| The polycystic ovary syndrome (PCOS), one of the most common causes of ovulatory infertility, a common endocrine/metabolic disorder, affects 4-12% of women in reproductive age. It is a heterogeneous syndrome determined in most patients by the association of two main factors: hyperandrogenism and insulin resistance. Approximately 50% of PCOS women are overweight or obese and most of them have the abdominal phenotype. Obesity is defined as an excessively high amount of body fat or adipose tissue in relation to lean body mass. The amount of body fat (or adiposity) includes concern for both the distribution of fat throughout the body and the size of the adipose tissue deposits. Both environment and genetic factors contribute to PCOS and obesity. Different combinations of multiple gene polymorphisms and of environmental factors explain the heterogeneity of PCOS.Insulin resistance may play a pivotal role in the promotion or the maintenance of PCOS, which could have some health implications later in life. It is thought insulin resistance is associated with both type 2 diabetes (T2D) and polycystic ovary syndrome (PCOS). There is an association of T2D with several polymorphisms in candidate genes related to insulin resistance. However, the association of these polymorphisms with PCOS is still a matter of controversy. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is one of the genes involved in the differentiation of adipose tissue. It has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis and cancer. Adiponectin, a newly discovered protein, is secreted exclusively by differentiated adipocytes and has been reported to improve insulin sensitivity in animal models of obesity,and insulin-sensitizing peroxisome proliferator-activated receptor-agonists increase adiponectin concentrations in humans with T2D.In this paper, we did more detailed work on the obese heterogeneity in polycystic ovary syndrome women. Clinical characteristics, hormonal assays and the metabolic profiles, including the insulin sensitivity index (ISI), were compared between normal-weight and obese PCOS women.In an attempt to shed light on the high percentage of obesity in PCOS, we examined single nucleotide polymorphisms (SNPs)in exons 6 and 2 of the PPAR-gamma gene in 127 PCOS patients and in 79 healthy controls matched for ageand body mass index (BMI) by DNA sequencing. We also checked-up polymorphisms in exon 2 and intron 2 in the adiponectin gene to illustrate its correlation with clinical and biochemical parameters in all participants.Part I Investigation of the obese heterogeneity in polycystic ovary syndrome women1 , The clinical features, hormonal profiles and metabolic abnormalities of the obese polycystic ovary syndrome women[Abstract] Objective To investigate and analyze the clinical presentation, hormonal profiles and metabolic abnormalities in obese women with polycystic ovary syndrome. Methods We performed a cross-sectional study of 192 women with polycystic ovarian syndrome(24±6yr).They were divided into 2 groups according to body mass index(BMI): group A (n=70),BMI ≥ 25(kg·m-2); group B(n=122), BMI<25(kg·m-2).104 age-matched bilateral tubal block factor infertile women served as control group: group C(n=25),BMI≥25(kg·m-2); group D(n=79), BMI<25(kg·m-2). Assessed anthropometric measurements and clinical manifestations of hyperandrogenism , and tested the measurement of serum levels of LH,FSH,T,DHEAS,SHBG,E2,PRL and 17-OHP.The metabolic profile was investigated by measurements of oral glucose tolerance test(OGTT) and serum lipid levels, which include total cholesterol(Chol),triglycerides(TG),high-density lipoprotein(HDL),and low-density lipoprotein(LDL).The extent of insulin resistance , pancreatic beta cell fuction and hyperandrogenism was estimated by homeostasis model assessment(HOMA) and free androgen index(FAI) respectively. Results (1) Clinical phenotypes: The presence of obesity was estimated to be 36.46%(70/192),among those, 80.00%(56/70) were central obesity. Group A,C showed increased frequency of acanthosis nigricans compared with group B(P<0.05). (2)Endocrine parameters: LH,LH/FSH ratio level was higher in group B than in group A,C,D (P<0.01);TT level was higher in groupA,B than in group C,D (P<0.05). SHBG was lower in group A(108.70 ± 81.35nmol·L-1),C(150.34±106.23nmol·L-1) compared with group B(192.49 ± 98.30nmol·L-1),D(231.84 ± 90.09nmol·L-1) (P<0.01, P<0.05 ,respectively). FAI level was higher in group A(3.40 ± 1.84) than in groupB(1.75 ± 1.20), C(1.65 ± 0.90) and D(0.84 ± 0.45), P<0.01.(3) Metabolic profiles: The prevalence of IR was estimated to be 43.23%(83/192),higher prevalence were observed in group A(82.86%) compared with group B(20.49%) , P<0.01.FINS,HOMA IR,GAUC,IAUC and TG were higher in group A than in groupB(P<0.01). Yet the fasting plasma glucose levels were comparable between group A and B.BMI and WHR were positively correlated with FAI and HOMA-IR,whereas negatively correlated with LH/FSH ratio.Conclusion Obese PCOS women have more severe hyperandrogenism,IR and hyperinsulinism than normal-weght PCOS women,which may have some health implications later in life.2, Adipocytokine assays in the role of insulin resistance in women with polycystic ovary syndrome.Objective To investigate the relationship among adipocytokines and the extent of insulin resistance in women with polycystic ovary syndrome. Methods 60 women with polycystic ovarian syndrome(14～34yr) were divided into 2 groups according to body mass index(BMI) and waist-to-hip ratio(WHR): group A (n=36),BMI≥25(kg·m-2) or WHR >0.85; group B(n=24), BMI<25(kg·m-2) and WHR ≤0.85. 26 healthy infertile women(26±8yr) served as control group:group C(n=26), BMI<25(kg·m-2) and WHR <0.85. Anthropometric measurements , hormonal profiles and the metabolic profiles, including fasting plasma glucose and insulin concentrations, total cholesterol,triglycerides,high-density lipoprotein,and low-density lipoprotein, were compared. Plasma leptin and free fatty acids concentrations were measured in duplicate by enzyme-linked immunosorbent assay. Adiponectin,interleukin-6 (IL-6) and tumor necrosis factor-[alpha] (TNF- α ) were measured in duplicate by radioimmunoassay.The extent of insulin resistance and pancreatic beta cell fuction was estimated by homeostasis model assessment (HOMA).Results (1) Adipocytokine assays: Adiponectin and TNF-α level was higher in group B (17.44 ± 9.40 mg/L,0.97±0.33μg/L) than in group A (9.85 ± 7.32mg/L,0.82 ± 0.21μg/L) , P<0.01, p<0.05,respectively; Leptin was lower in group B (23.89±13.19μg/L) and C (21.65±13.85μg/L) compared with group A(42.35 + 21.24μg/L), P all =0.000.(2) Leptin was positively correlated with BMI, WHR and HOMA-IR (r=0.552, 0.320 and 0.292 respectively, P=0.000, 0.005 and 0.018 respectively), whereas adiponectin was negatively correlated with BMI, WHR and HOMA-IR (r=-0.311, r=-0.394 and -0.282 respectively , P=0.005, P=0.000 and 0.023 respectively) .TNF- α was positively correlated with HOMA-IR (r=0.466, P=0.025). Multiple regression analysis revealed that serum adiponectin concentrations was the most significant predictor of HOMA-IR(contributory=-0.165). Conclusion Higher levels of leptin and TNF- α , lower levels of adiponectin in obese PCOS women and higher levels of TNF- α in non-obese PCOS, suggests different adipocytokines mayplay different role for insulin resistance in PCOS women.Part II Association of the Pro12Ala, CAC478CAT polymorphisms in PPAR y gene with the obese heterogeneity in polycystic ovary syndrome women.Objective To investigate the association of single-nucleotide polymorphisms (SNPs) in exons 2 and 6 of the PPAR-gamma gene with obese heterogeneity and insulin resistance in polycystic ovary syndrome (PCOS)women. Methods We carried out a cross-sectional case-control study including 118 PCOS women and a control group of 79 bilateral tubal block factor infertile women(matched with BMI and ages) .All participants underwent an oral glucose tolerance test (OGTT). They were genotyped for the polymorphisms Pro12Ala and CAC478CAT in PPAR-gamma gene by DNA sequencing. The allele distributions , clinical characteristics, hormonal assays and the metabolic profiles, including the homeostasis model assessment score, were compared between not only PCOS women and controls, but also normal-weight and obese PCOS women. Results (1) No homozygous carrier for Ala12Ala was identified among the 197 women ( 79 controls , 66 normal-weight and 52 obese PCOS women) A higher frequency of the mutant heterozygous CG was observed in the controls than that in the PCOS women (17.7% vs 5.9%, P< 0.01). However, no relationship was found between the SNPs and the obese heterogeneity in polycystic ovary syndrome women. In addition, the presence of the CC genotype was associated with lower TNF-α ? IAUC, HOMA-IS than the CG genotype(P<0.05). In contrast with the PCOS women, the heterozygous CG. genotype in controls had a significantly greater BMI and WHR than homozygous CC genotype. (2) The distributions of CAC478CAT polymorphisms were different both in PCOS women vs controls (63.8% vs 46.2%, P=0.013) and obese PCOS women vs non-obese PCOS women (75.6% vs 57.3%, P=0.041), indicating that the individual polymorphisms are associated with increased risk for both PCOS and obesity. This had also been proved by One-Way ANOVA and Binary Logistic Regression. Conclusion We concluded that the SNPs in exons 2 and 6 of the PPAR-gamma gene are associated with the decreased genetic susceptibility to PCOS in Chinese women. The CAC478CAC genotype had greater BMI than the CT and TT genotype women in PCOS. The Pro12Ala genotype does not appear to improve insulin sensitivity indexes in the PCOS groups, but most possibly plays some role in the obese heterogeneity in controls.Part III Association of the 45(T/G), 276(G/T) polymorphisms in apM 1 gene with the obese heterogeneity in polycystic ovary syndrome women.Objective We examined the possible association of polymorphisms in exon 2 and intron 2 of the apM 1 gene with polycystic ovary syndrome (PCOS) and their influence on insulin resistance indexes, serum adiponectin in Chinese women with PCOS. Methods We genotyped samples from 114 women with PCOS and from 78 healthy controls (matched with BMI and ages) for the 45T>G and 276G>T polymorphisms in the adiponectin gene by DNA sequencing. The fasting blood samples were obtained and the 75-g oral glucose tolerance test (OGTT) were performed.We also tested the hormonal profiles , lipid profiles and serum adipocytokines concentrations. Results(l) The distributions of genotypes and alleles of the 45T>G polymorphisms in exon 2 were different in women with PCOS and controls (30.7% vs 19.87%, P=0.018), indicating that exon 2 polymorphisms may be associated with increased risk for PCOS. Carriers of the GG genotype had lower FINS, HOMA-IR than those with the TG and TT genotype (all P<0.05). However, this polymorphisms were not found to be associated with obese heterogeneity in PCOS women.(2)The frequency of T alleles in intron 2 were higher in obese PCOS(38.9%) than in non-obese PCOS (23.2%) women, P=0.011. Carriers of the TT genotype had greater BMI, hyperinsulinemia, homeostasis model assessment score and serum leptin level than those with the GG and GT genotype (all P<0.05). In addition, women with PCOS carriering T alleles in intron 2 had lower serum adiponectin concentrations than the carriers of G alleles (P<0.05) . Conclusion Adiponectin gene polymorphisms at positions exon 2 are associated with increased risk for PCOS and polymorphisms in intron 2 are associated with the obese heterogeneity in Chinese women. The 276G>T polymorphisms in intron 2 does not appear to strongly influence genetic susceptibility to PCOS.However, this genomic variants may be associated with the metabolic variables related to insulin resistance in patients with PCOS.
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