【作者】 李欣；

【导师】 陈士岭；

【作者基本信息】 南方医科大学 ， 临床医学（专业学位）， 2021， 博士

【摘要】 目的早发性卵巢功能不全(prematureovarianinsuffciency,POI)是一种女性40岁之前由于卵巢功能减退或缺失引起的临床综合征,其引起的一系列生殖内分泌问题及远期并发症严重损害女性的身心健康和生育。随着生活环境恶化、生活压力增大、生育年龄推迟和肿瘤患者放化疗治疗,POI的发病率逐年增高,然而发病机制仍未明确。探讨POI可能的发病机制,寻找潜在的特异性标志物,为疾病的早诊断和早治疗提供依据,预防远期并发症,成为亟待解决的问题。方法1、参照《2017年版早发性卵巢功能不全的临床诊疗中国专家共识》的诊断依据,收集POI患者100例与对照组患者76例,采集患者的基本临床资料和实验室指标,分析POI患者的糖脂代谢特征及其与性激素水平的关系。2、收集POI患者与对照组患者血浆各26例,采用基于超高效液相色谱分析的代谢组学技术筛选代谢差异物,基于主成分分析法、偏最小二乘法判别分析等寻找显著差异代谢物,随后利用随机森林模型对差异代谢物重要度进行排序,利用受试者工作特征曲线来筛选潜在的生物标志物。结果1、糖脂代谢特征POI患者的空腹血糖水平高于对照组患者,差异有统计学意义(P<0.05);与对照组患者相比,POI患者的血脂代谢存在异常,表现为血清总胆固醇和低密度脂蛋白胆固醇水平升高、高密度脂蛋白胆固醇水平下降,差异有统计学意义(P<0.05),甘油三酯水平未发现差异(P>0.05)。POI患者血清基础FSH水平与血清TC、LDL-c、nHDL-c水平呈正相关关系(P<0.05),而基础E2水平与血清TC、LDL-c、nHDL-c水平呈负相关关系(P<0.05)。2、代谢组学结果相比于对照组,POI组的血浆代谢物存在显著差异。在正、负离子模式下分别注释到576和385种差异代谢物,其中显著差异代谢物各有79和64种,以游离脂肪酸、磷脂及氨基酸为主。POI组的游离脂肪酸水平显著升高。与磷脂代谢相关的磷脂酰胆碱、溶血磷脂酰胆碱、溶血磷脂酰乙醇胺等水平均显著下降。除半胱氨酸谷胱甘肽含量上升外,组氨酸、甲硫氨酸、亮氨酸、脯氨酸等多种氨基酸含量显著下降,差异有统计学意义(P<0.05)。其中,花生四烯酸酰胺、半胱氨酸、L-苏糖酸、DL-β-亮氨酸水平较对照组存在显著差异(P<0.05),是潜在的生物标志物。结论1、与对照组相比,POI组空腹血糖水平升高,但临床意义尚未明确;血脂代谢存在异常,可能与远期心血管疾病发病风险增加有关。2、POI组的血浆代谢物和对照组相比存在显著差异,以游离脂肪酸、磷脂及氨基酸为主,筛选出的差异代谢物如花生四烯酸酰胺、半胱氨酸、L-苏糖酸、DL-β-亮氨酸等可能有助于疾病的早期诊断及远期并发症的预防。更多还原

【Abstract】 ObjectivePremature ovarian insufficiency(POI)is a clinical syndrome caused by ovarian dysfunction or deficiency in women before 40 years old.It causes a series of reproductive endocrine problems and long-term complications,which seriously damage women’s physical and mental health and fertility.The incidence rate of POI is increasing with the deterioration of living environment,increasing pressure of life,delayed birth age and chemotherapy or radiotherapy.To explore the possible pathogenesis of POI,to find potential specific markers,to provide basis for early diagnosis and treatment,and to prevent long-term complications has become an urgent problem to be solved.MethodRefer to the diagnostic based on the Chinese expert consensus on the clinical diagnosis and treatment of early-onset ovarian insufficiency(2017 Edition),100 patients with POI and 76 patients in the control group were collected,and the basic clinical data and laboratory indexes of the patients were collected to analyze the characteristics of glucose and lipid metabolism of patients with POI and its relationship with sex hormone level.26 plasma samples from POI group and 26 plasma samples from control group were collected.Metabonomics technology based on ultra performance liquid chromatography was used to screen metabolisms,and significant difference metabolites were found based on principal component analysis and partial least squares discriminant analysis.Then,the importance of different metabolites was ranked by random forest model,and the potential biomarkers were screened by receiver operating characteristic curve.Result1.Characteristics of glucose and lipid metabolismThe fasting blood glucose level of POI group was higher than that of the control group(P<0.05).Compared with the control group,the lipid metabolism of POI group was abnormal,which revealed that the levels of serum total cholesterol and low-density lipoprotein cholesterol were increased,while the level of high-density lipoprotein cholesterol was decreased,with statistical significance(P<0.05),and there was no difference in triglyceride level(P>0.05).Serum FSH level was positively correlated with serum TC,LDL-C and nHDL-C levels(P<0.05),while serum E2 level was negatively correlated with serum TC,LDL-C and nHDL-C levels(P<0.05).2.Metabonomics resultsCompared with the control group,the plasma metabolites of patients with POI were significantly different.576 and 385 metabolites were identified respectively under the positive and negative mode,of which 79 and 64 were significantly different metabolites,mainly free fatty acids,phospholipids and amino acids.The level of free fatty acids in patients with POI increased significantly.The levels of phosphatidylcholine,lysophosphatidylcholine and lysophosphatidylethanolamine were significantly decreased.In addition to the increase of cysteine and glutathione,the levels of histidine,methionine,leucine,proline and other amino acids decreased significantly(P<0.05).Among them,arachidonoyl amide,L-cysteine,L-threonine and DL-β-leucine levels were significantly different from those of the control group(P<0.05),which were potential biomarkers.ConclusionCompared with the control group,the fasting blood glucose level in patients with POI was higher,but the clinical significance was not clear.The abnormal lipid metabolism may be related to the increased risk of long-term cardiovascular disease.Compared with the control group,the plasma metabolites of patients with POI were different,mainly free fatty acids,phospholipids and amino acids.The selected metabolites such as arachidonoyl amide,L-cysteine,L-threonine,DL-β-leucine and so on may contribute to the early diagnosis of the disease and the prevention of long-term complications.更多还原