MicroRNAs与多囊卵巢综合征及胰岛素分泌的相关研究进展

MicroRNAs(miRNAs)是近年发现的一类通过抑制靶基因翻译来调控细胞发育、分化、增殖、凋亡及疾病发生发展等多种过程的小分子非编码单链RNA。多囊卵巢综合征(PCOS)是育龄期女性最常见的内分泌疾病之一,并与高胰岛素血症、胰岛素抵抗关系密切。目前PCOS的病因、发病机制及其与高胰岛素血症、胰岛素抵抗之间的关系仍不十分清楚。而miRNAs作为在各种生命过程中均具有强大作用的转录后调控因子,为这些问题的研究开辟了新的思路。综述miRNAs与PCOS及胰岛素分泌相关的研究进展。     

胰岛素受体基因第17外显子1058位点多态性与多囊卵巢综合征关系的荟萃分析

多囊卵巢综合征(polycystic ovary syndrome,PCOS)是生育期妇女常见的内分泌及生殖功能障碍性疾病.PCOS的发生机制至今尚不清楚.近年来,有研究表明,PCOS是以胰岛素抵抗为特征的内分泌代谢性疾病,胰岛素抵抗不仅是PCOS患者的一项重要特征,而且可能是发生PCOS的主要病理基础,在PCOS发病的早期起一定的作用.近年来国内外研究发现,与胰岛素抵抗相关的胰岛素受体基因第17外显子1058位点存在CC、TT和cT 3种基因型,这种基因多态性与PCOS的发病相关.但也有一些研究结果显示,该基因多态性与PCOS的发病风险不相关.解决这些问题的有效方法是应用循证医学的基本原理与方法进行荟萃分析(Meta分析).荟萃分析能够通过科学、系统的方法,将研究目的相同的多个研究结果进行定量合并分析和综合评价,以提高统计检验功效,解决研究结果不一致的问题,使研究结论更全面可靠.目前,荟萃分析已经成为循证医学的主要分析方法之一.为了客观地评价胰岛素受体基因多态性与:PCOS发病的相关性,本研究对国内外有关研究进行了荟萃分析,现报道如下.     

多囊卵巢综合征基因多态性的研究进展

多囊卵巢综合征(PCOS)是常见的、复杂的生殖内分泌异常和代谢紊乱性疾病,具有高雄激素血症、稀发排卵或无排卵、胰岛素抵抗以及卵巢多囊样改变的特征,全球发病率约6%~12%,是无排卵性不孕的主要原因。其遗传特性已被证明,但参与其发病的基因尚未完全阐明。目前PCOS易感基因主要有雄激素相关基因、糖代谢相关基因和脂肪代谢相关基因等。但由于PCOS的异质性,尚无明确公认的致病基因,较为肯定的是PCOS是环境和诸多因素共同作用的结果。PCOS基因多态性的研究方法主要有传递不平衡检验、候选基因分析研究和全基因组关联研究(GWAS),特别是GWAS被称作PCOS致病基因研究中的"重大事件"。     

PAI-1基因启动子区4G/5G基因多态性与多囊卵巢综合征

多囊卵巢综合征(polycystic ovary syndrome,PCOS)是育龄期女性最常见的生殖内分泌疾病,病因迄今不明,具有高度的家族聚集性,提示遗传因素在其发病中起重要作用。纤溶酶原激活物抑制剂1(plasminogen activator inhibitor-1,PAI-1)是纤溶系统的主要生理抑制剂,大量研究表明PAI-1基因启动子区4G/5G基因多态性可通过升高血浆PAI-1水平及活性影响胰岛素的敏感性,参与胰岛素抵抗(insulin resistance,IR)的形成。IR是PCOS主要的病理生理机制,与PCOS患者肥胖、自然流产等的发生密切相关,提示PAI-1基因启动子区4G/5G基因多态性与PCOS的发生、发展可能有着密切的关系。因此,PAI-1基因启动子区4G/5G基因多态性与PCOS的相关研究也成为近年研究热点,主要涉及PCOS的发病、肥胖、IR、自然流产及远期并发心血管疾病等,但相关结论尚存争议。     

胰岛素降解酶基因多态性与多囊卵巢综合征相关性的研究

目的:探讨胰岛素降解酶基因(IDE)多态性与多囊卵巢综合征(PCOS)发病的关系。方法:用聚合酶链反应-限制性片段多态性技术,检测315例PCOS患者(PCOS组)和327例健康妇女(对照组)的IDE基因多态性。结果:IDE基因rs1887922位点基因型分布及等位基因频率在PCOS组总体以及各亚组(胰岛素抵抗组及非胰岛素抵抗组),与健康对照组之间比较均无显著差异。而IDE基因rs2209972位点基因型分布虽然在P- COS组总体及非胰岛素抵抗亚组与健康对照组之间比较无显著差异;但PCOS组总体相应位点的C等位基因频率高于对照组,差异有显著性(P<0.05),PCOS胰岛素抵抗亚组相应位点的基因型频率及等位基因频率均高于对照组,差异有统计学意义(P<0.05)。rs2209972位点不同基因型PCOS患者空腹胰岛素水平及HOMA-IR存在显著差异(P<0.05)。结论:胰岛素降解酶基因多态性可能与PCOS患者胰岛素抵抗相关。     

多囊卵巢综合征患者组织胰岛素抵抗

多囊卵巢综合征（PCOS）是一种发病多因性、临床表现呈多态性的内分泌综合征。其发病原因至今尚未阐明，近年大量研究表明胰岛素抵抗（IR）与PCOS之间关系密切，胰岛素抵抗可能是PCOS发生发展的主要因素之一。胰岛素作用的经典靶器官是肝脏、脂肪及肌肉。目前，对PCOS患者组织胰岛素抵抗的研究主要有脂肪、肌肉、卵巢及子宫内膜．对其作一综述。     

多囊卵巢局部胰岛素抵抗

多囊卵巢综合征(PCOS)是糖代谢异常与生殖功能障碍高度关联的一种特殊疾病,也是开展能量代谢与生殖活动关系研究的难得临床模型。PCOS是以卵巢功能障碍为显著标志,但目前研究发现胰岛素抵抗主要限于胰岛素作用的经典靶组织———骨骼肌、脂肪、肝脏等。很显然,以卵巢组织外的胰岛素抵抗和高胰岛素血症来解释卵巢本身的功能异常可能是不准确的。此外,胰岛素抵抗和高胰岛素血症是PCOS和2型糖尿病的共同表现,且胰岛素敏感性下降均为35%～40%,但是卵巢功能障碍仅存在于PCOS患者,而不常见于2型糖尿病患者。这表明PCOS患者卵巢本身的糖代…     

脂肪细胞因子与多囊卵巢综合征

多囊卵巢综合征(PCOS)是一种伴有肥胖,胰岛素抵抗的常见代谢性疾病,而脂肪细胞因子在参与肥胖、胰岛素抵抗及相关疾病的发生中起着重要作用.综述近年来研究较多的脂肪细胞因子瘦素、肿瘤坏死因子-α、抵抗素及脂联素在PCOS患者中的表达情况及其作用特点,为PCOS的病因学研究提供新的思路.     

多囊卵巢综合征患者组织胰岛素抵抗

多囊卵巢综合征(PCOS)是一种发病多因性、临床表现呈多态性的内分泌综合征.其发病原因至今尚未阐明,近年大量研究表明胰岛素抵抗(IR)与PCOS之间关系密切,胰岛素抵抗可能是PCOS发生发展的主要因素之一.胰岛索作用的经典靶器官是肝脏、脂肪及肌肉.目前,对PCOS患者组织胰岛素抵抗的研究主要有脂肪、肌肉、卵巢及子宫内膜,对其作一综述.     

脂联素与多囊卵巢综合征的研究进展

多囊卵巢综合征(PCOS)是一种复杂、多系统的内分泌代谢疾病,病因多元,受多基因遗传和环境因素等共同影响。PCOS女性的肥胖比例明显高于普通女性,故PCOS患者常易出现明显的脂肪功能紊乱和代谢综合征。近年对脂肪组织分泌的重要细胞因子脂联素及脂联素受体的研究发现,脂联素与PCOS中的胰岛素抵抗、远期心血管疾病的发生密切相关;高分子质量脂联素较总脂联素或许更能反映PCOS血清脂联素水平与胰岛素抵抗的关系;脂联素编码基因的多态性使脂联素基因在PCOS中存在易感性。因此,脂联素已成为PCOS的研究热点。     

Looking for polycystic ovary syndrome genes: rational and best strategy

Polycystic ovary syndrome (PCOS) is a common, complex genetic disorder. Its inherited basis was established by studies demonstrating an increased prevalence of PCOS and hyperandrogenemia, insulin resistance, and disordered insulin secretion in relatives of women with PCOS. To date, efforts in elucidating the genetic basis of PCOS have focused on candidate genes chosen from logical pathways, such as steroid synthesis or insulin signaling. Whereas several positive results have been reported, no genes are universally accepted as important in PCOS pathogenesis, largely due to lack of replication of positive results. This has resulted, in part, from various factors, most importantly lack of a universally accepted diagnostic scheme for PCOS, ability to assign PCOS diagnosis only in women of reproductive age, inadequate coverage of genes by the analysis of only one or two variants, and of small case-control cohorts in most studies. Candidate gene selection has been limited by our incomplete knowledge of the pathophysiology of PCOS. In the future, strict and uniform diagnostic criteria, improved application of the candidate gene approach using haplotype-based analyses, intermediate phenotypes, replication of positive results in large cohorts, more family-based studies, gene selection from expression studies, and whole-genome approaches will enhance gene discovery in PCOS.     

Frequency of adiponectin gene polymorphisms in polycystic ovary syndrome and the association with serum adiponectin,androgen levels,insulin resistance and clinical parameters

Aim.?Although the association between adiponectin gene polymorphisms and insulin resistance has been investigated in many studies, there are only a few studies, which have investigated adiponectin gene polymorphisms in patients with polycystic ovary syndrome (PCOS). The objectives of this study were to determine the frequency of T45G polymorphisms localised in exon 2 of the adiponectin gene in a Turkish population with PCOS and to determine the association of T45G polymorphisms with insulin resistance and serum adiponectin levels in PCOS.

Materials and methods.?Ninety-six patients with PCOS and 93 healthy control subjects were included in the study. Insulin resistance was estimated via HOMA-IR. Serum adiponectin levels were measured by ELISA. For determination of adiponectin gene polymorphisms, PCR was performed with appropriate primers after genomic DNA was obtained from the peripheral blood of the patients and control subjects.

Results.?Adiponectin levels were low in patients with PCOS than control subjects. There was no significant statistical difference between the PCOS and control groups with respect to the frequency of polymorphisms and the genotype distribution. Adiponectin gene polymorphisms were not associated with the anthropometric parameters, hyperandrogenism and adiponectin levels in PCOS. However, the fasting insulin level and insulin resistance were significantly higher and more frequent, respectively, in the polymorphic group compared to the other genotypes among patients with PCOS.

Conclusion.?The risk of PCOS, hyperandrogenism in patients with PCOS and low serum adiponectin levels cannot be directly attributed to T45G adiponectin gene polymorphisms in exon 2, rather these polymorphisms may be associated with insulin resistance and hyperinsulinemia in PCOS.     

Hyperinsulinism and its interaction with hyperandrogenism in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. It has become increasingly evident that insulin resistance plays a significant role both as a cause and result of the syndrome. The purpose of this review is to summarize the possible mechanisms leading to insulin resistance and resultant hyperinsulinism (HI) and their interaction with hyperandrogenism (HA) in PCOS. We conducted a computerized search of MEDLINE for relevant studies in the English literature published between January 1966 and January 2000. We reviewed all studies that investigated the roles of insulin, insulin receptor, and insulin gene in insulin resistance and its interaction with hyperandrogenism in PCOS. Insulin resistance in PCOS seems to involve a postbinding defect in the insulin receptor and/or in the receptor signal transduction. Current research has focused on identifying a genetic predisposition for insulin resistance in this syndrome. The answer to the question whether HI or HA is the initiating event is still unclear inasmuch as there are clinical and molecular evidences to support both of these approaches. Our view is that whichever is the triggering insult, a vicious cycle is established where HI acts to aggravate HA and vice versa. In this model, obesity and genetic predisposition seem to be the independent factors that can give rise or contribute to HI, HA, or both simultaneously. It seems that "hyperinsulinemic hyperandrogenism" represents a significant subgroup of PCOS, which probably needs to be renamed and reclassified in the light of this new approach.     

The polycystic ovary syndrome: what does insulin resistance have to do with it?

About half of infertility cases are attributable to female factors, of which anovulation is the leading cause. Most cases of anovulation are due to the polycystic ovarian syndrome (PCOS). Clinically PCOS, present in 5% of all women, consists of anovulation, acne, hirsutism, reversed LH-to-FSH ratio and often resistance to insulin. In some cases PCOS appears in familial clusters but its genetic cause is unknown. Several genes were suggested as possible culprits for PCOS but their involvement has not been proven. The central paradox regarding the role of insulin in PCOS is the high responsiveness to insulin by the ovary, as opposed to the resistance of the whole body. On the backdrop of knowledge of several paralogous genes for each of the participating proteins in the insulin signal transduction pathways, it is possible that different paralogues propagate the intracellular signal in the ovary as opposed to peripheral tissues. Studies by microarray techniques of the different gene expression profiles in the two ovarian cells and peripheral cells such as adipocytes could clarify whether the ovarian defect in PCOS is identical to the peripheral defect in insulin signal transduction, or whether serum insulin concentrations simply serve to reveal the ovarian defect.     

Genetic variants associated with insulin signaling and glucose homeostasis in the pathogenesis of insulin resistance in polycystic ovary syndrome: a systematic review

Background

Polycystic ovary syndrome must be recognized as a serious issue due to its implication on long term health regardless of an individual’s age. PCOS and insulin resistance are interlinked, as approximately 40 % of women with PCOS are insulin resistant. However, the detailed molecular basis for insulin resistance that is coupled with PCOS remains poorly understood.

Objective

To review the published evidence that polymorphisms in genes that are involved in insulin secretion and action are associated with an increased risk of PCOS.

Methods

We reviewed articles published through November 2012 which concerned polymorphisms of genes related to insulin signaling and glucose homeostasis as well as their associations with PCOS. The articles were identified via Medline searches.

Conclusions

No consistent evidence emerged of a strong association between the risk of PCOS and any known gene that is related to insulin signaling and glucose homeostasis. Moreover, recent genome-wide association studies are inconsistent in identifying the associations between PCOS and insulin metabolism genes. Many of the studies reviewed were limited by heterogeneity in the PCOS diagnosis and by not have having a sufficient number of study participants. Further studies are warranted to determine predisposing risk factors which could modify environmental factors and thus reduce the risk of PCOS. Large genome-wide association studies devoted solely to PCOS will be necessary to identify new candidate genes and proteins that are involved in PCOS risk.     

The contributions of resistin and adiponectin gene single nucleotide polymorphisms to the genetic risk for polycystic ovary syndrome in a Japanese population

Polycystic ovary syndrome (PCOS) is a heterogeneous group of disorders that occur fairly commonly in women of reproductive age and are characterized by a variety of clinical manifestations, including insulin resistance that is independent of obesity. Recent studies suggest that altered adipocytokine gene expression is closely associated with insulin resistance and that single nucleotide polymorphisms (SNPs) modulate the expression and/or function of these genes, thereby affecting insulin sensitivity. With that in mind, we investigated whether SNPs at position ?420 of the resistin gene (RETN) and/or ?11377 of the adiponectin gene (ADIPOQ) modulate the susceptibility to PCOS. We evaluated the genotypes of 117 women with PCOS and 380 healthy fertile controls and measured the index of insulin resistance and hormonal profiles in the PCOS women. The RETN?420G/G homozygous variant genotype occurred significantly more frequently among the PCOS group than among the control group (15.4% vs. 8.4%, p = 0.035). PCOS women with the RETN?420G/G genotype also showed significantly higher BMIs and greater insulin resistance than those with RETN?420 C/C or C/G genotypes. The ADIPOQ SNP at ?11377 showed no association with PCOS. We conclude that the RETN G/G at ?420 genotype is associated with PCOS in Japanese women.     

Polycystic ovary syndrome and type 2 diabetes mellitus

Polycystic ovary syndrome (PCOS) is a medical condition that has brought multiple specialists together. Gynecologists, endocrinologists, cardiologists, pediatricians, and dermatologists are all concerned with PCOS patients and share research data and design clinical trials to learn more about the syndrome. Insulin resistance is a common feature of PCOS and is more marked in obese women, suggesting that PCOS and obesity have a synergistic effect on the magnitude of the insulin disorder. It leads to increased insulin secretion by beta-cells and compensatory hyperinsulinemia. Hyperinsulinemia associated with insulin resistance has been causally linked to all features of the syndrome, such as hyperandrogenism, reproductive disorders, acne, hirsutism and metabolic disturbances. If beta-cell compensatory response declines, relative or absolute insulin insufficiency develops which may lead to glucose intolerance and type 2 diabetes. Moreover, insulin resistance in PCOS may be considered a risk factor for gestational diabetes (GD).     

The genetics of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder. There is evidence for a genetic component in PCOS based on familial clustering of cases. The majority of the evidence supports an autosomal dominant form of inheritance. Steroidogenesis has been shown to be upregulated in PCOS theca cells, suggesting that the genetic abnormality in PCOS affects signal transduction pathways controlling the expression of a family of genes. Although a number of candidate genes have been proposed, the putative PCOS gene(s) has yet to be identified. Linkage and association studies implicate a region near the insulin receptor gene at chr 19p13.3. New genetic approaches, such as microarray technology, hold promise for elucidation of the pathophysiology underlying PCOS.     

Molecular progress in infertility: polycystic ovary syndrome

OBJECTIVE: To review the evidence that polycystic ovary syndrome is a genetic disease.DESIGN: Review of published literature.RESULTS: The existing literature provides a strong basis for arguing that PCOS clusters in families. However, the mode of inheritance of the disorder is still uncertain, although the majority of studies are consistent with an autosomal dominant pattern, modified perhaps by environmental factors. In addition, studies on PCOS cells (theca, muscle, and adipocytes) in culture have documented a persistent biochemical and molecular phenotype that distinguishes them from normal cells. Although several loci have been proposed as PCOS genes including CYP11A, the insulin gene, and a region near the insulin receptor, the evidence supporting linkage is not overwhelming. The strongest case can be made for the region near the insulin receptor gene, as it has been identified in two separate studies. However, the responsible gene at chromosome 19p13.3 remains to be identified. Association studies have provided a number of potential loci with genetic variants that may create or add to a PCOS phenotype, including Calpain 10, IRS-1 and -2, and SHBG.CONCLUSIONS: Collectively, these findings are consistent with the concept that a gene or several genes are linked to PCOS susceptibility. Because the mutations/genotypes associated with PCOS are rare, and their full impact on the phenotype incompletely understood, routine screening of women with PCOS or stigmata of PCOS for these genetic variants is not indicated at this time. Currently the treatment implications for individually identified genetic variants is uncertain and must be addressed on a case by case basis.