多囊卵巢综合征易感基因及心理因素的研究

发布时间：2018-05-05 20:52

本文选题：多囊卵巢综合征 + 胰岛素降解酶　；参考：《山东大学》2007年博士论文

【摘要】： 研究背景多囊卵巢综合征(PCOS)是育龄女性最常见的内分泌紊乱疾病，典型表现为不同程度的月经异常、卵巢多囊性改变、高雄激素血症，并常伴有随年龄增长而日益明显的胰岛素抵抗／高胰岛素血症和高脂血症，其病因至今尚不清楚。它的家族聚集现象提示遗传因素在其发病机制中起重要作用，PCOS复杂的生化特征可能各自存在着遗传易感性，或者他们之间存在着某种共同的遗传学联系。多方面的研究结果显示，该病可能是多个基因异常和多种环境因素如营养、精神、心理等因素共同作用的结果，而精神、心理因素很可能是PCOS的重要诱因和导致其远期并发症的重要因素。因此，本研究拟从基因水平探讨PCOS的发病机理并分析PCOS患者的心理特点及其对PCOS发病的影响。 (1)胰岛素抵抗(IR)和高胰岛素血症与PCOS发病密切相关。IR的发生可能涉及胰岛素合成、运输、利用、贮存及降解等代谢过程的多个器官，其机理可能涉及胰岛β细胞功能失调、胰岛素清除率低下、胰岛素受体数目减少及变异以及胰岛素受体后缺陷。近年来的研究显示，由于胰岛素降解酶(insulin degrading enzyme，IDE)基因变异导致的IDE功能不良，可引起体内胰岛素清除和降解异常，导致胰岛素抵抗。相关文献的报道显示IDE基因突变与2型糖尿病密切相关。但目前我们尚未见到关于IDE基因与PCOS病理变化相关性的研究。因此，我们拟通过分析PCOS病人与对照组之间IDE基因多态分布频率的差异，研究IDE基因在PCOS发病中的相关作用。 (2)生长激素释放肽(ghrelin)作为生长激素促分泌素受体(GHS-R)的一种内源性配体，在刺激生长激素分泌、调节能量平衡等方面表现出多样性的调节作用，Ghrelin能够诱导下丘脑分泌PRL和肾上腺皮质激素，对下丘脑-垂体-卵巢轴发挥负反馈作用，抑制中枢LH的脉冲式分泌，减少雄激素的释放量，并且与胰岛素相互作用，影响糖代谢动态平衡。因而它与肥胖、2型糖尿病、代谢综合征及胰岛素抵抗等密切相关。但到目前为止，我们没有检索到关于Ghrelin基因多态与PCOS相关性的研究报道，因此本研究拟通过对Ghrelin基因Arg-51-Gin和Leu-72-Met多态与PCOS不同表型相关性的研究，探讨Ghrelin在PCOS发病及病理变化过程中的作用。 (3)目前，人们对PCOS的研究主要集中在病理生理学及治疗方面，PCOS的心理学问题常常被忽略，PCOS的临床许多方面都可以导致情绪应激，不孕、月经不调、多毛和向心性肥胖可能造成PCOS患者的心理障碍，而心理因素又很可能是PCOS的重要诱因和导致其远期并发症的重要因素。因此，本研究拟从PCOS的心理障碍方面，基于己有的研究成果，研究PCOS的心理健康特点及影响因素，探讨精神心理因素在PCOS发病病理变化过程中的作用。目的①通过分析PCOS病人的临床、内分泌及代谢特征，确定PCOS病人胰岛素抵抗的相关因素。②通过分析PCOS组与正常对照组之间IDE基因SNPrs1887922、rs2209972、rs4646953、rs1544210的基因型分布及等位基因频率的差异，比较不同基因型PCOS病人临床、内分泌及代谢特征的差别，研究相关基因突变与PCOS不同表型的相关性，探讨IDE基因在PCOS发病及病理变化过程中的相关作用。③通过分析Ghrelin基因多态Arg-51-Gin和Leu-72-Met在PCOS组及正常对照组之间基因型分布及等位基因频率的差异，研究该多态与PCOS不同表型的相关性，探讨Ghrelin基因在PCOS发病及病理变化过程中的作用。④通过心理问卷调查，比较PCOS患者与非PCOS不孕患者及健康对照身心症状的差异，研究PCOS患者的心理健康特点及其影响因素，探讨精神心理因素在PCOS发病及病理变化过程中的作用。方法①本研究依据2003年鹿特丹标准选择PCOS患者315例，并选择同期就诊的327名健康妇女作为对照。分别测定激素、生化指标、OGTT，测量身高、体重、腰围和臀围，计算体重指数、腰臀比例及HOMA-IR。提取其抗凝血的DNA，根据所研究基因的序列设计相应引物，应用PCR扩增相应片段后，进行限制性内切酶酶切，电泳分析。②本研究另选择PCOS不孕患者77例，并选择同期就诊的非PCOS不孕患者200例，健康的已婚已育妇女100例作为对照，分别进行体格检查及B超检查，并填写自行设计的一般性问卷及SCL-90问卷。结果①PCOS患者中BM≥25kg／m~2者占47％，高雄激素血症者占61％，LH／FSH≥2者为22.8％，空腹胰岛素异常者为13.6％，空腹血糖异常者为7.9％，血CH0水平异常者占17.7％，血TG异常者占6.8％，临界高血压者占18.6％，高血压者占11.1％。②PCOS妇女IR组BMI、WHR、TG水平高于非IR组，差异具显著性，但非IR组LH水平高于IR组，且差异具显著性：PCOS妇女肥胖组OGTT各时点血糖水平、胰岛素水平及HOMA-IR、甘油三脂水平均高于非肥胖组，差异具有显著性，非肥胖组LH水平显著高于肥胖组，差异具有显著性：PCOS妇女高雄激素血症组血LH水平、胆固醇水平及LDL水平高于非高雄激素血症组，差异具有显著性。③ 相关分析结果显示，PCOS患者HOMA-IR与BMI及腰围呈显著正相关，与血T及LH水平没有相关性，与血CHO水平没有相关性，与血TG水平呈现正相关关系。④ PCOS组与对照组相比，年龄无显著性差异。但PCOS组BMI、WHR高于对照组，LH和T水平也显著高于对照组，差异均有统计学意义。⑤ IDE基因SNP rs1887922、rs4646953、rs1544210在对照组与PCOS组的基因型分布及等位基因频率均无显著性差异，而且这三种SNP不同基因型PCOS妇女在临床、内分泌激素及代谢特征方面没有差异。PCOS组SNPrs2209972基因型分布与对照组比较无显著性差异，但C等位基因频率较对照组升高，差异具有统计学意义。SNP rs2209972不同基因型PCOS妇女临床特征、内分泌激素水平没有差异，糖耐量状态及脂代谢水平没有差异。但各个时点胰岛素水平及HOMA-IR均存在显著性差异。SNP rs1887922、rs4646953、rs1544210、rs2209972连锁不平衡检验值D'＜0.5，r~2＜0.05。⑥ PCR-RFLP分析结果显示在中国汉族人群中不存在Ghrelin基因Arg-51-Gln多态，该位点中国汉族人均为GG纯合子。⑦ Ghrelin基因Leu-72-Met多态在对照组与PCOS组的基因型分布及等位基因频率均无显著性差异。X~2检验结果显示Leu-72-Met多态在PCOS IR组与非IR组、高雄激素组与非高雄激素组、肥胖组与非肥胖组均无显著性差异，而且各组间等位基因频率亦无显著性差异。方差分析结果显示，不同基因型PCOS妇女年龄、BMI、WHR、FSH、LH、PRL、E_2水平均无显著性差异。但不同基因型PCOS妇女血睾酮水平的差异性为临界值P=0.05，经过两两比较，CC及CA基因型PCOS妇女血睾酮水平较AA基因型PCOS妇女显著升高，差异具有统计学意义。不同基因型PCOS妇女OGTT各时点葡萄糖水平、胰岛素水平无显著性差异，但两两比较结果显示，CC基因型妇女HOMA-IR与AA基因型PCOS妇女比较差异具有显著性，而CA基因型妇女HOMA-IR虽高于AA基因型PCOS妇女，但差异没有统计学意义。⑧ PCOS组妇女除恐怖与精神病性因子外，SCL-90其余各因子得分及SCL-90总分与对照组妇女比较均有显著性差异。其中躯体化、强迫、人际关系敏感、抑郁、敌对性因子得分及SCL-90总分与非PCOS不孕组妇女比较有显著性差异。非PCOS女性因素不孕组妇女及非PCOS男性因素不孕组妇女强迫、人际关系敏感、抑郁、焦虑、偏执因子得分及SCL-90总分均较对照组妇女显著升高，差异具有统计学意义，而且非PCOS女性因素不孕组抑郁因子得分较非PCOS男性因素不孕组妇女有显著性差异。⑨PCOS患者个人基本资料对患者心理状况产生影响，其中年龄、结婚年限、经济状况、受教育程度、生活区域对SCL-90评分的影响具有统计学意义。患者的临床症状对其心理健康状况产生不良影响，其中不孕、多毛、肥胖、月经紊乱是影响SCL-90评分的主要因素。结论①多囊卵巢综合征患者存在肥胖、胰岛素抵抗、脂代谢异常及高血压等代谢综合症的表现，发生率显著高于一般人群。肥胖尤其是腹型肥胖可加重胰岛素抵抗，高雄激素血症及高LH血症对IR没有影响。胰岛素抵抗与脂代谢异常有一定相关性。②IDE基因SNP rs1887922、rs4646953、rs1544210与PCOS病人临床、内分泌及代谢特征没有相关性。IDE基因SNP rs2209972与PCOS病人临床及内分泌特征没有相关性，，但与PCOS妇女胰岛素抵抗相关。在中国汉族人中SNP rs2209972、rs1887922、rs4646953、rs1544210不存在连锁不平衡现象。③中国汉族人群中不存在Ghrelin基因Arg-51-Gin多态。④Ghrelin基因Leu-72-Met多态与PCOS患者血睾酮水平密切相关，与其胰岛素抵抗有一定相关性，与其体重指数及脂代谢没有相关性。⑤不孕患者心理健康水平显著下降，而PCOS患者心理健康状况受到的影响尤其显著。PCOS患者的年龄、结婚年限、生活地域、受教育水平、经济状况、肥胖及多毛等对PCOS患者的心理健康水平产生不良影响，不孕、肥胖及多毛、月经紊乱等的影响尤其显著。
[Abstract]:Background polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of childbearing age, typically characterized by different levels of menstrual abnormalities, polycystic ovarian changes, and Kaohsiung steroids, often accompanied by an increasing age of insulin resistance / Gao Yi Island, and hyperlipidemia. The cause of the disease is still unclear. Its familial aggregation suggests that genetic factors play an important role in the pathogenesis of the disease. The complex biochemical characteristics of PCOS may have genetic susceptibility to each other, or there are some common genetic links between them. Mental and psychological factors are the result of common effects, and mental and psychological factors are probably important causes of PCOS and the important factors that lead to their long-term complications. Therefore, this study intends to explore the pathogenesis of PCOS from the level of gene and analyze the psychological characteristics of PCOS patients and its effect on the disease of PCOS.
(1) the pathogenesis of insulin resistance (IR) and hyperinsulinemia is closely related to the pathogenesis of PCOS. The occurrence of.IR may involve multiple organs in metabolic processes such as insulin synthesis, transport, utilization, storage and degradation. The mechanism may involve islet beta cell dysfunction, low insulin clearance, decrease in the number and variation of insulin receptor and insulin receptor. In recent years, studies have shown that the dysfunction of the insulin degrading enzyme (IDE) gene resulting in the poor function of IDE can cause abnormal insulin clearance and degradation in the body and lead to insulin resistance. The related literature reports that the mutation of the IDE gene is closely related to type 2 diabetes. But we have not yet seen I on the I. The study of the correlation between the DE gene and the pathological changes of PCOS. Therefore, we intend to study the correlation of the IDE gene in the pathogenesis of PCOS by analyzing the difference in the frequency of the polymorphic distribution of the IDE gene between the PCOS patients and the control group.
(2) the growth hormone releasing peptide (ghrelin), as an endogenous ligand for the growth hormone secretin receptor (GHS-R), shows diversity in stimulating growth hormone secretion and regulating energy balance. Ghrelin can induce the hypothalamus to secrete PRL and the suprarenal cortical hormone, and play negative feedback on the hypothalamus pituitary ovary axis. Use, inhibit the pulse secretion of the central LH, reduce the amount of androgen release, and interact with insulin and affect the dynamic balance of glucose metabolism. Therefore, it is closely related to obesity, type 2 diabetes, metabolic syndrome and insulin resistance. But so far, we have not checked the study of the correlation between the Ghrelin gene polymorphism and the PCOS Therefore, the purpose of this study is to explore the role of Ghrelin in the pathogenesis and pathological changes of PCOS through the study of the correlation between the Arg-51-Gin and Leu-72-Met polymorphisms of the Ghrelin gene and the different phenotypes of PCOS.
(3) at present, people's research on PCOS is mainly focused on pathophysiology and treatment. The psychological problems of PCOS are often ignored. Many aspects of PCOS can cause emotional stress, infertility, irregular menstruation, and hairy and centripetal obesity may cause psychological disorders in PCOS patients, and psychological factors are likely to be the important lure of PCOS. Therefore, this study intends to study the psychological health characteristics and influencing factors of PCOS from the psychological barriers of PCOS and to explore the role of psycho psychological factors in the pathological changes of the pathogenesis of PCOS.
Objective (1) to determine the related factors of insulin resistance in patients with PCOS by analyzing the clinical, endocrine and metabolic characteristics of PCOS patients. (2) to compare the genotype distribution of IDE gene SNPrs1887922, rs2209972, rs4646953, rs1544210 and the difference of allele frequency between the PCOS group and the normal control group, and compare the clinical manifestations of different genotype PCOS patients. The differences in the characteristics of endocrine and metabolic characteristics, the correlation between the related gene mutations and the different phenotypes of PCOS, and the correlation of the IDE gene in the pathogenesis and pathological changes of PCOS. (3) the difference of genotype distribution and allele frequency between the Ghrelin gene polymorphism Arg-51-Gin and Leu-72-Met in the PCOS group and the normal control group was analyzed. Investigate the correlation between the polymorphism and the different phenotypes of PCOS, explore the role of Ghrelin gene in the pathogenesis and pathological changes of PCOS. (4) compare the differences between PCOS patients and non PCOS infertile patients and healthy controls by psychological questionnaire survey, study the psychological health characteristics of PCOS patients and their influencing factors, and explore the mental and psychological factors in PCO The role of S in the pathogenesis and pathological changes.
Methods according to the Rotterdam standard of 2003, 315 cases of PCOS patients were selected and 327 healthy women were selected for the same period as the control. Hormone, biochemical index, OGTT, height, weight, waist and hip circumference were measured, body mass index, waist hip ratio and HOMA-IR. extraction of anticoagulant DNA, according to the sequence of the study gene. According to the corresponding primers, the restriction enzyme digestion and electrophoretic analysis were carried out after the corresponding fragments were amplified by PCR. (2) 77 cases of PCOS infertile patients were selected, and 200 cases of non PCOS infertility patients were selected for the same period, 100 healthy married women were selected as control, and the physical examination and B ultrasonic examination were performed respectively. The sex questionnaire and the SCL-90 questionnaire.
Results (1) the number of BM more than 25kg / m~2 accounted for 47% in PCOS, 61% in Kaohsiung, 2 in LH / FSH, 13.6% for abnormal fasting insulin, 17.7% in abnormal blood glucose, 6.8% in CH0, 18.6% in blood TG, 18.6% in critical hypertension, and for hypertension in IR group of PCOS women. The level of I, WHR and TG was higher than that of non IR group, but the level of LH in non IR group was higher than that in IR group, and the difference was significant: the level of blood glucose at OGTT at OGTT at OGTT, insulin level and HOMA-IR, and glycerin three fat level in PCOS women's group were higher than those in non obese group, and the difference was significantly higher than that in the obese group, and the difference was significantly higher than that of the obese group. The blood LH level, cholesterol level and LDL level in the PCOS women's Kaohsiung hormone group were higher than those in the non Kaohsiung steroid group. The correlation analysis showed that HOMA-IR was positively correlated with BMI and waist circumference, had no correlation with the level of T and LH in blood, and was not related to the level of CHO in blood, and showed a positive phase with the level of blood TG. There was no significant difference in age between the PCOS group and the control group, but the PCOS group BMI, WHR was higher than the control group, and the level of LH and T was significantly higher than that of the control group. The IDE gene SNP rs1887922, rs4646953, rs1544210 were not significantly different from the genotype distribution and allele frequency of the control group and the PCOS group. There was no difference in the clinical, endocrine hormone and metabolic characteristics of these three SNP genotypes PCOS women. There was no significant difference in the distribution of SNPrs2209972 genotypes between the.PCOS group and the control group, but the frequency of C allele was higher than the control group. The difference was statistically significant in the clinical characteristics of PCOS women of different genotype.SNP rs2209972, endocrine stimulation. There was no difference in the level of glucose tolerance and lipid metabolism, but there was a significant difference in insulin level and HOMA-IR at each time point.SNP rs1887922, rs4646953, rs1544210, rs2209972 linkage disequilibrium test value D'< 0.5, r~2 < 0.05. 6 PCR-RFLP analysis showed that there was no Ghrelin gene Arg in Chinese Han population. The -51-Gln polymorphism in the Chinese Han population was GG homozygote. There was no significant difference between the Leu-72-Met polymorphism of the Ghrelin gene and the allele frequency of the control group and PCOS group. The.X~2 test results showed that the Leu-72-Met polymorphism was in the PCOS IR group and non IR group, the Kaohsiung hormone group and the non Kaohsiung hormone group, the obese group and the non obese group were all. There was no significant difference, and there was no significant difference in allele frequency between each group. The results of variance analysis showed that there was no significant difference in the level of BMI, WHR, FSH, LH, PRL and E_2 in different genotype PCOS women, but the difference of serum testosterone level in different genotypes of PCOS women was the critical value P=0.05, after 22 comparison, CC and CA genotypes of PCOS women. The level of female blood testosterone was significantly higher than that of the AA genotype PCOS women. The difference was statistically significant. There was no significant difference between the glucose level and insulin level of OGTT in different genotypes of PCOS women, but the 22 comparison results showed that the difference between HOMA-IR and AA genotype PCOS women in CC genotype women was significant, while CA genotype women HOMA had a significant difference. Although the -IR was higher than the AA genotype PCOS women, the difference was not statistically significant. Except for the horror and psychotic factors, the scores of the other factors and the total SCL-90 score of the SCL-90 were significantly different from those of the control group. The scores of somatization, compulsion, interpersonal sensitivity, depression, hostility factor and SCL-90 total score and non PCOS in PCOS group were significantly different from those in the control group. Women in infertility group had significant differences. Women in non PCOS women and non PCOS male infertility groups were significantly higher than the control group in women's compulsion, interpersonal sensitivity, depression, anxiety, paranoia factor scores and SCL-90 total scores, and the difference was statistically significant, and the score of non PCOS female infertility group's depression factor score There were significant differences between women in the non PCOS male infertility group. The basic data of PCOS patients had an impact on the psychological status of the patients. Age, marriage years, economic conditions, education, and the impact of the living area on the SCL-90 score were statistically significant. Among them, infertility, hairy, obesity and menstrual disorder are the main factors that affect the SCL-90 score.
Conclusions (1) the incidence of obesity, insulin resistance, lipid metabolism and hypertension is significantly higher in patients with polycystic ovary syndrome than in the general population. Obesity, especially abdominal obesity, can aggravate insulin resistance, and Kaohsiung hormone and hyperLH have no effect on IR. Insulin resistance and abnormal lipid metabolism are certain. Correlation. (2) IDE gene SNP rs1887922, rs4646953, rs1544210 and PCOS patients, there is no correlation between the endocrine and metabolic characteristics of the.IDE gene, the.IDE gene SNP rs2209972 is not associated with the clinical and endocrine characteristics of the PCOS patients, but is related to the PCOS women's insulin resistance. There is no Ghrelin gene Arg-51-Gin polymorphism among the Chinese Han population. (4) the Leu-72-Met polymorphism of the Ghrelin gene is closely related to the blood testosterone level in the PCOS patients, and has a certain correlation with the insulin resistance, and has no correlation with the body mass index and lipid metabolism. 5. The mental health level of the infertile patients is significantly decreased, and PCO The psychological health of the patients with S was particularly affected by the age of the.PCOS patients, the years of marriage, the living area, the educational level, the economic situation, the obesity and the hairy and so on, which had an adverse effect on the mental health of the PCOS patients, and the effects of infertility, obesity and hairy, menstrual disorders and so on.

【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2007
【分类号】：R711.75;R395

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