【作者】 赵赟；

【导师】 林金芳； 赵耐青； 朱铭伟；

【作者基本信息】 复旦大学 ， 妇产科学， 2008， 硕士

【摘要】 第一部分目的了解青春期女孩的月经状况,循环中促性腺激素、硫酸脱氢表雄酮(DHEA-S)和皮质醇(C)的水平;并计算青春期女性循环中黄体生成素(LH)、黄体生成素/卵泡刺激素比值(LH/FSH)和硫酸脱氢表雄酮(DHEA-S)的生理界定值。方法对象为月经正常的女中学生325例,问卷调查月经史,测定血清C、LH、FSH和DHEA-S,并计算LH/FSH比值,取研究人群第95百分位数得出LH、LH/FSH和DHEA-S的生理高限值。结果正常青春期女性近95%在初潮2年内建立规律月经,初潮后5年内100%建立规律月经。青春中晚期(15～18岁)C、LH、FSH、LH/FSH、DHEA-S不随年龄变化,LH的生理界定值为16.11U/L,LH/FSH比值的生理界定值为1.54,DHEA-S的生理界定值为407μg/dl。结论以初潮后2年内能否建立规律月经作为初步筛查青春期月经状况是否正常的年限指标是合适的。LH、LH/FSH比值、DHEA-S的生理界定值是判断青春期女性生殖内分泌紊乱的依据。第二部分目的分析青春期多囊卵巢综合征患者的临床、内分泌代谢特征。方法对象为青春期PCOS患者167例,其中肥胖型(0BPCOS组)90例、非肥胖型(NOBPCOS组)77例。以年龄匹配、月经规则的女中学生325例作为对照,其中肥胖(0BCON组)18例,非肥胖(NOBCON组)307例。对上述对象进行临床体征评分,内分泌、代谢指标测定。采用循环中睾酮水平(T)、游离雄激素指数(FAI)及硫酸脱氢表雄酮(DHEA-S)评估高雄激素血症,用空腹胰岛素(FINS)、稳态模型指数(HOMA-IR)评估胰岛素敏感性。结果①青春期PCOS患者的月经初潮年龄(12.74±1.31岁)较对照组(13.10±0.99岁)提前(P＜0.05),84.85%的患者未能在初潮后2年内建立规律月经。青春期PCOS患者肥胖的发生率(53.89%)、其中腹部型肥胖的发生率(31.14%)均显著高于对照人群(分别为5.54%及0.62%,P均＜0.001)。②青春期PCOS患者的血浆睾酮水平(0.83±0.32ng/ml)、FAI(6.87±7.42)、DHEA-S(747±714μg/d1)均显著高于对照人群(分别为0.48±0.19ng/ml、1.77±1.74,227±98μg/dl,P均＜0.0001)。其中OBPCOS组的FAI(8.20±8.24)显著高于NOBPCOS组(5.27±5.96,P＜0.05)。病例组黄体生成素(LH)水平(12.23±6.92IU/L)、LH/FSH比值(1.89±0.99)均显著高于对照组(分别为7.42±11.09IU/L及0.70±0.64,P均＜0.01)。其中NOBPCOS组的LH(14.07±7.52IU/L)、LH/FSH比值(2.11±1.09)显著高于OBPCOS组(分别为10.64±5.961U/L及1.69±0.85,P均＜0.01)。③青春期PCOS患者HOMA-IR值(取自然对数0.96±0.69)、空腹胰岛素(17.40±15.67mIU/L)均显著高于对照人群(分别为0.77±0.52及10.83±5.27mIU/L,P均＜0.01);病理性胰岛素抵抗的发生率(29.94%)也显著高于对照人群(6.77%)。OBPCOS组黑棘皮症发生率(44.44%)、空腹胰岛素(21.73±17.21mlU/L)、HOMA-IR(1.27±0.62)及甘油三酯(TG)水平(1.40±0.63mmol/L)均显著高于NOBPCOS组(分别为6.49%、12.34±11.9lmIU/L、0.61±0.60、0.91±0.44mmol/L,P均＜0.01)。④肥胖、脂溢性脱发、糖尿病、高血压的家族史与青春期PCOS的发病相关(P均≤0.001),其中肥胖和脂溢性脱发为独立的风险因素。BMI是雄激素增高和胰岛素抵抗共同的独立风险因素。结论青春期PCOS的基本特征是:①月经初潮提前,初潮2年后仍存在持续的月经紊乱;②肥胖发生率增高;③循环中雄激素水平异常增高;④促性腺激素分泌失调;⑤存在病理性胰岛素抵抗。其中肥胖型患者的雄激素生物学活性更强,胰岛素抵抗程度更严重。第三部分目的回顾性研究二甲双胍治疗青春期多囊卵巢综合征的效果。方法对象为接受二甲双胍治疗满一年的青春期PCOS患者42例,以治疗前是否存在病理性胰岛素抵抗分为1R组(29例)和NIR组(13例),评估治疗前后的排卵状况、肥胖程度、胰岛素敏感性和血清生殖内分泌参数。结果治疗前所有患者均为无排卵,二甲双胍治疗后76.19%(32/42)的患者恢复排卵,与用药前相比有显著改善(P＜0.001);IR组和NIR组之间排卵恢复率未显示统计学差异(P＞0.05)。IR组和NIR组均出现体重、BMI、FINS、HOMA-IR、胰岛素曲线下面积、总睾酮及LH的下降(P均＜0.05);IR组还伴有FAI、LH/FSH比值的下降(P均＜0.05)。排卵的恢复与空腹胰岛素(偏回归系数-0.234,95%CI:-0.449～-0.018)、HOMA-IR(偏回归系数-1.266,95%Ci:-2.495～-0.037)均呈负相关(P＜0.05)。FAI与FINS呈正相关(r=0.3335,P=0.0309)。结论二甲双胍能成功改善青春期PCOS患者的排卵功能、生殖内分泌及代谢紊乱;排卵的恢复与胰岛素水平的下降相关。更多还原

【Abstract】 Section 1Objective To investigate the menstruation state,the level of follicle stimulating hormone（FSH）,luteininzinghormone（LH）,chotisol（C） and dehydro-epiandrosterone sulfate（DHEA-S） in the adolescent girls,and determine the physiological ceiling value of LH,LH/FSH ratio and DHEA-S. Methods We performed a study of 325 adolescent middle school girls with normal menstruation.We knew the menstruation state according to a questionnaire.Then tested the measurement of serum levels of C,FSH,LH, DHEA-S and calculated LH/FSH ratio.We analyzed how the parameters changed along with the age and conputed the physiological ceiling value of LH,LH/FSH ratio and DHEA-S as the 95th percentile of the normal adolescent girls. Results It would take 2 years for almost 95%of the normal adolescent girls to establish a regular menstruation after menarche,while 100%of the normal girls have their regular menstruation within 5 years after menarche.The physiological ceiling value of the main parameters（aged 15-18 years）:LH is 16.1IU/L;LH/FSH ratio is 1.54;DHEA-S is 407μg/dl.Conclusion It is suitable for adolescent girls using the limit of 2 years to screen the menstruation states.The diagnosis for disturbance of reproductive endocrinology should be according to the physiological ceiling values of the main parameters.Section 2Objective To investigate and analyze the clinical presentation,hormonal profile,and metabolic abnormalities of adolescent girls with polycystic ovary syndrome（PCOS）.Methods The data of the anthropometric measurements,clinical manifestations of hyperandrogenism,serum levels of luteininzing hormone（LH）,follicle stimulating hormone（FSH）, testosterone（T）,prolactin（PRL）,dehydro-epiandrosterone sulfate （DHEA-S）,sex-hormone-binding globulin（SHBG）,17-oxyhydroprogesterone （17-OHP）,fasting plasma glucose（FPG） and fasting insulin（FINS） detected after oral glucose tolerance test（OGTT）,serum lipid levels, including total cholesterol（Chol）,triglycerides（TG）,high-density lipoprotein（HDL）,and low-density lipoprotein（LDL）,fasting plasma insulin（FINS） and homeostasis model assessment（HOMA） so as to assess the insulin resistance（IR）,serum testosterone（T） and free androgen index（FAI） to estimate the extent of hyperandrogenism,were collected from 167 adolescent women with PCOS,aged 17±2,that were divided into 2 groups according to the body mass index（BMI） and waist-to-hip ratio（WHR）:Group OBPCOS（n=90） with the BMI≥25 kg·m^-2 or the WHR≥0.85 and Group NOBPCOS （n=77） with the BMI＜25 kg·m^-2 and the WHR＜0.85,and 395 age-matched women with regular menstruation served as controls that were divided into 2 groups as well:Group OBCON（n=18） with the BMI≥25 kg·m^-2 or the WHR≥0.85;and Group NOBCON（n=307） with the BMI＜25 kg·m^-2 and the WHR＜0.85,and underwent a cross-sectional study.Results（1） Clinical phenotype:Adolescent girls with PCOS had precocious menarche compaired with the controls.84.85%of them could not establish a regular menstruation within 2 years after menarche.The presence of obesity was 53.89%（90/167） of which 57.78%（52/90） was central obesity,showed increased frequency of obesity compared with the controls（5.54%,18/325）.The incidence of acanthosis nigricans was 26.95%（45/167）,44.44%in Group OBPCOS and 6.49% in Group NOBPCOS（P＜0.001）.Group OBPCOS showed increased frequency of acanthosis nigricans compared with Group NOBPCOS.（2） Hormonal profile:The LH/FSHratio of the patients was 1.89±0.99,significantly higher than that of the controls（0.70±0.64）（P＜0.01）.The LH/FSH ratio of Group NOBPCOS （2.11±1.09） was significantly higher than that of Group OBPCOS（1.69±0.85）（P＜0.01）.T and DHEA-S level were higher in Group OBPCOS and Group NOBPCOS than in Group OBCON and Group NOBCON（both P＜0.01）.SHBG was lower in Group A and Group C compared with Group B and Group D（both P＜0.01）. FAI level was 8.20±8.24 in Group OBPCOS,significantly higher than those of Groups NOBPCOS（5.27±5.96）,OBCON（4.02±4.63）,and NOBCON（1.63±1.31）（all P＜0.05）.（3） Metabolic profile:The prevalence of pathological IR was 29.94%（50/167）,significantly higher than that of the controls（6.77%,22/325,P＜0.001）,with a higher prevalence rate in Group OBPCOS（45.56%,41/90） compared with Group NOBPCOS（11.69%,9/77）（P＜0.001）.The FINS and HOMA-IR of the patients were significantly higher than those of the controls,and those of Groups OBPCOS and OBCON were both significantly higher than those of Groups NOBPCOS and NOBCON（all P＜0.01）. The TG of Group OBPCOS was significantly higher than that of Group NOBPCOS （P＜0.01）.（4） The family histories of obesity,a]opecia seborrheica, diabetes mellitus and hypertension were associated with adolescent PCOS（all P≤0.001）.BMI was an independent risk factor of both hyperandrogenism and insulin resistance.Conclusion Adolescent PCOS is featured by premature menophania,failure to establish regular menstruation with 2 years after menarche,increased prevalence of obesity,hyperandrogenism,pathological insulin resistence.Obese girls with PCOS have more severe hyperandrogenism and IR than normal-weight PCOS girls,which may have some health implications later in life.Section 3Objective To evaluate the effects of metformin treatment in the adolescent girls with PCOS,and the role of insulin on metformin’s efficacy.Methods This was a retrospective study.The patient population was 42 adolesecnt girls with PCOS undertaking metformin for 1 year.They were divide into Group IR（n=29） and Group NIR（n=13） according to pathological IR. Menstrual disturbance,insulin metabolism,and reproductive endocrinic parameters were assessed before and at the end of a treatment period of 1 year.Results All the patients were suffering from anovulation before treatment.The ovulation failure was successfully improved in 76.19% （32/42） of the patients after 1 year’s metformin,significantly higher than that before treatment,and there were no difference of ovulation rate between Group IR and Group NIR（P＞0.05）.The body weight,body mass index, fasting insulin,HOMA-IR,area under the insulin-time curve,total testosterone,LH in both groups and free androgen index,LH/FSH ratio in Group IR were also improved（all P＜0.001）.The retrieve of ovulation was negative correlated with fasting insulin and HOMA-IR（both P＜0.05）.The free androgen index was negative correlated with fasting insulin（P＜0.05）. Conclusion Metformin treatment improves ovulatory function,reproductive endocrinology and metabolic disorder in adolescent girls with PCOS.The recovery of ovulating is associated with the role of decreasing serum level of insulin.更多还原