Fetal programming of polycystic ovary syndrome

Polycystic ovary syndrome(PCOS) is a common endocrine disorder that affects up to 6.8% of reproductive age women.Experimental research and clinical observations suggest that PCOS may originate in the very early stages of development,possibly even during intrauterine life.This suggests that PCOS is either genetically-transmittedor is due to epigenetic alterations that develop in the intrauterine microenvironment.Although familial cases support the role of genetic factors,no specific genetic pattern has been defined in PCOS.Several candidate genes have been implicated in its pathogenesis,but none can specifically be implicated in PCOS development.Hypotheses based on the impact of the intrauterine environment on PCOS development can be grouped into two categories.The first is the "thrifty" phenotype hypothesis,which states that intrauterine nutritional restriction in fetuses causes decreased insulin secretion and,as a compensatory mechanism,insulin resistance.Additionally,an impaired nutritional environment can affect the methylation of some specific genes,which can also trigger PCOS.The second hypothesis postulates that fetal exposure to excess androgen can induce changes in differentiating tissues,causing the PCOS phenotype to develop in adult life.This review aimed to examine the role of fetal programming in development of PCOS.     

腹型肥胖与多囊卵巢综合征

腹型肥胖、超重和肥胖是多囊卵巢综合征（PCOS）的常见症状。腹型肥胖和胰岛素抵抗可能引起卵巢和肾上腺分泌过多的雄激素,而雄激素过多分泌本身就可引起脂肪向腹部沉积。PCOS患者内脏脂肪的最新基因组学和蛋白组学研究发现其基因表达和蛋白质组成存在异常。本文综述了有关雄激素过多引起腹壁脂肪沉积,进一步促进PCOS患者卵巢和肾上腺雄激素的过多分泌的机制。     

多囊卵巢综合征与脂肪因子相关性的研究进展

多囊卵巢综合征(polycystic ovary syndrome,PCOS)是育龄期妇女最常见的一种内分泌及代谢紊乱性疾病,其主要特征为肥胖、胰岛素抵抗、高雄激素表现、持续性无排卵以及卵巢多囊样改变等。近年来发现肥胖与PCOS的发生有着密切的联系,随着对脂肪细胞的内分泌作用进一步了解,逐渐认识到脂肪所产生的脂肪细胞因子可能是导致PCOS发生的重要因素之一。现就国内外这一方面的研究进展做一综述。     

Role of insulin and insulin resistance in androgen excess disorders

Insulin has complex effects on cell growth, metabolism and differentiation, and these effects are mediated by a cell-surface bound receptor and eventually a cascade of intracellular signaling events. Among the several metabolic and growth-promoting effects of insulin, insulin resistance is defined as an attenuated effect of insulin on glucose metabolism, primarily the limited export of blood glucose into skeletal muscle and adipose tissue. On the other hand, not all the signaling pathways and insulin-responsive tissues are equally affected, and some effects other than the metabolic actions of insulin are overexpressed. Ovaries and the adrenal glands are two examples of tissues remaining sensitive to insulin actions where insulin may contribute to increased androgen secretion. Polycystic ovary syndrome (PCOS) is the most common form of androgen excess disorder (AED), and its pathogenesis is closely associated with insulin resistance. Patients with idiopathic hirsutism also exhibit insulin resistance, albeit lower than patients with PCOS. Although it is not as evident as in PCOS, patients with congenital adrenal hyperplasia may have insulin resistance, which may be further exacerbated with glucocorticoid overtreatment and obesity. Among patients with severe insulin resistance syndromes, irrespective of the type of disease, hyperinsulinemia promotes ovarian androgen synthesis independently of gonadotropins. It is highly debated in whom and how insulin resistance should be diagnosed and treated among patients with AEDs, including PCOS. It is not suitable to administer an insulin sensitizer relying on only some mathematical models used for estimating insulin resistance. Instead, the treatment decision should be based on the constellation of the signs, symptoms and presence of obesity; acanthosis nigricans; and some laboratory abnormalities such as impaired glucose tolerance and impaired fasting glucose.     

胰岛素抵抗与多囊卵巢综合征

多囊卵巢综合征(PCOS)是妇科常见的内分泌疾病,其发病机理可能涉及下丘脑、垂体、肾上腺、胰岛素抵抗、肥胖等多种因素。国外对胰岛素抵抗的研究较多,现就胰岛素抵抗与PCOS进行综述。     

艾塞那肽在PCOS治疗中的作用及应用前景

艾塞那肽(EX)是一种胰高血糖素样肽-1(GLP-1)类似物,主要用于改善Ⅱ型糖尿病血糖控制不佳及需要减重的患者,是近年来新出现的治疗糖尿病的新型靶点药物。EX具有改善胰岛β细胞的功能、促进葡萄糖依赖性胰岛素的分泌、显著降低餐后血糖、抑制胰高血糖素分泌及减重等众多作用。鉴于多囊卵巢综合征(PCOS)患者常伴有胰岛素抵抗,并且可能合并GLP-1分泌功能受损,目前,学者们开始探索将EX应用于PCOS的治疗。本综述的主要目的是初步阐明EX在PCOS患者治疗中的作用机制,并展望其在生殖内分泌领域的应用前景。     

Obesity-Induced Infertility and Hyperandrogenism Are Corrected by Deletion of the Insulin Receptor in the Ovarian Theca Cell

Women with polycystic ovary syndrome (PCOS) exhibit elevated androgen levels, oligoanovulation, infertility, and insulin resistance in metabolic tissues. The aims of these studies were to determine the role of insulin signaling in the development and function of ovarian theca cells and the pathophysiologic effects of hyperinsulinism on ovarian function in obesity. We disrupted the insulin receptor (IR) gene specifically in the theca-interstitial (TI) cells of the ovaries (Cyp17IRKO). No changes in reproductive development or function were observed in lean Cyp17IRKO female mice, suggesting that insulin signaling in TI cell is not essential for reproduction. However, when females were fed a high-fat diet, diet-induced obesity (DIO) wild-type (DIO-WT) mice were infertile and experienced increased circulating testosterone levels, whereas DIO-Cyp17IRKO mice exhibited improved fertility and testosterone levels comparable to those found in lean mice. The levels of phosphorylated IRS1 and CYP17 protein were higher in the ovary of DIO-WT compared with DIO-Cyp17IRKO or lean mice. Ex vivo studies using a whole ovary culture model demonstrated that insulin acts independently or additively with human chorionic gonadotropin to enhance androstenedione secretion. These studies reveal the causal pathway linking hyperinsulinism with ovarian hyperandrogenism and the infertility of obesity.     

Increased risk of psychiatric disorders in Chinese women with polycystic ovary syndrome

<正>Objective:To assess the psychological health status and quality of everyday life of women with polycystic ovary syndrome(PCOS). Methods:A total of 846 patients were assessed with Self-Rating Anxiety Scales(SAS) and Self-Rating Depression Scales(SDS)(292 of PCOS patients,294 of non-PCOS infertile patients and 260 of healthy control).Specific questionnaires were employed to rate the quality of everyday life and adverse effects of different psychiatric factors. Results:The scores of SDS and SAS of PCOS patients were higher than those of non-PCOS infertile patients and healthy control.In addition,the negative psychiatric and psychological impact of PCOS was severe.The quality of everyday life in PCOS patients was undermined to certain extents. Conclusions:The features of polycystic ovary syndrome bring stress to patients,causing psychological disorder. The quality of everyday life in affected women is impaired partly.These results implicate that psychological support should be considered in the treatment of PCOS-associated infertility.     

同型半胱氨酸在多囊卵巢综合征中的研究进展

多囊卵巢综合征(PCOS)是女性常见的内分泌疾病,主要以排卵障碍、卵巢呈多囊样改变和高雄激素血症为特征。同型半胱氨酸(Hcy)是在蛋氨酸循环期间形成的含硫氨基酸,最新发现高同型半胱氨酸血症(HHcy)与PCOS密切相关,影响着PCOS的卵母细胞质量、高雄激素血症、胰岛素抵抗(IR)和高胰岛素血症,并且是其远期并发症如不良妊娠结局、心血管疾病、妊娠糖尿病的潜在危险因素。本文综述近年Hcy与PCOS的相关研究,旨在为PCOS临床诊断和治疗提供新的依据。     

多囊卵巢综合征卵泡内信号转导通路与高雄激素血症的关系

多囊卵巢综合征(PCOS)是一种常见的影响育龄期妇女的内分泌疾病,病因尚未明确,是导致无排卵性不孕的主要原因.高雄激素血症是PCOS的主要特征之一,高雄激素水平可能会导致卵泡闭锁,但雄激素生成机制的改变尚不明确,可能依赖于多个传导通路的相互作用.明确PCOS高雄激素血症相关的信号转导通路,可以为PCOS的治疗提供新思路...     

Genetics of the polycystic ovarian syndrome and therapeutic perspectives

PCOS is the most frequent endocrine disorder of premenopausal women. The common clinical signs of PCOS are hirsutism, menstrual irregularities with chronic anovulation and a trend toward overweight or obesity. Diagnosis is based upon high plasma levels of androgens and the ultrasound image of polycystic ovaries. The high prevalence of PCOS at first degree female relatives suggest an important genetic component of this syndrome. Linking studies in sisters presenting phenotypical traits of PCOS and in their parents allowed the investigation of certain candidate genes presumed to be involved in the physiopathology of PCOS. The genes encoding enzymes involved in androgen synthesis, protein transducers of insulin signals and the paracrine regulating factors of gonadotrophins and ovarian function have been analysed. To date, no determinant gene mutation was reported. However, several loci were detected, especially a locus within the insulin receptor. Mutations or gene polymorphisms and their function remain to be identified. These research attempts should explain the physiopathology of PCOS and open new therapeutic perspectives. The usage of medication increasing the sensitivity to insulin action is an example of applying these particular aspects.     

多囊卵巢综合征与复发性流产的研究进展

复发性流产(RSA)的发生与多种因素相关,包括年龄、遗传、内分泌与代谢障碍、免疫因素、子宫发育异常、血栓形成倾向、感染、精液质量和生活方式等。多囊卵巢综合征(PCOS)是一种以持续性无排卵、多卵泡不成熟、雄激素水平升高和胰岛素抵抗为主要特征的生殖功能障碍与糖代谢异常并存的内分泌紊乱综合征。PCOS患者RSA的发生率明显高于普通人群,30%~40%的PCOS患者存在自然流产史。目前,PCOS患者易发生RSA的具体发病机制尚不明确,可能与高黄体生成素血症、高雄激素血症、胰岛素抵抗、肥胖、高泌乳素血症、黄体功能不全、血栓形成等有关。本文从上述方面对PCOS患者发生RSA的常见原因及其预防进行综述。     

AMP kinase activation increases glucose uptake, decreases apoptosis, and improves pregnancy outcome in embryos exposed to high IGF-I concentrations

Women with polycystic ovarian syndrome are at increased risk of miscarriage. Although evidence exists that metformin reduces this risk, the mechanism is unknown. This study tests the hypothesis that AMP kinase (AMPK) activation with metformin directly improves insulin signaling within the blastocyst, leading to improved pregnancy outcomes. Murine embryos were exposed to 200 nmol/l IGF-I, similar to the concentrations that can occur during polycystic ovary syndrome (PCOS). Resulting blastocysts were compared with embryos cocultured with excess IGF-I plus metformin and embryos cultured in control medium for the following: AMPK phosphorylation, insulin-stimulated glucose uptake, and apoptosis. Study and control blastocysts were also transferred into control animals. On embryonic day (E) 14.5, resulting fetuses were examined for size and rates of fetal implantation and resorption. Compared with control blastocysts, blastocysts exposed to high concentrations of IGF-I showed a decrease in AMPK activation and insulin-stimulated glucose uptake and an increase in the number of apoptotic nuclei. Blastocysts cocultured in metformin and excess IGF-I performed as well as controls in all studies. 5-Aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside, another AMPK activator, also prevented the effects of excess IGF-I on blastocysts. Implantation rates and fetal size at day 14.5 were significantly lower among IGF-I-exposed embryos transferred into control mothers compared with control embryos transferred into control mothers. Both of these parameters were reversed by co-incubation with metformin and IGF-I before transfer. Activation of embryonic AMPK may be the mechanism responsible for the improved pregnancy outcomes seen in PCOS patients taking metformin.     

An investigation of acarbose effects in PCOS women with postprandial hyperglycemia

<正> Objectives:To investigate the effects of insulin resistance on serum androgen leveland ovulation of women with polycystic ovary syndrome (PCOS) and observe clinic roleof acarbose in the treatment of hyperinsulinemia,postprandial hyperglycemia andanovulation.Methods:14 women accompanied by postprandial hyperglycemia with PCOS wereadministrated by acarbose for 12 weeks.14 age-matched individuals who had similarbody mass index and normal menstruation were served as controls.Results:Serum T levels declined significantly from 4.09±1.04 nmol/L to 1.71±0.54 nmol/L(P<0.001),after acarbose treatment for 12 weeks.12 out of 14 cases re-stored ovulation and menstrual cycles after acarbose treatment,among which 4 gotpregnant.Conclusion.Acarbose may play a role on reducing postprandial hyperglycemia andHbAic levels,increase ISI and FSG/FI,indirectly reduce serum androgen levels throughreducing plasma insulin level and recover ovarian ovulation in PCOS women with postprandial hyperglycemia.     

维生素D与多囊卵巢综合征相关性的研究进展

维生素D缺乏在多囊卵巢综合征(PCOS)妇女中常见,它与PCOS妇女的胰岛素抵抗、高雄激素表现、心血管疾病危险及生育功能下降有关。适当补充维生素D可减轻PCOS的危险因素,改善PCOS妇女的健康。     

Evidence that insulin is imprinted in the human yolk sac

Allelic variation in the size of the insulin (INS) variable number tandem repeat (VNTR) correlates with the expression of both INS in the pancreas and thymus and IGF2 (the gene downstream of INS) in the placenta. In addition, the shorter, class I alleles are associated with type 1 diabetes, whereas the longer, class III alleles are associated with type 2 diabetes, polycystic ovary syndrome (PCOS), and size at birth. Parent-of-origin effects have been reported for type 2 diabetes and PCOS, thus implicating a role for genomic imprinting in these phenotypes. In mice, Ins2 is imprinted and paternally expressed in the yolk sac. In humans, evidence for the imprinting of INS is circumstantial, with occasional monoallelic expression in the thymus. In the present study, we found evidence for the imprinted paternal expression of INS in the human yolk sac. Two other imprinted genes from the same cluster are also expressed monoallelically in the human yolk sac. IGF2 was expressed solely from the paternal allele, and H19 was expressed solely from the maternal allele. These data suggest not only further functional roles for the human yolk sac in early fetal growth, but also evidence for a potential causal link between the control of insulin expression during development and insulin/growth-related diseases in later life.     

多囊卵巢综合征患者胰岛素受体基因外显子17多态性的研究

目的探讨胰岛素受体（INSR）基因外显子17多态性与多囊卵巢综合征（PCOS）发病的关系。方法应用聚合酶链反应限制性内切酶片段长度多态性分析（PCR—RFLP）法对中国汉族96例PCOS患者和56例对照者INRS基因外显子17第1,058位点的多态性进行检测,分析并比较INRS基因外显子17第1,058位点T、C等位基因频率与PCOS胰岛素抵抗、高雄激素血症之间的关系。结果（1）PCOS患者INSR基因外显子17第1,058位点T等位基因出现频率为41．7％,明显高于正常对照组的14．3％（P〈0.05）。（2）PCOS患者出现T等位基因者的体重指数（BMI）明显低于出现C等位基因患者（P〈0.05）。（3）PCOS胰岛素抵抗组与非胰岛素抵抗组T、C等位基因出现频率无统计学差异（P〉0．05）。（4）PCOS高雄激素组与无高雄激素组INSR基因T、C等位基因频率无统计学差异（P〉0．05）。结论INSR基因17外显子C／T单核酸多态性与PCOS患者肥胖密切相关,与PCOS的高雄激素血症、胰岛素抵抗（IR）无明显关系。认为INSR基因第17外显子C／T单核酸多态性仅系PCOS的一个易感基因,对PCOS的发病无决定性作用。     

多囊卵巢综合征患者妊娠期血清、胎盘局部雄激素水平的检测及评价

目的了解多囊卵巢综合征(PCOS)患者行体外受精-胚胎移植(IVF-ET)治疗后,妊娠期胎盘局部是否存在雄激素水平的升高,并探讨胎盘局部高雄激素水平与PCOS患者不良妊娠结局的关系。方法 17例PCOS行IVF-ET治疗后妊娠患者为观察组,19例非遗传学因素(输卵管因素,流产后继发不孕)行IVF-ET治疗后妊娠患者为对照组,采用放射免疫分析法(RIA)、酶联免疫吸附法(ELISA)对其外周血、胎盘组织局部总睾酮(TT)、性激素结合球蛋白(SHBG)等指标进行测定。并根据外周血雄激素水平,将观察组分为高雄组(n=12)及非高雄组(n=5)。结果 PCOS高雄患者妊娠期外周血及胎盘局部TT、游离睾酮指数(FAI)较对照组及非高雄组明显升高,且有显著性差异(P均0.001);PCOS高雄组SHBG较对照组及非高雄组稍有降低,但无显著差异(P0.05)。结论具有高雄激素血症的PCOS患者胎盘局部雄激素水平升高。     

线粒体基因突变与多囊卵巢综合征的相关性

线粒体基因是独立于核基因外的遗传物质,其独特的结构功能、遗传特性以及与个体胰岛素抵抗之间的相关性,可能与导致生育期妇女不孕的多囊卵巢综合征相关联,从而有可能为多囊卵巢综合征复杂病因和发病机制的研究开辟一条新途径,为临床诊治提供新的思路。     

安徽省育龄妇女多囊卵巢综合征患病状况流行病学研究

目的了解安徽省育龄妇女多囊卵巢综合征（PCOS）的患病状况、临床特点及危险因素。方法以2003年鹿特丹PCOS诊断标准,按照临床流行病学多阶段分层随机抽样方法,抽取1,024名育龄妇女进行调查。结果安徽省育龄妇女PCOS群体患病率为5．4％;检出的PCOS患者中月经稀发、高雄激素血症和卵巢多囊样改变（PCO）分别占90．9％、63．6％、72．7％,月经稀发为最主要临床表现;PCOS人群月经不规则、多毛、痤疮、皮肤油腻／溢脂、PCO、不育症的发生率显著高于非PCOS人群（P≤0．01）,PCOS组的血清睾酮、雄烯二酮和游离睾酮指数均显著高于非PCOS组（P〈O．05）;不同特征育龄妇女PCOS发病率比较,初潮后建立规则月经周期时间延长、母亲不育与育龄妇女PCOS相关性有显著统计学意义（P〈0．05）。结论安徽省育龄妇女PCOS的群体患病率为5．4％;PCOS妇女不育症的发生率为10．9％;月经稀发可作为PCOS的首先筛选指标,初潮后建立规则月经周期延长及母亲不育可能是PCOS的危险因素。