多囊卵巢综合症与心血管疾病相关性的探讨

多囊卵巢综合症(Polycystic ovary syndfome,PCOS)是一种育龄期妇女常见病,临床上常伴有月经稀少、不孕、多毛和肥胖等症状,双侧卵巢呈囊性增大,女性内分泌出现紊乱,PCOS中有50%妇女表现为肥胖,尽管多数妇女以不孕和月经异常就诊,但有研究表明PCOS患者的远期并发症如心血管疾病的发生率远远高于正常人群。本文主要探讨了PCOS与心血管疾病的相关性。     

Kiss1和GPR54基因多态性与多囊卵巢综合征相关性分析

本研究旨在探讨Kiss1和GPR54基因多态性与多囊卵巢综合征的相关性。利用超声检查卵巢体积、血清睾酮、游离雄激素指数情况;临床评估患者身高(cm)和体重(kg)、BMI、静息血压、痤疮和黑棘皮病的分布;ELISA酶联免疫法检测血清中的kisspeptin和睾酮水平,使用Next generation sequencing方法(LGC group, Germany)对基因(Kiss1, GPR54)进行测序。结果显示,PCOS患者比对照组女性具有更高的BMI和mFG评分,PCOS患者血清Kisspeptin和睾酮浓度显著提高,且LH浓度也显著高于对照组(p<0.05)。GPR54和Kiss1 2个基因在患者体内存在多态性;测序分析结果显示GPR54基因存在的2个新的SNP位点(chr19:918686, A→G和chr19:918735, A→G),这2个新的多态性位于内含子区域(内含子2),Kiss1基因也存在两个SNP,位于非翻译变体5的末端(rs5780218)和外显子3 (rs4889),即GPR54基因存在A→G多态性,Kiss1基因为CTT→CT/G→C多态性,且相关性关联分析结果表明,GPR54基因型多态性(Chr19:918735)与PCOS风险增加相关(p<0.05);而Kiss1 SNP的基因型与PCOS风险之间没有关联。此外,PCOS与GPR54和Kiss1基因的单倍型没有显著关联。本研究推论对PCOS发生风险的遗传影响可能不仅是通过直接改变Kiss1/GPR54相互作用,而且还可能通过改变个体与环境因素的相互作用。     

Polycystic Ovary Syndrome,Depression, and Affective Disorders

ObjectiveTo assess the prevalence of depression and psychologic disorders and their effect on the quality of life in women with polycystic ovary syndrome.MethodsWe performed a PubMed search of major relevant articles published during the period from 1985 to 2009 dealing with polycystic ovary syndrome, associated psychologic morbidity, and the relationship to clinical and biochemical changes affecting the quality of life.ResultsIn patients with polycystic ovary syndrome, the presence of depression and allied disorders was frequently noted to diminish mental well-being, affect, and self-worth. The symptoms often associated with this syndrome, such as hirsutism, obesity, irregular menses, and subfertility, were a major source of psychologic morbidity. Obesity was the most prevalent cause of mental distress, whereas other features such as hirsutism and infertility were less well defined as major factors. Although the findings in some studies have been inconclusive, the presence of clinically significant eating disorders and a 7-fold increase in the suicide rate have been reported in women with polycystic ovary syndrome.ConclusionWomen with polycystic ovary syndrome have a high risk for depression and affective disorders that impair their quality of life. The presence of obesity, eating disorders, hirsutism, poor self-image, and a significant suicide rate makes evaluation of their emotional state an integral part of their assessment and treatment. For adequate treatment of the woman with polycystic ovary syndrome, a biopsychosocial model should be used, with all aspects of the patient’s mental status considered before implementation of optimal intervention. (Endocr Pract. 2009;15:475-482)     

Association Study of Gene LPP in Women with Polycystic Ovary Syndrome

Background

Previous genome-wide association study (GWAS) of polycystic ovary syndrome (PCOS) in Han Chinese population has found that SNPs in LPP gene were nominally significant in PCOS patients (P around 10E-05). Replication of the GWAS was applied to further confirm the relationship between LPP gene and PCOS.

Methods

Three polymorphisms of LPP gene (rs715790, rs4449306, rs6782041) were selected and replicated in additional 1132 PCOS cases and 1142 controls. Genotyping of LPP gene was carried out by Taqman-MGB method.

Results

In rs715790, the allele frequency is significantly different between the PCOS group and the control group. Meta-analysis showed that the allele frequencies of the three SNPs rs715790 (P_meta = 1.89E-05, OR = 1.23), rs4449306 (P_meta = 3.0E-04, OR = 1.10), rs6782041 (P_meta = 2.0E-04, OR = 1.09), were significantly different between PCOS cases and controls.

Conclusions

Our results suggest that LPP gene might be a novel candidate for PCOS.     

Pathway Analysis Based on a Genome-Wide Association Study of Polycystic Ovary Syndrome

Background

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, and it is affected by both environmental and genetic factors. Although the genetic component of PCOS is evident, studies aiming to identify susceptibility genes have shown controversial results. This study conducted a pathway-based analysis using a dataset obtained through a genome-wide association study (GWAS) to elucidate the biological pathways that contribute to PCOS susceptibility and the associated genes.

Methods

We used GWAS data on 636,797 autosomal single nucleotide polymorphisms (SNPs) from 1,221 individuals (432 PCOS patients and 789 controls) for analysis. A pathway analysis was conducted using meta-analysis gene-set enrichment of variant associations (MAGENTA). Top-ranking pathways or gene sets associated with PCOS were identified, and significant genes within the pathways were analyzed.

Results

The pathway analysis of the GWAS dataset identified significant pathways related to oocyte meiosis and the regulation of insulin secretion by acetylcholine and free fatty acids (all nominal gene-set enrichment analysis (GSEA) P-values < 0.05). In addition, INS, GNAQ, STXBP1, PLCB3, PLCB2, SMC3 and PLCZ1 were significant genes observed within the biological pathways (all gene P-values < 0.05).

Conclusions

By applying MAGENTA pathway analysis to PCOS GWAS data, we identified significant pathways and candidate genes involved in PCOS. Our findings may provide new leads for understanding the mechanisms underlying the development of PCOS.     

Osteocalcin Levels on Oral Glucose Load in Women being Investigated for Polycystic Ovary Syndrome

ObjectiveOsteocalcin (OC) might play a hormone-like role in energy metabolism and the regulatory circuit between the pancreas and osteoblasts. Effects of a 75-g oral glucose tolerance test (OGTT) on total OC, undercarboxylated (ucOC), and carboxylated osteocalcin (cOC) in insulin-resistant (IR) and noninsulin-resistant (nIR) premenopausal women was evaluated, and the relationships of changes in OC, ucOC, and cOC with area under the curve (AUC) insulin and the Matsuda index were examined.MethodsIn this cross-sectional study, 105 premenopausal women underwent OGTT; 18 were IR (homeostatic model assessment of insulin resistance [HOMA-IR] > 2.6; (2 with type 2 diabetes, 2 with impaired glucose tolerance), and 87 were nIR (3 with impaired glucose tolerance). Changes in total OC, ucOC, and cOC were evaluated 60 and 120 minutes after glucose loading.ResultsAt baseline, IR subjects had significantly lower levels of total OC, cOC, and ucOC. In nIR women, total OC decreased by 19% from 18.0 ng/mL (14.5-24.7) at baseline to 14.6 ng/mL (10.9-17.8) after 120 minutes, ucOC decreased by 22% from 3.2 ng/mL (2.1-4.5) to 2.5 ng/mL (1.7-3.5), and cOC decreased by 26% from 14.9 ng/mL (12.1-20.4) to 11.1 ng/mL (9.0-14.5) (P < .001, respectively). No significant decreases were noted in IR subjects. The declines in OC and cOC predicted AUCinsulin (ΔOC: β = 0.301, P = .001; ΔcOC: β = 0.315, P < .001) and the Matsuda index (ΔOC: β = − 0.235, P = .003; ΔcOC: β = − 0.245, P = .002).ConclusionsGlucose intake lowers levels of OC, ucOC, and cOC in nIR women, the extent of which predicts IR and insulin sensitivity in premenopausal women. OC parameters seem suppressed in IR women. There might be a differential osteoblast response to oral glucose in IR and nIR women, with OC reflecting this finding. (Endocr Pract. 2014;20:5-14)     

Association between Fat Mass- and Obesity- Associated (FTO) Gene Polymorphism and Polycystic Ovary Syndrome: A Meta-Analysis

Aims

Many studies have investigated the relationship between FTO gene polymorphism and polycystic ovary syndrome (PCOS) susceptibility but revealed mixed results. In this study, we aimed to perform a meta-analysis to clarify this association.

Methods

Published literature from PubMed, Embase and CNKI was retrieved. Meta-analysis was performed to calculate pooled odds ratio (OR) with 95% confidence interval (CI) using the random- or fix- effects model.

Results

A total of 5 studies (4778 cases and 4272 controls) were included in our meta-analysis. The results suggested that FTO rs9939609 polymorphism (or its proxy) was marginally associated with PCOS risk after adjustment for body mass index (BMI) (OR = 1.26; 95%CI: 1.02–1.55). However, the marginal association was not stable after sensitivity analysis. In the subgroup analysis by ethnicity, the association was significant in East Asians (OR = 1.43, 95%CI = 1.30–1.59) but not in Caucasians (OR = 1.04, 95%CI = 0.85–1.29).

Conclusions

Our present meta-analysis indicated that FTO rs9939609 polymorphism (or its proxy) might not be associated with risk of PCOS in overall population. However, in East Asians, there might be a direct association between FTO variant and PCOS risk, which is independent of BMI (adiposity).     

高雄激素相关的慢性炎症与多囊卵巢综合征的研究进展

多囊卵巢综合征是育龄妇女常见的慢性炎症代谢性疾病,70%以上患者出现高雄激素血症。下丘脑-垂体-性腺相关激素是月经周期和卵巢活动的调节器,脑神经元分泌的Kisspeptin、褪黑素通过下丘脑-垂体-卵巢轴调节Gn RH神经元AMH、Gn RH的表达,卵巢促性腺激素、雄激素水平增高,有利于慢性炎症的形成,促进多囊卵巢综合征的发生发展。本文综述了近几年多囊卵巢综合征中雄激素相关的慢性炎症研究,并根据相关研究提出了一些见解,希望能为多囊卵巢综合征的研究提供一些新的思路。     

肥胖对多囊卵巢综合征的影响

多囊卵巢综合征(Polycystic Ovary syndrome,PCOS)是女性最常见的生殖内分泌紊乱性疾病,严重影响女性健康。PCOS患者中有50%-70%存在肥胖,肥胖严重影响女性生殖功能,目前关于肥胖对PCOS影响的临床和实验研究很多,但是关于肥胖对PCOS女性生殖影响方面尚未进行系统的归纳总结,本文就肥胖影响PCOS女性生殖障碍的机制、肥胖对PCOS促排卵和辅助生殖技术的应用效果的影响等进行综述,目的是进一步明确肥胖本身及肥胖的治疗在PCOS生殖方面的影响,为PCOS的临床诊疗提供依据。     

多囊卵巢综合征伴胰岛素抵抗的研究进展

多囊卵巢综合征（polycystic ovary syndrome,PCOS）是国内外研究者、医患人员非常关心的育龄期妇女常见的内分泌代谢疾病,其主要表现为闭经、月经量减少、肥胖、不孕、体多毛等。多数伴有胰岛素抵抗（insulin resistance,IR）的发生,胰岛素抵抗（insulin resistance,IR）是指正常水平的胰岛素促进葡萄糖摄取及利用能力下降,机体各组织、器官代偿性分泌胰岛素以维持机体血糖稳定的一种代谢状态。近年来的研究不断证实PCOS患者2型糖尿病、血脂代谢紊乱及代谢综合征（metabolicsyndrome,MS）等并发症的发病率明显增高。运动能够改善2型糖尿病患者胰岛素抵抗的说法已经得到了共识,其分子机制也逐渐分明。PCOS患者胰岛素抵抗的研究目前仍处于进一步探讨阶段,但是经过近几年的努力已经有了新的进展,若在PCOS胰岛素抵抗患者的治疗过程中给予一定的运动干预,相信一定能够有新的突破。本文就PCOS患者胰岛素抵抗研究的机制、诊断及治疗方法的新进展简单做一综述。     

Evaluation of Para- and Perirenal Fat Thickness and its Association with Metabolic Disorders in Polycystic Ovary Syndrome

Objective: The aim of this study was to compare para- and perirenal fat (PFT) and subcutaneous abdominal fat (SFT) measurements between patients with polycystic ovary syndrome (PCOS) and control subjects and to assess the possible relation with metabolic disorders.Methods: This study included 68 patients with PCOS and 40 age- and body mass index (BMI)-matched healthy controls. We evaluated anthropometric, hormonal, and metabolic parameters, and abdominal ultrasonography was performed to measure PFT and SFT.Results: The mean PFT values were 6.1 ± 2.9 mm in patients with PCOS and 4.3 ± 2.3 mm in healthy controls (P = .002). SFT values were also higher in the patient group (9.6 ± 5 mm) compared to healthy subjects (3.5 ± 0.5 mm) (P = .017). A significant positive correlation was found between PFT and BMI (r = 0.368), waist circumference (WC) (r = 0.441), Ferriman-Gallwey (FG) score (r = 0.313), blood pressure (systolic, SBP, r = 0.213; diastolic, DBP, r = 0.215), plasma glucose (r = 0.195), homeostasis model assessment-insulin resistance (HOMA-IR, r = 0.273), SFT (r = 0.555). Conversely, negative correlations were found between PFT and estradiol (r = -0.218) and sex hormone-binding globulin (SHBG, r = -0.304). Nonobese PCOS patients (6.1 ± 3.07 mm) had higher PFT values than nonobese controls (3.47 ± 1.5 mm); however, SFT measurements did not differ (P = .086). In multiple linear regression analysis, SFT (P = .006) was a significant and independent predictor for PFT, along with WC (P = .023). In a stepwise model, SFT was the predictor of PFT (P = .001).Conclusion: PFT values were higher particularly in nonobese PCOS patients compared to nonobese control subjects. There was a significant interaction between PCOS and obesity on PFT.Abbreviations: BMI = body mass index; CT = computed tomography; DBP = diastolic blood pressure; FPG = fasting plasma glucose;; HDL-cholesterol = high-density lipoprotein cholesterol; HOMA-IR = homeostasis model assessment-insulin resistance; hsCRP = high-sensitivity C-reactive protein; LDL-cholesterol = low-density lipoprotein cholesterol; LH = luteinizing hormone; NCAH = nonclassic congenital adrenal hyperplasia; 17-OHP = 17-hydroxyprogesterone; PCOS = polycystic ovary syndrome; PFT = para- and perirenal fat; SAT = subcutaneous abdominal adipose tissue; SBP = systolic blood pressure; SFT = abdominal subcutaneous fat thickness; TG = triglyceride; US = ultrasound; VAT = visceral abdominal adipose tissue; WC = waist circumference     

达必佳治疗91 例多囊卵巢综合征临床分析

目的：探索一种有效的药物治疗多囊卵巢综合征的方法。方法：19例多囊卵巢综合征的病人每月肌注长效促性腺激素释放激素类似物达必佳3,75mg,共三月。结果：19例病人治疗后LH均降低,LH／FSH正常,卵巢恢复正常大小,卵巢多囊征明显好转。结论：达必佳治疗多囊卵巢综合征是有效的。     

Modulation of Systemic Immune Responses through Commensal Gastrointestinal Microbiota

Colonization of the gastrointestinal (GI) tract is initiated during birth and continually seeded from the individual’s environment. Gastrointestinal microorganisms play a central role in developing and modulating host immune responses and have been the subject of investigation over the last decades. Animal studies have demonstrated the impact of GI tract microbiota on local gastrointestinal immune responses; however, the full spectrum of action of early gastrointestinal tract stimulation and subsequent modulation of systemic immune responses is poorly understood. This study explored the utility of an oral microbial inoculum as a therapeutic tool to affect porcine systemic immune responses. For this study a litter of 12 pigs was split into two groups. One group of pigs was inoculated with a non-pathogenic oral inoculum (modulated), while another group (control) was not. DNA extracted from nasal swabs and fecal samples collected throughout the study was sequenced to determine the effects of the oral inoculation on GI and respiratory microbial communities. The effects of GI microbial modulation on systemic immune responses were evaluated by experimentally infecting with the pathogen Mycoplasma hyopneumoniae. Coughing levels, pathology, toll-like receptors 2 and 6, and cytokine production were measured throughout the study. Sequencing results show a successful modulation of the GI and respiratory microbiomes through oral inoculation. Delayed type hypersensitivity responses were stronger (p = 0.07), and the average coughing levels and respiratory TNF-α variance were significantly lower in the modulated group (p<0.0001 and p = 0.0153, respectively). The M. hyopneumoniae infection study showed beneficial effects of the oral inoculum on systemic immune responses including antibody production, severity of infection and cytokine levels. These results suggest that an oral microbial inoculation can be used to modulate microbial communities, as well as have a beneficial effect on systemic immune responses as demonstrated with M. hyopneumoniae infection.     

Adiponectin and Its Receptors in the Ovary: Further Evidence for a Link between Obesity and Hyperandrogenism in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS), characterized by ovarian androgen excess, is the commonest endocrine disorder in women. Obesity increases androgen synthesis, a phenomenon attributed to the accompanying hyperinsulinemia. Our hypothesis was that adipokines, fat cell-derived hormones, play a direct role in modulating ovarian androgen secretion. Therefore, the aims of this study were to explore the effects of adipokines (in particular, adiponectin) on ovarian steroidogenesis and compare the expression of adiponectin receptors in ovaries from women with and without PCO. Sections of archived human ovaries (nine from women with normal ovaries and 16 with PCOS, classified histologically, with reference to menstrual history and ultrasound) were analysed by quantitative morphometry and the proportion of positive-labelling cells compared. In addition, studies of androgen production in relation to adipokine function in primary bovine theca cell culture were also performed. A significantly lower proportion of theca cells expressed adiponectin receptors 1 and 2 (AdipoR1, AdipoR2) in polycystic ovaries than in normal ovaries. In cultured theca cells, adiponectin suppressed androstenedione production and gene expression of LH receptor and key enzymes in the androgen synthesis pathway. Moreover, knockdown of genes for AdipoR1 and AdipoR2 was associated with increased androstenedione secretion by bovine theca cells. These results provide evidence for a direct link between fat cell metabolism and ovarian steroidogenesis, suggesting that disruption of adiponectin and/or its receptors plays a key role in pathogenesis of hyperandrogenism in PCOS.     

Association Analysis between the Polymorphisms of HSD11B1 and H6PD and Risk of Polycystic Ovary Syndrome in Chinese Population

Objectives

To evaluate whether single nucleotide polymorphisms of HSD11B1 (rs846908) and H6PD (rs6688832 and rs17368528) are associated with polycystic ovary syndrome (PCOS) in Chinese population.

Materials and Methods

A case-control study was implemented to investigate the association between HSD11B1 and H6PD polymorphisms and PCOS. Patients with PCOS (n = 335) and controls (n = 354) were recruited in this study. Genetic variants of HSD11B1 (rs846908) and H6PD (rs6688832 and rs17368528) were analyzed by TaqMan method.

Results

We found a significantly 0.79-fold lower risk of G allele of rs6688832 in control group compared with the patients with PCOS (adjusted OR, 0.79; 95%CI = 0.63–0.99; P = 0.040). Additionally, significant difference in the levels of follicle stimulating hormone (FSH) was observed between AA and AG genotype in rs6688832. The rs6688832 AG genotype was associated with lower level of FSH (P = 0.039) and higher risk of hyperandrogenism (P = 0.016) in patients with PCOS. When all subjects were divided into different subgroups according to age and body mass index (BMI), we found that the frequency of G allele of rs6688832 was significantly higher in controls than that in PCOS patients in the subgroup of BMI > 23 (adjusted OR, 0.70; 95% CI = 0.50–0.98; P = 0.037).

Conclusions

Our findings showed a statistical association between H6PD rs6688832 and PCOS risk in Chinese population. The G allele of rs6688832 in H6PD might exert potential genetic protective role against the development of PCOS, especially in overweight women. PCOS patients with AG genotype of rs6688832 might confer risk to the phenotype of hyperandrogenemia of PCOS.