卵巢衰老评价体系的建立及其对心血管疾病影响的初探

发布时间：2018-05-13 07:45

本文选题：AMH + Inhibin　；参考：《华中科技大学》2016年博士论文

【摘要】：研究背景：抗苗勒氏管激素(antimullerian hormone, AMH)和抑制素B(inhibinB)在临床上的应用日益被重视,然而其在健康人群中的正常参考范围却一直未被建立；对中国健康育龄妇女来说,尤其缺乏可应用于临床的基于社区健康人群所建立的准确的参考范围,这种情况部分限制了抗苗勒氏管激素和抑制素在临床实践中的应用。而且,在正常健康女性人群中,抗苗勒氏管激素、抑制素与其它临床指标如体质指数BMI,窦状卵泡数目AFC以及其他性别相关激素之间的相互关系至今未见文献报道。研究目的：以建立正常女性的年龄特异性抗苗勒氏管激素和抑制素参考值范围为目的,同时探索在健康女性人群中抗苗勒氏管激素、抑制素与其它临床指标的关系。研究设计：为建立准确可靠的抗苗勒氏管激素、抑制素参考值范围,我们开展了一项历时3年(2011年10月-2014年12月),跨越不同地域的多中心、大样本量的横断面研究。在沈阳(华北),佛山(华南),成都(华西),郑州、宜昌及武汉(华中)6个城市以广告宣传招募志愿者的形式招募了总计2055例20-55岁女性,年龄范围跨越整个育龄期直至绝经期。同时,我们制定了严格的纳入标准以确保纳入的研究对象符合健康人群要求,经过筛选,其中符合本实验纳入标准者有1590例,占比77.37%,以纳入的健康人群为研究对象制定AMH, inhibinB参考范围。我们分别利用两种试剂盒(Beckman Gen Ⅱ AMH assay及Ansh Labs AMH assay)检测血清基础AMH水平,用Beckman Gen Ⅱ AMH assay检测了血清基础inhibin B的水平。也检测了卵泡期血清FSH,LH,E2,T,PRL和PRG的水平,同时通过经阴道超声检查确定AFC的数目。主要结果：两种AMH试剂盒检测有很好的一致性,但同一样本的AMH检测数值有所不同,Beckman Gen Ⅱ AMH assay较Ansh Labs AMH assay的检测数值偏高。两种试剂盒都证实：血清抗苗勒氏管激素AMH水平随年龄增长呈逐渐下降的趋势,Beckman Gen Ⅱ AMH assay试剂盒的检测结果显示AMH下降趋势可被该二次方程log(AMH)=(-1.970+0.296*Age-0.006*Age2)最好地拟合。Ansh Labs AMH assay试剂盒的检测结果却显示AMH与年龄Age的最佳拟合方程是log(AMH)=(-0.707+0.116*Age-0.002*Age2)。我们按年龄将研究人群划分为6个亚组：20-25,25-30,30-33,33-37,37-40,40-55岁;Beckman Gen Ⅱ AMH assay试剂盒的检测结果显示各年龄组AMH中值水平为：6.23,5.65,4.55,3.74,2.78和1.09 ng/ml。各组5th-95th百分位数范围(即本研究确定的参考值范围)为：2.06-12.66,1.77-13.83,1.48-11.45,0.87-9.76,0.56-9.49,and 0.08-5.70 ng/ml。Ansh Labs AMH assay试剂盒的检测结果显示各年龄组AMH中值水平为：5.55,4.80,3.76,3.42,2.44和0.77ng/ml。各组5th-95th百分位数范围为：1.43-13.14,1.31-13.55,1.06-10.97,0.69-9.52,0.38-8.03,0.04-4.79 ng/ml。AMH水平与AFCs,T,LH,PRL,PRG的水平呈正相关关系,与BMI和FSH水平呈负相关,与E2没有显著的相关关系。在控制了混杂变量“年龄”与"BMI"之后,AMH与PRL的相关关系变得不显著,而AMH与除PRL外的其它变量的相关关系未见改变。Inhibin B水平随年龄的变化趋势在40岁之前比较平稳,在40岁之后急剧下降,T检验和Wilcoxon检验均显示20-40岁与40-55岁两个年龄组之间的InhibinB水平有显著性差异。我们按年龄将研究人群划分为2个亚组：20-40,40-55岁；Beckman Inhibin B assay试剂盒的检测结果显示两年龄组Inhibin B中值水平为：83.13和56.32 pg/ml:两组5th-95th百分位数范围为：34.38-143.75,2.6-142.33pg/ml.Inhibin B与AMH呈正相关(R=0.57,P0.001),与AFC呈正相关(R=0.34,P0.001),与T呈正相关(R=0.01,P=0.002)；Inhibin B与下列4个指标负相关：FSH(R=-0.41,P0.001),LH(R=-0.20,P0.001),age(R=-0.30,P 0.001),BMI(R=-0.28,P0.001)；Inhibin B与PRG、PRL无显著相关关系。结论：本研究建立了基于健康人群的中国女性血清AMH和Inhibin B的正常参考范围,有利于临床医生更好的解读和阐释该指标的临床意义。研究背景：AFC和血清FSH,LH,E2,T等检测是评价卵巢功能或诊断疾病的重要指标,在临床上应用广泛。但现今,指导临床诊断的各指标参考范围均是普通性参考范围(universal ranges)而非年龄特异性参考范围(age-specific ranges),而这些指标比如AFC和生殖相关激素均是与年龄密切相关并随着年龄增长而变化的激素,故准确的年龄特异性参考范围要比普通性参考范围更有临床诊断价值。研究目的：我们以建立正常女性的年龄特异性AFC和血清FSH,LH,E2,T参考值范围为目的,同时探索健康女性人群中各个临床指标的相互关系。研究设计：见上部分(与建立抗苗勒氏管激素、抑制素B参考范围的设计类似)。研究结果：AFC随年龄增长而下降,其随年龄的下降趋势可被以下方程最佳拟合：AFC=9.0998+0.6128*Age-0.0159*Age2。FSH随年龄增长而升高,其随年龄的升高趋势可被以下方程拟合最佳：FSH=12.7885-0.5031*Age+0.0101*Age2。其他性别相关激素随年龄变化的趋势同样可由最佳方程拟合：比如LH=11.5678-0.4101*Age+0.0059*Age2,E2=85.6229-3.002*Age+0.0546*Age2, T=33.1488+0.4427*Age-0.0176*Age2。我们按人群年龄分为3个亚组：20-30,30-40,40-55岁,分别制定了AFC,FSH,LH,E2和T在各个年龄组的参考范围：各年龄组AFC中值水平为：14,11,5个；各年龄组FSH中值水平为：6.50,6.95,7.99 mIU/ml:各年龄组LH中值水平为：4.375,3.92,4.53 mIU/ml:各年龄组E2中值水平为：40.255,42.261,40.705pg/ml；各年龄组T中值水平为：31.54,26.56,18 pg/dl。我们还发现：AFC与年龄、BMI和FSH水平负相关,与LH和T水平正相关。FSH与年龄、LH正相关,与AFC、BMI, T负相关；LH与年龄、BMI负相关,与AFC、FSH和E2正相关；E2与与年龄没有显著关系,与LH、T正相关,与BMI负相关；结论：我们建立了正常女性的年龄特异性AFC和血清FSH,LH,E2,T参考值范围,并在健康女性人群中确定了各指标的相互关系。研究目的：明确与女性心血管疾病发病风险相关的卵巢衰老关键因子。研究方法：在同济医院的健康体检中心进行广告招募,招募符合纳入标准的女性志愿者共计536人参与该研究。所有受试者于月经第1-5天早餐空腹采肘静脉促凝血3-4m1,离心得到上层血清。检测血清FSH, LH, E2,T,PRL等激素水平,酶联免疫吸附技术(ELISA)检测血清抗苗勒氏管激素AMH的水平,经阴道超声检测其两侧卵巢内2-10mm的卵泡数目AFC。同时,检测预示心血管疾病发病风险的指标,包括血脂四项(总胆固醇TC,总甘油三酯TG,高密度脂蛋白HDL-C,低密度脂蛋白LDL-C)以及超敏C反应蛋白的水平。然后,分析代表卵巢功能的各种指标与心血管疾病风险的指标间的相关性。研究结果：通过双变量Pearson线性相关分析可知,AMH与TC,TG,LDL-C负相关；FSH与TC,TG,LDL-C正相关；E2与TC,TG,LDL-C负相关;LH与TC,TG,LDL-C正相关;AFC与TC,TG,LDL-C负相关；T与LDL-C正相关；PRL与HDL-C正相关,与h-CRP负相关。通过Logistic回归分析可知,AMH与FSH可进入以总的心血管疾病风险为Y值的回归方程。结论：女性卵巢功能与心血管疾病发病风险密切相关,其中卵巢衰老相关的各项指标中,AMH与AFC比FSH,LH,E2等指标在预警心血管疾病上可能更有优势；AMH可以作为预测心血管疾病风险的一个指标。研究目的：验证抗苗勒氏管激素(AMH)及月经情况与心血管疾病(包括冠心病和其它心血管疾病)的发病是否有相关性。研究方法：2013年10月至2015年12月,在同济医院心血管内科收集到经冠脉造影确诊冠心病的年龄范围在40-55岁之间的女性病人,共计128例,作为病例2组：同期收集因心慌心悸胸闷胸痛等症状入院治疗,但经冠脉造影不能确诊冠心病者,共计101例,设为病例1组。同期在同济医院周边的数个社区进行广告招募,按年龄分层匹配,募集到健康女性243例,作为正常对照(设为0组)。利用问卷调查包括月经情况和孕产史等一般资料,并进行血清激素AMH,血脂和超敏C反应蛋白的检测。利用方差分析比较病例2组、病例1组和对照0组在AMH水平、月经情况上有无差异；另外比较3组之间的其它指标包括：卵巢功能相关指标(孕次,产次)和CVD相关风险因子(血脂、血压、血糖)等有无差异。研究结果：年龄在各组间均无差异,即三组基线年龄相似,三组之间在研究指标上具有可比性。方差分析发现三组间各指标差异性：AMH水平、月经情况(即绝经与否)、孕次均表现为：在0组与1组,0组与2组有差异,但1组与2组之间无差异。产次在3组间均无差异；收缩压：3组间均有差异：舒张压：0组与2组有差异,但0组与1组,1组与2组之间无差异;TC和HDL-C和LDL-C:在3组间均无差异；TG：0组与1组有差异,但0与2组、1与2组无差异：血糖：0组与1组,0组与2组有差异,但1组与2组之间无差异;BMI在3组间均无差异;结论：AMH水平、月经情况等卵巢功能指标与冠心病密切相关,而且AMH水平、月经情况的差异性出现在TC、HDL-C和LDL-C指标变化之前,可能具有更早期的预测价值。
[Abstract]:Background: the clinical application of antimullerian hormone (AMH) and inhibin B (inhibinB) is becoming more and more important in clinical practice. However, the normal reference range in healthy people has not been established. An accurate reference range, which partially restricts the application of anti Mullerian tube hormones and inhibin in clinical practice. Moreover, in normal healthy women, the relationship between the anti Mullerian tube hormone, inhibin and other clinical indicators such as the body mass index BMI, the number of sinus follicular numbers AFC and other sex related hormones The purpose of this study was to establish a reference range of age specific anti Mullerian tube hormone and inhibin for normal women, and to explore the relationship between anti Muller's hormone and inhibin and other clinical indicators in healthy women. Design: to establish a reliable and reliable anti Mullerian tube hormone and inhibin. In the range of reference values, we carried out a cross-sectional study of multi centers across different regions for 3 years (December October 2011 -2014). 6 cities in Shenyang (North China), Foshan (Southern China), Chengdu (Huaxi), Zhengzhou, Yichang, and Wuhan (Hua Zhong) recruited 2055 20-55 year old women in the form of advertising and recruitment of volunteers. Sex, the age range spanned the whole childbearing age and the menopause. At the same time, we made strict inclusion criteria to ensure that the subjects included in the study met the requirements of the healthy population. After screening, 1590 cases were included in the standard of the experiment, accounting for 77.37%, and the AMH, inhibinB reference range of the included healthy people was made for the study object. The level of serum base AMH was detected by two kits (Beckman Gen II AMH assay and Ansh Labs AMH assay). The level of serum base was detected by Beckman Gen II AMH. Two AMH kits have good consistency, but the AMH detection value of the same sample is different, and the detection value of Beckman Gen II AMH assay is higher than that of Ansh Labs AMH assay. The two kits have confirmed that the AMH level of serum anti Mullerian tube hormone is gradually decreasing with age. The detection results of the box show that the AMH descending trend can be best fitted to the detection results of the.Ansh Labs AMH assay kits by the two order equation log (AMH) = (-1.970+0.296*Age-0.006*Age2), but the best fitting equation of AMH and Age is log (AMH) =. We divide the study population into 6 subgroups according to age: 25,25-30,30-33,33-37,37-40,40-55 years old; the detection results of Beckman Gen II AMH assay kit showed that the median of AMH in each age group was the 5th-95th percentile range of 6.23,5.65,4.55,3.74,2.78 and 1.09 ng/ml. (that is, the range of reference values determined by this study) was 2.06-12.66,1.77-13.83,1.48-11.45,0.87-9.76,0.56-9.49, and 0.08. The detection results of -5.70 ng/ml.Ansh Labs AMH assay kit showed that the median of AMH in each age group was: the 5th-95th percentile range of 5.55,4.80,3.76,3.42,2.44 and 0.77ng/ml. groups was: 1.43-13.14,1.31-13.55,1.06-10.97,0.69-9.52,0.38-8.03,0.04-4.79 ng/ml.AMH level was positively related to the level of AFCs, MI and FSH were negatively correlated with E2, and the correlation between AMH and PRL became insignificant after controlling the mixed variables "age" and "BMI", while the correlation between AMH and other variables except PRL did not change the trend of.Inhibin B level with age and was more stable before 40 years of age, after 40 years of age. The decrease, T test and Wilcoxon test showed that there was a significant difference between 20-40 and 40-55 years old and two age groups. We divided the study group into 2 subgroups according to age, 20-40,40-55 years, and the Beckman Inhibin B assay kits showed that the median of Inhibin B in the two age group was 83.13 and 56.32 pg/ml:. The two 5th-95th percentile range is that 34.38-143.75,2.6-142.33pg/ml.Inhibin B is positively correlated with AMH (R=0.57, P0.001), and is positively correlated with AFC (R=0.34, P0.001), and is positively related to T (R=0.01, P=0.002). There is no significant correlation between Inhibin B and PRG and PRL. Conclusion: This study established a normal reference range of Chinese women's serum AMH and Inhibin B based on healthy people. It is beneficial for clinicians to better interpret and explain the clinical significance of this index. Background: AFC and serum FSH, LH, E2, T and other tests are the evaluation of ovarian function or diagnostic disease. The important index of disease is widely used in clinical practice. But today, the reference range for guiding clinical diagnosis is the common reference range (Universal ranges) rather than the age specific reference range (age-specific ranges). These indicators, such as AFC and reproductive related hormones, are closely related to age and vary with age. The accurate age specific reference range is more clinical diagnostic value than the common reference range. Objective: to establish the range of reference values of age specific AFC and serum FSH, LH, E2, T in normal women, and to explore the correlation of various clinical indicators in healthy women. Part (similar to the design of an anti Mullerian tube hormone, inhibin B reference range). Research results: AFC decreases with age, and its decrease with age can be best fitted to the following equation: AFC=9.0998+0.6128*Age-0.0159*Age2.FSH increases with age, and its age increases with the following equation to fit the best. FSH=12.7885-0.5031*Age+0.0101*Age2. other sex related hormones can also be fitted by the best equation for age. For example, LH=11.5678-0.4101*Age+0.0059*Age2, E2=85.6229-3.002*Age+0.0546*Age2, and T=33.1488+0.4427*Age-0.0176*Age2. are divided into 3 subgroups according to the age of the population: 20-30,30-40,40-55 years, respectively. The reference range of AFC, FSH, LH, E2 and T in all age groups: the median of AFC in each age group is 14,11,5, and the median of FSH in each age group is: 6.50,6.95,7.99 mIU/ml: in all age groups: the median level is: the median of each age group of 4.375,3.92,4.53, and the median of each age group. 31.54,26.56,18 pg/dl. we also found that AFC was negatively correlated with age, BMI and FSH levels, positive correlation with LH and T levels, LH positive, AFC, BMI, T. The range of age specific AFC and serum FSH, LH, E2, T reference values of normal women and the relationship between the indexes were determined in healthy women. Objective: to clarify the key factors of ovarian senescence related to the risk of cardiovascular disease in women. A total of 536 female volunteers were enrolled in the study. All the subjects were involved in the study. All the subjects received the elbow vein procoagulant 3-4m1 on the 1-5 day of the morning's breakfast and centrifugally obtained the upper serum. The serum levels of serum FSH, LH, E2, T and PRL were detected. The serum level of serum anti Mullerian tube hormone AMH was detected by enzyme linked immunosorbent assay (ELISA), and transvaginal ultrasound was used. At the same time, the number of 2-10mm follicles in the ovary on both sides of the ovary was detected at the same time, and the index of the risk of cardiovascular disease was detected, including four blood lipids (total cholesterol TC, total triglyceride TG, high density lipoprotein HDL-C, low density lipoprotein LDL-C) and the level of hypersensitive C reactive protein. Then, various indexes representing ovarian function and heart blood were analyzed. The correlation between the indicators of the risk of disease. Results: through the bivariate Pearson linear correlation analysis, AMH is negatively correlated with TC, TG, LDL-C; FSH is positively correlated with TC, TG, LDL-C; E2 and TC, TG are positively related; Through Logistic regression analysis, we can see that AMH and FSH can enter the regression equation with the total risk of cardiovascular disease as Y. Conclusion: female ovarian function is closely related to the risk of cardiovascular disease. Among the indexes related to ovarian senescence, AMH and AFC may be more advantageous in early warning of cardiovascular disease than FSH, LH, E2. AMH can be used as an indicator of the risk of cardiovascular disease. Purpose: to verify the correlation between anti Mullerian tube hormone (AMH) and menstruation and the incidence of cardiovascular diseases (including coronary heart disease and other cardiovascular diseases). Methods of study were collected from October 2013 to December 2015 in Tongji Hospital in cardiovascular medicine. The age range of coronary heart disease between 40-55 years old female patients, a total of 128 cases, as the 2 groups of cases: the same period collected for the symptoms of palpitation and chest pain, chest pain, chest pain and other symptoms hospitalized, but the coronary angiography can not be diagnosed with coronary heart disease, a total of 101 cases, set up as 1 groups in the same period of Tongji Hospital around a number of communities recruited, press recruitment, according to the hospital Age stratified matching, 243 healthy women were recruited as normal controls (set up as 0 groups). The questionnaire survey included general data on menstruation and pregnancy history, and the detection of serum hormone AMH, blood lipid and hypersensitivity C reactive protein. Use variance analysis to compare 2 groups of cases, cases 1 and control 0 at AMH levels, menstrual conditions The difference between the 3 groups included: ovarian function related indexes (gestation times, birth times) and CVD related risk factors (blood lipids, blood pressure, blood sugar) and other differences. The results of the study were that there were no differences in age between groups, that is, the baseline age of the three groups was similar and the three groups were comparable in the study index. Variance analysis found three The difference between groups: AMH level, menstrual condition (menopause or not), both in the 0 and 1 groups, the 0 group and the 2 groups, but there is no difference between the 1 and the 2 groups. There is no difference between the 3 groups. The systolic pressure is different between the 3 groups: the diastolic pressure is different from the 2 groups, but the 0 and 1 group, the 1 group and the 2 group, and the difference between the 0 group and the 2 group, and the difference between the 1 and the 2 groups; TC and HDL-C and LDL-C: were not different between the 3 groups, but there were differences between group TG:0 and group 1, but there was no difference between group 0 and 2, 1 and 2 groups, 0 group and 1 group, 0 group and 2 group, but there was no difference between group 1 and 2 group, and there was no difference between 0 groups. Conclusion: the ovarian function indexes such as AMH level, menstrual condition are closely related to coronary heart disease, and AMH level, menstruation The difference in situation appears before TC, HDL-C and LDL-C indicators change, and may have a more early predictive value.

【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R711.75

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