本文選題：多囊卵巢綜合征 + 胰島素降解酶��； 參考：《山東大學(xué)》2007年博士論文

【摘要】： 研究背景多囊卵巢綜合征(PCOS)是育齡女性最常見的內(nèi)分泌紊亂疾病，典型表現(xiàn)為不同程度的月經(jīng)異常、卵巢多囊性改變、高雄激素血癥，并常伴有隨年齡增長而日益明顯的胰島素抵抗／高胰島素血癥和高脂血癥，其病因至今尚不清楚。它的家族聚集現(xiàn)象提示遺傳因素在其發(fā)病機(jī)制中起重要作用，PCOS復(fù)雜的生化特征可能各自存在著遺傳易感性，或者他們之間存在著某種共同的遺傳學(xué)聯(lián)系。多方面的研究結(jié)果顯示，該病可能是多個基因異常和多種環(huán)境因素如營養(yǎng)、精神、心理等因素共同作用的結(jié)果，而精神、心理因素很可能是PCOS的重要誘因和導(dǎo)致其遠(yuǎn)期并發(fā)癥的重要因素。因此，本研究擬從基因水平探討PCOS的發(fā)病機(jī)理并分析PCOS患者的心理特點(diǎn)及其對PCOS發(fā)病的影響。 (1)胰島素抵抗(IR)和高胰島素血癥與PCOS發(fā)病密切相關(guān)。IR的發(fā)生可能涉及胰島素合成、運(yùn)輸、利用、貯存及降解等代謝過程的多個器官，其機(jī)理可能涉及胰島β細(xì)胞功能失調(diào)、胰島素清除率低下、胰島素受體數(shù)目減少及變異以及胰島素受體后缺陷。近年來的研究顯示，由于胰島素降解酶(insulin degrading enzyme，IDE)基因變異導(dǎo)致的IDE功能不良，可引起體內(nèi)胰島素清除和降解異常，導(dǎo)致胰島素抵抗。相關(guān)文獻(xiàn)的報道顯示IDE基因突變與2型糖尿病密切相關(guān)。但目前我們尚未見到關(guān)于IDE基因與PCOS病理變化相關(guān)性的研究。因此，我們擬通過分析PCOS病人與對照組之間IDE基因多態(tài)分布頻率的差異，研究IDE基因在PCOS發(fā)病中的相關(guān)作用。 (2)生長激素釋放肽(ghrelin)作為生長激素促分泌素受體(GHS-R)的一種內(nèi)源性配體，在刺激生長激素分泌、調(diào)節(jié)能量平衡等方面表現(xiàn)出多樣性的調(diào)節(jié)作用，Ghrelin能夠誘導(dǎo)下丘腦分泌PRL和腎上腺皮質(zhì)激素，對下丘腦-垂體-卵巢軸發(fā)揮負(fù)反饋?zhàn)饔�，抑制中樞LH的脈沖式分泌，減少雄激素的釋放量，并且與胰島素相互作用，影響糖代謝動態(tài)平衡。因而它與肥胖、2型糖尿病、代謝綜合征及胰島素抵抗等密切相關(guān)。但到目前為止，我們沒有檢索到關(guān)于Ghrelin基因多態(tài)與PCOS相關(guān)性的研究報道，因此本研究擬通過對Ghrelin基因Arg-51-Gin和Leu-72-Met多態(tài)與PCOS不同表型相關(guān)性的研究，探討Ghrelin在PCOS發(fā)病及病理變化過程中的作用。 (3)目前，人們對PCOS的研究主要集中在病理生理學(xué)及治療方面，PCOS的心理學(xué)問題常常被忽略，PCOS的臨床許多方面都可以導(dǎo)致情緒應(yīng)激，不孕、月經(jīng)不調(diào)、多毛和向心性肥胖可能造成PCOS患者的心理障礙，而心理因素又很可能是PCOS的重要誘因和導(dǎo)致其遠(yuǎn)期并發(fā)癥的重要因素。因此，本研究擬從PCOS的心理障礙方面，基于己有的研究成果，研究PCOS的心理健康特點(diǎn)及影響因素，探討精神心理因素在PCOS發(fā)病病理變化過程中的作用。 目的①通過分析PCOS病人的臨床、內(nèi)分泌及代謝特征，確定PCOS病人胰島素抵抗的相關(guān)因素。②通過分析PCOS組與正常對照組之間IDE基因SNPrs1887922、rs2209972、rs4646953、rs1544210的基因型分布及等位基因頻率的差異，比較不同基因型PCOS病人臨床、內(nèi)分泌及代謝特征的差別，研究相關(guān)基因突變與PCOS不同表型的相關(guān)性，探討IDE基因在PCOS發(fā)病及病理變化過程中的相關(guān)作用。③通過分析Ghrelin基因多態(tài)Arg-51-Gin和Leu-72-Met在PCOS組及正常對照組之間基因型分布及等位基因頻率的差異，研究該多態(tài)與PCOS不同表型的相關(guān)性，探討Ghrelin基因在PCOS發(fā)病及病理變化過程中的作用。④通過心理問卷調(diào)查，比較PCOS患者與非PCOS不孕患者及健康對照身心癥狀的差異，研究PCOS患者的心理健康特點(diǎn)及其影響因素，探討精神心理因素在PCOS發(fā)病及病理變化過程中的作用。 方法①本研究依據(jù)2003年鹿特丹標(biāo)準(zhǔn)選擇PCOS患者315例，并選擇同期就診的327名健康婦女作為對照。分別測定激素、生化指標(biāo)、OGTT，測量身高、體重、腰圍和臀圍，計(jì)算體重指數(shù)、腰臀比例及HOMA-IR。提取其抗凝血的DNA，根據(jù)所研究基因的序列設(shè)計(jì)相應(yīng)引物，應(yīng)用PCR擴(kuò)增相應(yīng)片段后，進(jìn)行限制性內(nèi)切酶酶切，電泳分析。②本研究另選擇PCOS不孕患者77例，并選擇同期就診的非PCOS不孕患者200例，健康的已婚已育婦女100例作為對照，分別進(jìn)行體格檢查及B超檢查，并填寫自行設(shè)計(jì)的一般性問卷及SCL-90問卷。 結(jié)果①PCOS患者中BM≥25kg／m~2者占47％，高雄激素血癥者占61％，LH／FSH≥2者為22.8％，空腹胰島素異常者為13.6％，空腹血糖異常者為7.9％，血CH0水平異常者占17.7％，血TG異常者占6.8％，臨界高血壓者占18.6％，高血壓者占11.1％。②PCOS婦女IR組BMI、WHR、TG水平高于非IR組，差異具顯著性，但非IR組LH水平高于IR組，且差異具顯著性：PCOS婦女肥胖組OGTT各時點(diǎn)血糖水平、胰島素水平及HOMA-IR、甘油三脂水平均高于非肥胖組，差異具有顯著性，非肥胖組LH水平顯著高于肥胖組，差異具有顯著性：PCOS婦女高雄激素血癥組血LH水平、膽固醇水平及LDL水平高于非高雄激素血癥組，差異具有顯著性。③ 相關(guān)分析結(jié)果顯示，PCOS患者HOMA-IR與BMI及腰圍呈顯著正相關(guān)，與血T及LH水平?jīng)]有相關(guān)性，與血CHO水平?jīng)]有相關(guān)性，與血TG水平呈現(xiàn)正相關(guān)關(guān)系。④ PCOS組與對照組相比，年齡無顯著性差異。但PCOS組BMI、WHR高于對照組，LH和T水平也顯著高于對照組，差異均有統(tǒng)計(jì)學(xué)意義。⑤ IDE基因SNP rs1887922、rs4646953、rs1544210在對照組與PCOS組的基因型分布及等位基因頻率均無顯著性差異，而且這三種SNP不同基因型PCOS婦女在臨床、內(nèi)分泌激素及代謝特征方面沒有差異。PCOS組SNPrs2209972基因型分布與對照組比較無顯著性差異，但C等位基因頻率較對照組升高，差異具有統(tǒng)計(jì)學(xué)意義。SNP rs2209972不同基因型PCOS婦女臨床特征、內(nèi)分泌激素水平?jīng)]有差異，糖耐量狀態(tài)及脂代謝水平?jīng)]有差異。但各個時點(diǎn)胰島素水平及HOMA-IR均存在顯著性差異。SNP rs1887922、rs4646953、rs1544210、rs2209972連鎖不平衡檢驗(yàn)值D'＜0.5，r~2＜0.05。⑥ PCR-RFLP分析結(jié)果顯示在中國漢族人群中不存在Ghrelin基因Arg-51-Gln多態(tài)，該位點(diǎn)中國漢族人均為GG純合子。⑦ Ghrelin基因Leu-72-Met多態(tài)在對照組與PCOS組的基因型分布及等位基因頻率均無顯著性差異。X~2檢驗(yàn)結(jié)果顯示Leu-72-Met多態(tài)在PCOS IR組與非IR組、高雄激素組與非高雄激素組、肥胖組與非肥胖組均無顯著性差異，而且各組間等位基因頻率亦無顯著性差異。方差分析結(jié)果顯示，不同基因型PCOS婦女年齡、BMI、WHR、FSH、LH、PRL、E_2水平均無顯著性差異。但不同基因型PCOS婦女血睪酮水平的差異性為臨界值P=0.05，經(jīng)過兩兩比較，CC及CA基因型PCOS婦女血睪酮水平較AA基因型PCOS婦女顯著升高，差異具有統(tǒng)計(jì)學(xué)意義。不同基因型PCOS婦女OGTT各時點(diǎn)葡萄糖水平、胰島素水平無顯著性差異，但兩兩比較結(jié)果顯示，CC基因型婦女HOMA-IR與AA基因型PCOS婦女比較差異具有顯著性，而CA基因型婦女HOMA-IR雖高于AA基因型PCOS婦女，但差異沒有統(tǒng)計(jì)學(xué)意義。⑧ PCOS組婦女除恐怖與精神病性因子外，SCL-90其余各因子得分及SCL-90總分與對照組婦女比較均有顯著性差異。其中軀體化、強(qiáng)迫、人際關(guān)系敏感、抑郁、敵對性因子得分及SCL-90總分與非PCOS不孕組婦女比較有顯著性差異。非PCOS女性因素不孕組婦女及非PCOS男性因素不孕組婦女強(qiáng)迫、人際關(guān)系敏感、抑郁、焦慮、偏執(zhí)因子得分及SCL-90總分均較對照組婦女顯著升高，差異具有統(tǒng)計(jì)學(xué)意義，而且非PCOS女性因素不孕組抑郁因子得分較非PCOS男性因素不孕組婦女有顯著性差異。⑨PCOS患者個人基本資料對患者心理狀況產(chǎn)生影響，其中年齡、結(jié)婚年限、經(jīng)濟(jì)狀況、受教育程度、生活區(qū)域?qū)CL-90評分的影響具有統(tǒng)計(jì)學(xué)意義�；颊叩呐R床癥狀對其心理健康狀況產(chǎn)生不良影響，其中不孕、多毛、肥胖、月經(jīng)紊亂是影響SCL-90評分的主要因素。 結(jié)論①多囊卵巢綜合征患者存在肥胖、胰島素抵抗、脂代謝異常及高血壓等代謝綜合癥的表現(xiàn)，發(fā)生率顯著高于一般人群。肥胖尤其是腹型肥胖可加重胰島素抵抗，高雄激素血癥及高LH血癥對IR沒有影響。胰島素抵抗與脂代謝異常有一定相關(guān)性。②IDE基因SNP rs1887922、rs4646953、rs1544210與PCOS病人臨床、內(nèi)分泌及代謝特征沒有相關(guān)性。IDE基因SNP rs2209972與PCOS病人臨床及內(nèi)分泌特征沒有相關(guān)性，，但與PCOS婦女胰島素抵抗相關(guān)。在中國漢族人中SNP rs2209972、rs1887922、rs4646953、rs1544210不存在連鎖不平衡現(xiàn)象。③中國漢族人群中不存在Ghrelin基因Arg-51-Gin多態(tài)。④Ghrelin基因Leu-72-Met多態(tài)與PCOS患者血睪酮水平密切相關(guān)，與其胰島素抵抗有一定相關(guān)性，與其體重指數(shù)及脂代謝沒有相關(guān)性。⑤不孕患者心理健康水平顯著下降，而PCOS患者心理健康狀況受到的影響尤其顯著。PCOS患者的年齡、結(jié)婚年限、生活地域、受教育水平、經(jīng)濟(jì)狀況、肥胖及多毛等對PCOS患者的心理健康水平產(chǎn)生不良影響，不孕、肥胖及多毛、月經(jīng)紊亂等的影響尤其顯著。
[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.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2007
【分類號】：R711.75;R395

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