PCOS have epigenetic and transcriptional changes in skeletal muscle that, in part, can explain the metabolic abnormalities seen in these women.

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P–589 The effects of vanillic acid on production of testosterone and function of insulin in adipose and ovarian tissues in rat model of polycyctic ovary syndrome

Human Reproduction ◽

10.1093/humrep/deab130.588 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

H R Nejabati ◽

V Shahnazi ◽

M Ghaffar. Novin ◽

M Nouri

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Rat Model ◽

Vanillic Acid ◽

Polycystic Ovary ◽

Vaginal Smear ◽

Therapeutic Effects ◽

Model Assessment ◽

Ovary Syndrome

Abstract Study question What is the possible therapeutic effects of vanillic acid (VA) on the treatment of Polycystic Ovary Syndrome (PCOS)? Summary answer Vanillic acid successfully alleviated metabolic and endocrine abnormalities in adipose and ovarian tissues in a rat model of PCOS. What is known already Polycystic Ovary Syndrome (PCOS), as a common endocrine disorder, is accompanied by hyperandrogenism, insulin resistance, ovulation problems, and infertility. In this study, the effects of vanillic acid (VA) on metabolic and endocrine abnormalities were evaluated in the adipose and ovarian tissues of a letrozole-induced rat model of PCOS. Study design, size, duration In this study, a letrozole-induced rat model was established and then the experimental groups were treated by VA and MET through oral gavage for one month. Before and after the treatment with drugs, the vaginal smear was carried out . Ovarian and adipose tissues were collected and frozen at − 80 for further analysis following euthanasia of the rats. Participants/materials, setting, methods Thirty Six -week- old Wistar rats were divided into four groups (six rats per each group). Twenty-four rats were received letrozole for five weeks. Then, two experimental groups were treated by metformin (MET), and VA . Serum lipid profile, fasting glucose levels, and hormonal assays were done by corresponding commercial kits. The phosphorylation of AMP-activated protein kinase (AMPK) was detected by western blotting and the expression of studied genes were measured by Real-time PCR. Main results and the role of chance Our results showed that both VA and MET successfully reversed the abnormal estrous cycles of PCOS rats and reduced the serum testosterone levels and Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) gene expression. Furthermore, they improved Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and decreased the serum glucose and triglyceride levels, and gene expression of resisitin. The phosphorylation of AMPK was significantly decreased in adipose and ovarian tissues in PCOS group and both therapeutic factors successfully activated the AMPK in these tissues. However, VA had not such a significant effect in adipose tissue. Limitations, reasons for caution The main limitation of the current study was its design as a rat model, which may have limitation in the translation of knowledge to the clinics. Wider implications of the findings: In summary, to the best of our knowledge, this study is the first study reported beneficial effects of VA on the treatment of PCOS. The findings of the current study shed light on an urgent need for discovering novel therapeutic pharmaceuticals regarding the treatment of the PCOS. Trial registration number 0

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