【作者】 张莹；

【导师】 臧文巧；

【作者基本信息】 郑州大学 ， 免疫学， 2020， 硕士

【摘要】 背景多囊卵巢综合征（Polycystic Ovary Syndrome,PCOS）不孕症是一种女性人群中具有较高发病率的生殖内分泌紊乱性疾病,发病率达到了5%-10%,占无排卵性不孕症患者的30%-60%。绝大部分多囊卵巢综合征不孕症患者均表现出胰岛素抵抗以及不同程度的糖耐量异常,同时还会导致其甲状腺功能、免疫系统以及卵巢功能发生改变。多囊卵巢综合征不孕症多见于青春期阶段,其发生发展与多种因素密切相关,包括了激素、基因以及环境的共同作用,但目前关于多囊卵巢综合征不孕症的发病原因尚未明确。为此,探索引起多囊卵巢综合征不孕症的临床表现特征和发病原因,是近年来的研究热点。目的借助临床研究和动物模型研究,探索多囊卵巢综合征不孕症患者的甲状腺功能以及卵巢功能相关指标的特点,以及在疾病中发生发展的作用。方法1.临床研究:选取2018年1月-2019年12月生殖中心接诊的多囊卵巢综合征不孕症患者35例作为观察组,另从生殖中心选取多囊卵巢综合征患者30例作为对照1组,另选取健康女性30例作为对照2组。对其甲状腺功能（游离三碘甲状腺原氨酸,FT₃、血清游离甲状腺素,FT₄和促甲状腺激素,TSH、抗甲状腺球蛋白抗体,ATG、抗甲状腺过氧化物酶抗体,TPO-Ab）;卵巢功能（血清促卵泡生成素,FSH、促黄体生成素,LH、雌激素,E₂）进行测定,根据测定结果进行分组对比、相关性以及多元回归分析。2.动物模型研究:购入C₃H品系雌性小鼠30只和雄性小鼠15只,分别设定为空白组,模型对照组,用药组（给予吡格列酮二甲双胍复方制剂）,每组各10只雌性小鼠,观察三组小鼠的血清甲状腺激素（FT₃、FT₄、TSH）、甲状腺自身抗体（ATG、TPO-Ab）、卵巢功能（FSH、LH、E₂）指标情况以及卵巢、甲状腺病理组织学特点和妊娠率。结果1.临床研究:多囊卵巢综合征不孕症患者对比健康人群和多囊卵巢综合征的人群表现出FT₃、FT₄显著下降,TSH显著升高,甲状腺自身抗体指标ATG阳性率、TPO-Ab>60U/ml阳性率显著升高,卵巢功能指标FSH显著下降和LH、E₂显著升高。（2）卵巢功能指标（FSH、LH、E₂）与甲状腺功能指标（FT₃、FT₄、TSH）、自身抗体指标（ATG、TPO-Ab）均呈现出相关性。（3）多因素分析结果证实,FT₃、FT₄、TSH、ATG阳性、TPO-Ab>60U/ml阳性、FSH、LH、E₂均是导致多囊卵巢综合征合并不孕症的独立危险因素（P<0.05,P<0.01）。2.动物模型研究:（1）空白组小鼠的卵巢外观形态并未发生异常改变,同时可以在卵巢中发现各级发育状态的黄体与卵泡,颗粒细胞在卵泡中呈现为整齐排列状;模型组小鼠的卵巢外观表现出显著的桑葚状改变,闭锁卵泡的直径明显增大、数量也显著增加,卵泡则呈现为明显的囊性扩张状态,卵母细胞表现出放射冠状消失;用药组小鼠在用药干预后,镜下观察发现不同发育时期的卵泡,多为初级卵泡,在卵母细胞周围排列着整齐的颗粒细胞。（2）空白组小鼠的甲状腺滤泡呈椭圆形或者圆形,滤泡腔中有丰富的淡红色胶质,分布均匀,无炎细胞浸润,在滤泡间有丰富的血管,小叶间有大量薄壁纤维组织间隔,无纤维化病灶;模型对照组小鼠的甲状腺组织中存在明显的淋巴细胞浸润情况,且甲状腺滤泡明显萎缩,并且逐步消失;用药组小鼠甲状腺滤泡呈现为椭圆形或者圆形,滤泡腔中充满了淡红色胶质,分布也非常的均匀,散布在淋巴细胞中,但仍然有一定的纤维组织增生情况。（3）模型对照组小鼠与空白组小鼠比较,其FT₃、FT₄、TGAb、TPO-Ab、LH、LH/FSH均表现出显著的升高（P<0.05）,同时FSH、TSH、E₂均表现出显著的下降（P<0.05）。用药组小鼠FT₃、FT₄、TGAb、TPO-Ab、LH、LH/FSH均表现出显著的下降（P<0.05）,并且FSH、TSH、E₂均表现出不同程度的升高（P<0.05）。（4）空白组妊娠率达到100%,模型对照组小鼠妊娠率为20%,用药组小鼠妊娠率为70%。结论多囊卵巢综合征不孕症患者表现出FT₃、FT₄显著下降,TSH显著升高,自身抗体指标ATG阳性率、TPO-Ab>60U/ml阳性率显著升高,卵巢功能指标FSH显著下降和LH、E₂显著升高。甲状腺功能（FT₃、FT₄、TSH、ATG阳性率、TPO-Ab>60U/ml）、卵巢功能（FSH、LH、E₂）的指标与多囊卵巢综合征不孕症密切相关。更多还原

【Abstract】 BackgroundPolycystic ovary syndrome（PCOS）infertility is a reproductive endocrine disorder with a high incidence in female population,the incidence rate reaches5%-10%,accounting for anovulatory infertility 30%-60%of patients.The vast majority of infertility patients with polycystic ovary syndrome show insulin resistance and varying degrees of impaired glucose tolerance,which can also lead to changes in their thyroid function,immune system and ovarian function.Polycystic ovary syndrome infertility is more common in puberty,and its occurrence and development are closely related to many factors,including the combined effects of hormones,genes,and the environment.However,the cause of infertility with polycystic ovary syndrome is not yet clear.For this reason,exploring the clinical manifestations and causes of infertility caused by polycystic ovary syndrome has become a research hotspot in recent years.ObjectiveWith the help of clinical research and animal model research,explore the characteristics of thyroid function,autoimmunity and ovarian function-related indicators in patients with polycystic ovary syndrome infertility,as well as the role of development in the disease.Methods1.Clinical research:35 cases of infertility patients with polycystic ovary syndrome received from the reproductive center from January 2018 to December2019 were selected as the observation group,and 30 cases of polycystic ovary syndrome patients from the reproductive center were selected as controls In group 1,30 healthy women were selected as control group 2.Its thyroid function（free triiodothyronine,FT₃,serum free thyroxine,FT₄ and thyroid stimulating hormone,TSH）;autoimmunity（anti-thyroglobulin antibody,ATG,anti-thyroid peroxidase antibody,TPO-Ab）;ovarian function（serum follicle stimulating hormone,FSH,luteinizing hormone,LH,estrogen,E₂）were measured,and group comparison,correlation and multiple regression analysis were performed according to the measurement results.2.Animal model study:30 female mice and 1 male mouse of the C₃H strain were purchased,and they were set as blank group,model control group,and medication group（given pioglitazone-metformin compound preparation）,each with10 female mice Rats,observe the serum thyroid function（FT₃,FT₄,TSH）,autoantibodies（ATG,TPO-Ab）,ovarian function（FSH,LH,E₂）indicators of the three groups of mice,as well as the histopathological characteristics of ovary and thyroid,and pregnancy rate.Results1.Clinical research:（1）Compared with healthy people and people with polycystic ovary syndrome,patients with infertility with polycystic ovary syndrome showed that FT₃ and FT₄ were significantly decreased,TSH was significantly increased,and the positive rate of autoantibody index ATG,TPO-Ab>60U The positive rate of/ml increased significantly,the ovarian function index FSH decreased significantly and LH and E₂ increased significantly.（2）Ovarian function indexes（FSH,LH,E₂）and thyroid function indexes（FT₃,FT₄,TSH）and autoantibody indexes（ATG,TPO-Ab）all showed correlation.（3）Multivariate analysis results confirmed that FT₃,FT₄,TSH,ATG positive,TPO-Ab>60U/ml positive,FSH,LH,E₂are all independent risk factors leading to polycystic ovary syndrome complicated with infertility（P<0.05,P<0.01）.2.Animal model research:（1）The ovaries of the blank group did not change abnormally.At the same time,the corpus luteum and follicles of various developmental states can be found in the ovaries,and the granulosa cells are arranged neatly in the follicles;The appearance of the ovaries of mice showed significant mulberry-like changes,the diameter and number of atretic follicles increased significantly,and the follicles showed obvious cystic expansion,and the oocytes showed the disappearance of radiation coronal;After medication intervention,microscopic observation revealed that the follicles at different developmental stages were mostly primary follicles,with neat granular cells arranged around the oocytes.（2）The thyroid follicles of the mice in the blank group were oval or round,and the follicular cavity was rich in light red colloid,evenly distributed,without inflammatory cell infiltration,abundant blood vessels between the follicles,and a large number of thin lobules.The wall of fibrous tissue is separated,and there is no fibrotic lesion;there is obvious lymphocyte infiltration in the thyroid tissue of the model control group,and the thyroid follicles are obviously atrophy and gradually disappear;the thyroid follicles of the mice in the medication group appear oval or It is round,and the follicular cavity is filled with light red gum,and the distribution is also very even,scattered among the lymphocytes,but there is still a certain degree of fibrous tissue proliferation.（3）Comparing the model control group with the blank group,the FT₃,FT₄,TGAb,TPO-Ab,LH,LH/FSH all showed a significant increase（P<0.05）,while FSH,TSH,E₂ all showed Significant decline（P<0.05）.FT₃,FT₄,TGAb,TPO-Ab,LH,LH/FSH all showed significant decline in the medication group（P<0.05）,and FSH,TSH,E₂ all showed different degrees of increase（P<0.05）.（4）The pregnancy rate in the blank group reached 100%,the pregnancy rate in the model control group was 20%,and the pregnancy rate in the medication group was 70%.ConclusionInfertility patients with polycystic ovary syndrome showed a significant decrease in FT₃ and FT₄,a significant increase in TSH,a significant increase in the positive rate of autoantibody index ATG and TPO-Ab>60U/ml,and a significant decrease in ovarian function index FSH And LH,E₂ increased significantly.Thyroid function(FT3,FT4,TSH,ATG positive rate,TPO-AB>Indicators of 60U/ml and ovarian function（FSH,LH,E2）are closely related to infertility due to POLYcystic ovary syndrome.更多还原