Oral contraceptive pill (OCP) treatment alters the gene expression of intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) in polycystic ovary syndrome (PCOS) women compared to drug-naive PCOS women.

BACKGROUND: Polycystic ovary syndrome (PCOS) presents clinical symptoms of menstrual abnormalities, excessive hair growth (hirsutism), scalp hair loss, acne and infertility. Metabolic abnormalities such as obesity, insulin resistance, glucose intolerance and cardiovascular problems constitute an essential part of PCOS, all of which can have significant long-term health consequences. Low-grade chronic inflammation demonstrated by persistent moderately elevated serum levels of inflammatory and coagulatory markers plays a critical role in the pathogenesis of PCOS. Oral contraceptive pills (OCPs) constitute the mainstay of pharmacologic therapy for women with PCOS to regularize cyclicity and ameliorate androgen excess. On the other hand, OCP use is associated with various venous thromboembolic and proinflammatory events in the general population. PCOS women always carriers the increased lifetime risk of these events. The studies on the effect of OCPs on inflammatory, coagulation and metabolic parameters in PCOS are less robust. Therefore in this study, we investigated and compared the messenger RNA (mRNA) expression profiles of genes implicated in inflammatory and coagulation pathways between drug-naive and OCP-treated PCOS women. The selected genes include intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1). Furthermore, the correlation between the selected markers and various metabolic indices in the OCP group has also been explored. METHOD: The relative amounts of ICAM-1, TNF-α, MCP-1 and PAI-1 mRNA in peripheral blood mononuclear cells from 25 drug-naive PCOS subjects (controls) and 25 PCOS subjects who received OCPs containing 0.03 mg-ethinyl-estradiol and 0.15 mg-levonorgestrel for at least six months (cases) were estimated using real-time qPCR. The statistical interpretation was conducted using SPSS version 20.0 (SPSS, Inc, Chicago, IL), Epi Info version 2002 (Disease Control and Prevention Centres, Atlanta, GA) and GraphPad Prism 5 (GraphPad Software, La Jolla, CA) software. RESULT: Six months of OCP therapy enhanced the expression of inflammatory genes viz ICAM-1, TNF-α and MCP-1 mRNA in PCOS women by 2.54, 2.05 and 1.74 folds, respectively, in this study. However, PAI-1 mRNA in the OCP group showed no significant increase. Furthermore, in cases, ICAM-1 mRNA expression positively correlated with body mass index (BMI) (p = 0.01), fasting insulin (p = 0.01), insulin 2 h p = 0.02), glucose 2 h (p = 0.01) and triglycerides (p = 0.01). TNF-α mRNA expression positively correlated with fasting insulin (p = 0.0007). MCP-1 mRNA expression positively correlated with (BMI) (p = 0.002). CONCLUSION: OCPs helped reduce clinical hyperandrogenism and regularise menstrual cycles in women with PCOS. However, OCP use was associated with increased fold expression of inflammatory markers which positively correlated with metabolic abnormalities.

Association of -675 4G/5G PAI-1 and -2518A/G MCP-1 genetic polymorphisms with polycystic ovary syndrome in Kashmiri women: A case control study.

Background: Polycystic ovarian syndrome (PCOS) is a highly prevalent endocrine disorder among females of fertile age. It has been speculated to be associated with low-grade chronic inflammation like other inflammatory response-driven multifactorial illnesses such as diabetes mellitus (DM) and cancer. Monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) are biomarkers of inflammation and endothelial dysfunction, respectively. These have been found to be elevated in PCOS patients. The current research reveals that single nucleotide polymorphisms (SNPs) in their genes are strongly associated with the elevation of these biomarkers. The goal of this study was to see if there was a link between PAI-1 -675 4G/5G and MCP-1 -2518 A/G polymorphisms with the occurrence of PCOS. Material and Method: This study included 220 PCOS participants and 220 healthy controls. The allele-specific polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods were used to investigate PAI-1-675 4G/5G and MCP-1 -2518A/G SNPs, respectively. Results: The -675 4G/5G SNP in the PAI-1 gene was strongly linked to PCOS. The odds ratio (OR) for the 4G/4G genotype was (OR = 3.2; P = 0.001), whereas the OR for the 4G/5G genotype was (OR = 2.39; P = 0.001). The carriers with the 4G/4G and 4G/5G genotypes showed significantly increasing trends in the triglyceride levels (P < 0.05). The genotypic frequency of the -2518 A/G MCP-1 SNP differed significantly between the PCOS patients and healthy controls; the GG genotype remained a strong predictor of PCOS (OR = 8.7; P = 0.01) and the AG genotype (OR = 2.40; P = 0.01), indicating an elevated risk of predisposing women to PCOS. There was a significant variation in the glucose 2-h levels between -2518A/G MCP-1 genotypes with AG heterozygous and GG mutant genotype showing increasing trends of glucose 2-h levels (P < 0.05). Conclusion: Both PAI-1 -675 4G/5G and MCP-1 -2518A/G polymorphisms are associated with predisposition to PCOS and its complications in Kashmiri women.

Analysis of Intrinsic and Extrinsic Coagulation Pathway Factors in OCP Treated PCOS Women.

Human polycystic ovary syndrome (PCOS)-a cluster of diseases displays various symptoms associated with endocrine and gynecological disorders in childbearing women. Oral contraceptive pills (OCP) being a drug of choice minimizes symptoms and complications associated with the disorder. But, the controversial data available in literature regarding use of OCPs compels us to setup a study design regarding effect of OCP treatment in PCOS subjects and the possible outcomes specifically regarding coagulation pathways. Two PCOS study groups have been selected according to Rotterdam Criteria: one with OCP treatment (n = 50) and other without any drug treatment i.e., drug naive (n = 50). Anthropometry, Biochemistry, Hormones, Insulin and various clotting factors like Factor XI, Factor V, tPA, TAT-III and D-dimer were analyzed in both groups. The results showed worsening of IR, Metabolic parameters and coagulopathy in OCP group comparative to drug naive group indicating adverse effects of the OCP treatment which puts these women at risk for number of future clinical implications especially Cardiovascular and metabolic complications.

Effect of six-month use of oral contraceptive pills on plasminogen activator inhibitor-1 & factor VIII among women with polycystic ovary syndrome: An observational pilot study.

Background & objectives: Polycystic ovary syndrome (PCOS) is an endocrinopathy warranting lifelong individualized management by lifestyle and pharmacological agents mainly oral contraceptive pills (OCPs). This study was aimed to report the impact of six-month OCP use on plasminogen activator inhibitor-1 (PAI-1) and factor VIII (FVIII) in women with PCOS. Methods: PCOS women diagnosed on the basis of Rotterdam 2003 criteria, either treated with OCPs (ethinyl estradiol-0.03 mg, levonorgestrel-0.15 mg) for a period of six months (n=40) or drug-naïve (n=42), were enrolled in this study. Blood was drawn to estimate glucose, insulin levels and lipid profile. Chemiluminescence immunoassays were used to measure hormones (LH, FSH, PRL, T4). Plasma levels of PAI-I and FVIII were measured by commercially available kits. Results: Menstrual regularity, Ferriman-Gallwey score and serum total testosterone significantly improved in the OCP group compared to drug-naïve group (P<0.01). No significant difference was observed in PAI-1 levels of the two groups; however, significant decrease in FVIII levels was observed in OCP group as compared to drug-naïve group. PAI-1 levels of OCP group correlated positively with blood glucose two hours, triglycerides and insulin two hours, while FVIII levels of OCP group correlated negatively with fasting insulin and homoeostatic model assessment-insulin resistance. Interpretation & conclusions: OCPs use has differential effect on pro-coagulant markers among women with PCOS. Well-designed, long-term, prospective, large-scale studies are prerequisite to elucidate the efficacy and safety of OCP in the treatment of PCOS.

The Lys469glu/K469E Polymorphism of the Inflammatory Gene Intercellular Adhesion Molecule-1 Lacks any Apparent Role in the Polycystic Ovary Syndrome in Kashmiri Women: A Case Control Study

Background: Polycystic ovary syndrome (PCOS), associated with a state of low grade chronic inflammation, depends on multiple genetic and environmental factors. Elevated levels of inflammatory markers including intercellular adhesion molecule-1 (ICAM-1) have been demonstrated in affected women. Recent evidence indicates a significant linkage between chromosome 19p13 loci and multifactorial diseases that have an inflammatory component. The aim of this study was to assess the possible association of the lys469glu (K469E) polymorphism of the ICAM-1 gene located on chromosome 19p13 with risk of PCOS in Kashmiri women. Material and Methods: The K469E single nucleotide polymorphism (SNP) was analysed with DNA from peripheral blood leukocytes of 220 PCOS cases and 220 age matched non-PCOS healthy controls using PCR-RFLP. Results: Genotypic frequencies in cases were found to be 32 (14.5%) for EE, 98 (44.5%) for KE, and 90 (40.9%) for KK, with 130 (59.1%) for the KE+EE genotypes compared to healthy control values of 29 (13.2%) for EE, 113 (51.4%) for KE, 78 (35. 5%) for KK and 142 (64.5%) for KE+EE combined.The odds ratios for the EE, KE and KE:EE genotypes were 0.95(95% CI= 0.53-1.71)[p= 0.88], 0.75(95% CI= 0.50-1.12)[p =0.168] and 0.79 (95% CI =0.53-1.16) [p = 0.23], no statistically significant differences being found between cases and controls (χ2 =2.07; p=0.35). Conclusion: In conclusion, there was no apparent significant influence of the K469E polymorphism on risk of PCOS, or any clinical or laboratory parameters.

Does the Oral Contraceptive Pill Increase Plasma Intercellular Adhesion Molecule-1, Monocyte Chemoattractant Protein-1, and Tumor Necrosis Factor-α Levels in Women with Polycystic Ovary Syndrome: A Pilot Study.

STUDY OBJECTIVE: Polycystic ovary syndrome (PCOS), the most common endocrinopathy of women, is a state of chronic low-grade inflammation and is closely linked to type 2 diabetes mellitus and cardiovascular disease. Oral contraceptive pills (OCPs), is the usual first choice of treatment in women with PCOS. Because OCP use has been linked to the risk of venous thrombosis and there are limited data on the effect of OCP use on the inflammatory state of women with PCOS, our objective was to compare the levels of intercellular adhesion molecule (ICAM)-1, tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein (MCP)-1 between drug-naive and OCP-treated women with PCOS. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Consequent to women diagnosed with PCOS on the basis of Rotterdam 2003 criteria, either treated with OCPs (ethinylestradiol 0.03 mg, levonogestrel-0.15 mg) for a period of 6 months (n = 50) or drug-naive (n = 51) were enrolled in this cross-sectional study. RESULTS: The mean ages of patients and control participants were comparable (21.99 ± 4.78 vs 21.92 ± 5.83 years; P = .947) as was body mass index (24.47 ± 3.92 vs 23.66 ± 3.43; P = .271). Clinical and androgen excess symptoms were significantly better in the OCP group compared with the drug-naive group (P = .01, P = .04). Total cholesterol and low-density lipoprotein cholesterol levels were significantly higher in the OCP group (P = .01). Plasma ICAM-1 levels, TNF-α levels, and MCP-1 levels showed a higher trend in patients but reached statistical significance only in cases of ICAM-1 and TNF-α (P = .01). CONCLUSION: OCP treatment of 6 months increases plasma ICAM-1, MCP-1, and TNF-α levels among women with PCOS, although OCPs significantly help in ameliorating features of hyperandrogenism and regularizing menstrual cycles. These cytokines correlate positively with many metabolic parameters including plasma glucose, lipids, and homeostatic model assessment-insulin resistance. Further investigation with well designed, randomized, longitudinal studies might help to ascertain the effect of OCPs on proinflammatory profiles among women with PCOS.

The ICAM-1 Gly241Arg Polymorphism is Not Associated With Polycystic Ovary Syndrome - Results from a Case Control study in Kashmir, India.

BACKGROUND: Polycystic ovary syndrome (PCOS) is considered to be a multifactorial disorder resulting from the interaction of several predisposing and protective genetic variants. PCOS is associated with low-grade chronic inflammation. Elevated levels of inflammatory markers including intercellular adhesion molecule-1 (ICAM-1) are demonstrated in women with PCOS. Recent evidence indicates a significant linkage between a locus on chromosome 19p13 and multifactorial diseases that have an inflammatory component. The aim of the study was to assess the possible association of Gly241Arg polymorphism of ICAM-1 gene located on chromosome 19p13 in determining risk of PCOS in Kashmiri women. MATERIALS AND METHODS: Gly241Arg SNP in DNA from peripheral blood leukocytes of 220 PCOS cases and 220 age matched non-PCOS healthy controls was analysed using allel specific PCR. RESULTS: The genotype and allele frequency distributions of Gly241Arg SNP showed insignificant difference between the PCOS cases and control women, indicating no role of this SNP in PCOS susceptibility. The odds ratio for Arg/Arg genotype was 0.87 (95% CI=0.32-2.3) [P=0.79], for Gly/Arg genotype was 0.98 (95% CI= 0.66-1.47) [P=1] and for Arg/Arg+Gly/Arg genotype was 0.97 (95% CI=0.65-1.45) [P=0.92]. The genotypic frequencies of ICAM-1codon 241 showed statistically insignificant difference between cases and controls (χ2=0.07; p=0.96) Nor the studied polymorphism was found to affect clinical and laboratory parameters significantly. CONCLUSIONS: Although Gly241Arg polymorphism have not shown significant association with PCOS. Further, specifically designed studies on large cohorts are required to conclusively establish any role of ICAM-1 gene polymorphisms in PCOS in our study.