复方醋酸环丙孕酮联合盐酸吡格列酮对多囊卵巢综合征胰岛素抵抗的疗效研究
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摘要
目的:了解复方醋酸环丙孕酮联合盐酸吡格列酮对多囊卵巢综合征(PCOS)合并胰岛素抵抗(IR)患者内分泌、代谢、排卵功能及妊娠结局的疗效及优点,将为其作为一个新型的胰岛素增敏剂应用于PCOS胰岛素抵抗患者提供临床依据。
材料与方法:选择来自我院生殖医学门诊就诊的PCOS合并IR患者共52例,年龄(26.54±2.67)岁。随机分为两组,实验组23例,对照组29例。实验组给予口服复方醋酸环丙孕酮(复方CPA)联合盐酸吡格列酮,对照组给予口服复方CPA联合盐酸二甲双胍,均用药三个月。复方CPA于自然月经或黄体酮撤退性出血第5天开始服用1片/日,连续服用21天停药,于撤退性出血第5天开始下一周期治疗,共服药3个周期。盐酸吡格列酮每日口服15mg,盐酸二甲双胍为500mg,每日三次口服。停药后开始诱导排卵治疗,均采用同一诱导排卵方案。
所有患者均于治疗前的自然月经或黄体酮撤退性出血第3~5天9:00~10:00空腹坐位肘静脉采血,留取血清,分别测定黄体生成素(LH)、卵泡刺激素(FSH)、雌二醇(E2)、泌乳素(PRL)、雄烯二酮(A2)、空腹胰岛素(FIN),空腹血糖(FBS)、总胆固醇(TC)、甘油三脂(TG)、高密度脂蛋白(HDL-C)、低密度脂蛋白(LDL-C)、脂联素(Adiponectin,APN),计算胰岛素敏感指数(ISI)=1/(FBS×FIN),FBS/FIN比值以反映胰腺分泌胰岛素功能,应用Homa稳态模型评估患者的胰岛素抵抗(IR=FIN×FBS/22.5)和β细胞功能[IS=20×FIN/(FBS-3.5)]。治疗3个月后,月经第3~5天再次抽血测定以上指标,观察体重指数(BMI)、腰臀比(WHR),Ferriman-Gallwey多毛评分(F-G评分)改善,并记录服药期间不良反应,治疗前后由专人进行阴道超声检查,测量每侧卵巢内卵泡数目及应用椭圆法测定卵巢体积。
两组均采用克罗米芬(CC)+绝经期促性腺激素(HMG)或尿促卵泡素(FSH)低剂量缓增方案进行诱导排卵治疗连续3个周期。比较两组的周期排卵率,单卵泡发育率,累计妊娠率,黄素化卵泡不破裂综合征(LUFs)及卵巢过度刺激综合征(OHSS)的发生率。
采用SPSS11.5软件进行统计学分析。计量资料以 x±s表示,治疗前后各项指标的比较采用配对样本t检验,实验组与对照组用药后的各项指标的改善程度的比较采用成组设计的两样本比较t检验。实验组与对照组促排卵各项结果应用χ~2检验。APN与胰岛素抵抗、血脂及其他因素的相关性,采用pearson相关分析。P<0.05即有显著性差异。
结果:服药期间所有病例肝肾功能均正常,均未出现低血糖。实验组23例均未发现贫血、水肿,无恶心、呕吐、头晕、头痛等副反应及任何不适。对照组29例,16例出现恶心,10例呕吐,8例腹泻,3例头晕。
相关性分析:APN与IR呈显著负相关(p<0.05)。APN与TG、LDL-C呈显著负相关,与HDL-C均呈显著正相关(p<0.05),与其他因素无显著相关性(p>0.05)。
实验组用药前后各项指标的比较:体重、BMI、WHR均无改变。F-G评分、LH、LH/FSH、A2降低(p<0.01),FSH并未改变(p>0.05)。FIN、FBS/FIN、ISI、Homa IR、Homa IS均降低(p<0.01)。HDL-C升高,TC、TG、LDL-C均降低(p<0.05),APN升高(p<0.01)。
对照组用药前后各项指标的比较:WHR无改变但体重、BMI下降(p<0.05)。F-G评分、LH、LH/FSH、A2降低(p<0.01),FSH并未改变(p>0.05)。FIN、FBS/FIN、ISI、Homa IR较用药前降低(p<0.01),而Homa IS无降低(p>0.05)。血脂、脂联素均无显著性改变(p>0.05)。
两组用药各项指标改善的比较:实验组A2的下降较对照组有显著性意义(p<0.01),FIN、FBS/FIN、ISI、Homa IR、Homa IS降低均比对照组有显著性意义(p<0.05)。TC、TG、LDL-C、HDL-C、APN的改善与对照组相比有显著性意义(p<0.05)。
两组用药前后超声像改变的比较:每组用药后双侧卵巢体积均显著缩小,双侧卵巢卵泡数均明显减少(p<0.01)。但两组之间相比无显著性差异(p>0.05)。
两组用药后诱导排卵结局的比较:实验组周期排卵率96.22%,单卵泡发育率90.57%,累计妊娠率56.5%均高于对照组的92.6%,86.76%,51.72%,LUFs无发生低于对照组LUFs发生率(2.9%),但无显著性差异(p>0.05)。两组在排卵前期均无早发的内源性LH峰出现,均无OHSS发生。
结论:1复方CPA联合盐酸二甲双胍和复方CPA联合盐酸吡格列酮均能有效的改善PCOS伴IR患者的临床症状、缓解内分泌紊乱,而复方CPA联合盐酸吡格列酮的作用更为显著。
2复方CPA联合盐酸二甲双胍和复方CPA联合盐酸吡格列酮均能改善PCOS伴IR患者的糖代谢异常。复方CPA联合盐酸吡格列酮更为有效,并提示盐酸吡格列酮在抗高胰岛素血症的同时不增加胰岛β细胞负担,有利于保护胰岛β细胞功能。
3复方CPA联合盐酸吡格列酮及复方CPA联合盐酸二甲双胍治疗后,前者升高HDL-C、APN降低TC、TG、LDL-C而后者无改变,说明盐酸吡格列酮有改善脂代谢的作用、并能预防代谢综合征。
4 APN与HOMR IR呈显著负相关,说明APN水平降低与IR程度升高及胰岛素的敏感性下降相平行。提示PCOS与2型糖尿病发病机制可能存在某些共同之处。
5盐酸吡格列酮较盐酸二甲双胍副作用及不良反应少,患者耐受性好。
Objective: To know the affect of the endocrine, metabolism, ovulation, pregnancy outcome in PCOS patients with IR treated with CPA Co plus Pioglitazone.It can offer a way to cure PCOS patients with IR as a new drug of euglycemic agent.
Materials and Methods: Fifty-two proved PCOS patients were enrolled who were 26.54±2.67 aged. They were separated into two groups at random. The study group included twenty-three patients and the control group included twenty-nine patients. The study group was treated with CPA Co plus Pioglitazone for three cycles, and the control group was treated with CPA Co plus Metformin. Two groups were treated with CPA Co from day 5 to day 26 of natural menstruation or withdrawal bleeding every cycles. Pioglitazone was taken daily 15mg, Metformin was taken daily with 1500mg. After the treatment with these drugs, they accepted the same therapy for inducing ovulation.
Fasting blood samples of two groups were obtained on the day 3 to 5 of the menstrual cycle or withdrawal bleeding. All samples were used to assess serum levels of LH, FSH, E2, PRL, A2, fasting INS, fasting glucose, blood-fat, APN, and caculated the levels of ISI, HOMA IR, HOMA IS and the radio of FBS/FIN. Samples of the two groups were obtained and assessed again after three cycles of treatment. Side effects of these drugs such as nausea, disgorge, ect were evaluated. The changes of weight, waistline, buttock, hirsutism and acne were observed. Bilateral ovarian volume and follicle numbers of patients were measured with vaginal ultrasound (US) before and after treatment.
The protocol of induced ovulation was clomiphene (CC) + HMG/FSH low dose step-up protocol for the two groups for three cycles. To compare the rate of ovulation, single dominant follicle growth, pregnancy, LUFs and OHSS in the two groups.
Statistics analysis was performed with the SPSS 11.5. All data are presented as the mean±SD. The significant differences between before and after treatment was tested with paired t-test. The difference with the effect of after the treatment in both groups was group t-test. The induced ovulation result was tested withχ~2 test. The possible correlation of APN with other factors of PCOS was analyzed with Pearson correlation analysis. The level of statistical significance was set at P<0.05.
Results: The liver and renal function and the FBG of every patient was normal during the treatment. In the study group, all patients had no anaemia, dropsy, nausea, emesia, swirl, headache and so on. In the control group, sixteen patients felt nausea, ten patients felt emesia, eight patients felt diarrhea, three patients felt swirl.
In these patients, negative correlation was found between APN and IR, TG, LDL-C(p<0.05); Positive correlation was found between APN and HDL(p<0.05); There were no correlation between APN and the other paramenters(p>0.05).
In the study group, the mean serum LH, FSH, A2, fasting INS, ISI, Homa IR, Homa IS levels and LH/FSH ratio, FBS/FIN ratio, the score of F-G after treatment were significantly lower than before(P<0.01). The mean serum TC, TG, LDL-C levels were also lower (P<0.05). The mean serum HDL-C levels were higher(P<0.05). The mean serum APN levels were aslo higher(P<0.01). But the weight, BMI and WHR of patients have no difference than before.
In the control group, the mean serum LH, FSH, A2, fasting INS, ISI, Homa IR levels and LH/FSH ratio, FBS/FIN ratio, the score of F-G after treatment were significantly lower than before(P<0.01). But the mean serum TC, TG, LDL-C, HDL-C, APN levels and Homa IS have no change. The WHR of patients have no change too. But The weight and BMI of patients were lower than before(p<0.05).
There was significantly difference of the mean serum A2, fasting INS, ISI, Homa IR, Homa IS, TC, TG, LDL-C levels is lower in the study group than in the control group.
After 3 months of therapy, all of the patients' bilateral ovarian volumes and follicle numbers decreased significantly(P<0.01). But there were no significant differences between the two groups(p>0.05).
The result of induced ovulation: The ovulation rate per cycle, the single dominant follicle growth rate per cycle and the pregnancy rate was 96.22%,90.57%,56.5% in study group, and it is higher than 92.6%, 86.76%, 51.72% in control group. But there were no significant differences of them between two groups(p>0.05).There was no praecox endogenesis apex of LH confirmed by a urinary ovulation test paper. No patient suffered from ovarian hyperstimulation syndrome(OHSS). There was two cases of LUFs in control group higher than 0 case in study group.But there were no significant differences of them between two groups(p>0.05).
Conclusions: 1 the clinical manifestation and endocrine disturbance of PCOS patients with IR, but the study group has more significant effect. 2 Both treatments can improve the glycometabolism disturbance, but the study group has more significant effect. And indicate that Pioglitazone can defend the function of beta Cell of islet in the therapy of HI. 3 In the study group, the level of HDL-C and APN were increased, and the level of TC, TG and LDL-C were decreased. But in the control group those levels had no difference. It indicates that Pioglitazone can improve lipid metabolism and preclude metabolism syndrome. 4 Negative correlation was found between APN and IR. It indicates that decreasing of APN coincidents with increasing of IR and decresing of insulin sensitivity. It suggested that there were some linkage between PCOS and DIDMOAD. 5 Pioglitazone compared with Metformin has fewer side effects and adverse reaction, and can be well accepted by the patients.
材料与方法:选择来自我院生殖医学门诊就诊的PCOS合并IR患者共52例,年龄(26.54±2.67)岁。随机分为两组,实验组23例,对照组29例。实验组给予口服复方醋酸环丙孕酮(复方CPA)联合盐酸吡格列酮,对照组给予口服复方CPA联合盐酸二甲双胍,均用药三个月。复方CPA于自然月经或黄体酮撤退性出血第5天开始服用1片/日,连续服用21天停药,于撤退性出血第5天开始下一周期治疗,共服药3个周期。盐酸吡格列酮每日口服15mg,盐酸二甲双胍为500mg,每日三次口服。停药后开始诱导排卵治疗,均采用同一诱导排卵方案。
所有患者均于治疗前的自然月经或黄体酮撤退性出血第3~5天9:00~10:00空腹坐位肘静脉采血,留取血清,分别测定黄体生成素(LH)、卵泡刺激素(FSH)、雌二醇(E2)、泌乳素(PRL)、雄烯二酮(A2)、空腹胰岛素(FIN),空腹血糖(FBS)、总胆固醇(TC)、甘油三脂(TG)、高密度脂蛋白(HDL-C)、低密度脂蛋白(LDL-C)、脂联素(Adiponectin,APN),计算胰岛素敏感指数(ISI)=1/(FBS×FIN),FBS/FIN比值以反映胰腺分泌胰岛素功能,应用Homa稳态模型评估患者的胰岛素抵抗(IR=FIN×FBS/22.5)和β细胞功能[IS=20×FIN/(FBS-3.5)]。治疗3个月后,月经第3~5天再次抽血测定以上指标,观察体重指数(BMI)、腰臀比(WHR),Ferriman-Gallwey多毛评分(F-G评分)改善,并记录服药期间不良反应,治疗前后由专人进行阴道超声检查,测量每侧卵巢内卵泡数目及应用椭圆法测定卵巢体积。
两组均采用克罗米芬(CC)+绝经期促性腺激素(HMG)或尿促卵泡素(FSH)低剂量缓增方案进行诱导排卵治疗连续3个周期。比较两组的周期排卵率,单卵泡发育率,累计妊娠率,黄素化卵泡不破裂综合征(LUFs)及卵巢过度刺激综合征(OHSS)的发生率。
采用SPSS11.5软件进行统计学分析。计量资料以 x±s表示,治疗前后各项指标的比较采用配对样本t检验,实验组与对照组用药后的各项指标的改善程度的比较采用成组设计的两样本比较t检验。实验组与对照组促排卵各项结果应用χ~2检验。APN与胰岛素抵抗、血脂及其他因素的相关性,采用pearson相关分析。P<0.05即有显著性差异。
结果:服药期间所有病例肝肾功能均正常,均未出现低血糖。实验组23例均未发现贫血、水肿,无恶心、呕吐、头晕、头痛等副反应及任何不适。对照组29例,16例出现恶心,10例呕吐,8例腹泻,3例头晕。
相关性分析:APN与IR呈显著负相关(p<0.05)。APN与TG、LDL-C呈显著负相关,与HDL-C均呈显著正相关(p<0.05),与其他因素无显著相关性(p>0.05)。
实验组用药前后各项指标的比较:体重、BMI、WHR均无改变。F-G评分、LH、LH/FSH、A2降低(p<0.01),FSH并未改变(p>0.05)。FIN、FBS/FIN、ISI、Homa IR、Homa IS均降低(p<0.01)。HDL-C升高,TC、TG、LDL-C均降低(p<0.05),APN升高(p<0.01)。
对照组用药前后各项指标的比较:WHR无改变但体重、BMI下降(p<0.05)。F-G评分、LH、LH/FSH、A2降低(p<0.01),FSH并未改变(p>0.05)。FIN、FBS/FIN、ISI、Homa IR较用药前降低(p<0.01),而Homa IS无降低(p>0.05)。血脂、脂联素均无显著性改变(p>0.05)。
两组用药各项指标改善的比较:实验组A2的下降较对照组有显著性意义(p<0.01),FIN、FBS/FIN、ISI、Homa IR、Homa IS降低均比对照组有显著性意义(p<0.05)。TC、TG、LDL-C、HDL-C、APN的改善与对照组相比有显著性意义(p<0.05)。
两组用药前后超声像改变的比较:每组用药后双侧卵巢体积均显著缩小,双侧卵巢卵泡数均明显减少(p<0.01)。但两组之间相比无显著性差异(p>0.05)。
两组用药后诱导排卵结局的比较:实验组周期排卵率96.22%,单卵泡发育率90.57%,累计妊娠率56.5%均高于对照组的92.6%,86.76%,51.72%,LUFs无发生低于对照组LUFs发生率(2.9%),但无显著性差异(p>0.05)。两组在排卵前期均无早发的内源性LH峰出现,均无OHSS发生。
结论:1复方CPA联合盐酸二甲双胍和复方CPA联合盐酸吡格列酮均能有效的改善PCOS伴IR患者的临床症状、缓解内分泌紊乱,而复方CPA联合盐酸吡格列酮的作用更为显著。
2复方CPA联合盐酸二甲双胍和复方CPA联合盐酸吡格列酮均能改善PCOS伴IR患者的糖代谢异常。复方CPA联合盐酸吡格列酮更为有效,并提示盐酸吡格列酮在抗高胰岛素血症的同时不增加胰岛β细胞负担,有利于保护胰岛β细胞功能。
3复方CPA联合盐酸吡格列酮及复方CPA联合盐酸二甲双胍治疗后,前者升高HDL-C、APN降低TC、TG、LDL-C而后者无改变,说明盐酸吡格列酮有改善脂代谢的作用、并能预防代谢综合征。
4 APN与HOMR IR呈显著负相关,说明APN水平降低与IR程度升高及胰岛素的敏感性下降相平行。提示PCOS与2型糖尿病发病机制可能存在某些共同之处。
5盐酸吡格列酮较盐酸二甲双胍副作用及不良反应少,患者耐受性好。
Objective: To know the affect of the endocrine, metabolism, ovulation, pregnancy outcome in PCOS patients with IR treated with CPA Co plus Pioglitazone.It can offer a way to cure PCOS patients with IR as a new drug of euglycemic agent.
Materials and Methods: Fifty-two proved PCOS patients were enrolled who were 26.54±2.67 aged. They were separated into two groups at random. The study group included twenty-three patients and the control group included twenty-nine patients. The study group was treated with CPA Co plus Pioglitazone for three cycles, and the control group was treated with CPA Co plus Metformin. Two groups were treated with CPA Co from day 5 to day 26 of natural menstruation or withdrawal bleeding every cycles. Pioglitazone was taken daily 15mg, Metformin was taken daily with 1500mg. After the treatment with these drugs, they accepted the same therapy for inducing ovulation.
Fasting blood samples of two groups were obtained on the day 3 to 5 of the menstrual cycle or withdrawal bleeding. All samples were used to assess serum levels of LH, FSH, E2, PRL, A2, fasting INS, fasting glucose, blood-fat, APN, and caculated the levels of ISI, HOMA IR, HOMA IS and the radio of FBS/FIN. Samples of the two groups were obtained and assessed again after three cycles of treatment. Side effects of these drugs such as nausea, disgorge, ect were evaluated. The changes of weight, waistline, buttock, hirsutism and acne were observed. Bilateral ovarian volume and follicle numbers of patients were measured with vaginal ultrasound (US) before and after treatment.
The protocol of induced ovulation was clomiphene (CC) + HMG/FSH low dose step-up protocol for the two groups for three cycles. To compare the rate of ovulation, single dominant follicle growth, pregnancy, LUFs and OHSS in the two groups.
Statistics analysis was performed with the SPSS 11.5. All data are presented as the mean±SD. The significant differences between before and after treatment was tested with paired t-test. The difference with the effect of after the treatment in both groups was group t-test. The induced ovulation result was tested withχ~2 test. The possible correlation of APN with other factors of PCOS was analyzed with Pearson correlation analysis. The level of statistical significance was set at P<0.05.
Results: The liver and renal function and the FBG of every patient was normal during the treatment. In the study group, all patients had no anaemia, dropsy, nausea, emesia, swirl, headache and so on. In the control group, sixteen patients felt nausea, ten patients felt emesia, eight patients felt diarrhea, three patients felt swirl.
In these patients, negative correlation was found between APN and IR, TG, LDL-C(p<0.05); Positive correlation was found between APN and HDL(p<0.05); There were no correlation between APN and the other paramenters(p>0.05).
In the study group, the mean serum LH, FSH, A2, fasting INS, ISI, Homa IR, Homa IS levels and LH/FSH ratio, FBS/FIN ratio, the score of F-G after treatment were significantly lower than before(P<0.01). The mean serum TC, TG, LDL-C levels were also lower (P<0.05). The mean serum HDL-C levels were higher(P<0.05). The mean serum APN levels were aslo higher(P<0.01). But the weight, BMI and WHR of patients have no difference than before.
In the control group, the mean serum LH, FSH, A2, fasting INS, ISI, Homa IR levels and LH/FSH ratio, FBS/FIN ratio, the score of F-G after treatment were significantly lower than before(P<0.01). But the mean serum TC, TG, LDL-C, HDL-C, APN levels and Homa IS have no change. The WHR of patients have no change too. But The weight and BMI of patients were lower than before(p<0.05).
There was significantly difference of the mean serum A2, fasting INS, ISI, Homa IR, Homa IS, TC, TG, LDL-C levels is lower in the study group than in the control group.
After 3 months of therapy, all of the patients' bilateral ovarian volumes and follicle numbers decreased significantly(P<0.01). But there were no significant differences between the two groups(p>0.05).
The result of induced ovulation: The ovulation rate per cycle, the single dominant follicle growth rate per cycle and the pregnancy rate was 96.22%,90.57%,56.5% in study group, and it is higher than 92.6%, 86.76%, 51.72% in control group. But there were no significant differences of them between two groups(p>0.05).There was no praecox endogenesis apex of LH confirmed by a urinary ovulation test paper. No patient suffered from ovarian hyperstimulation syndrome(OHSS). There was two cases of LUFs in control group higher than 0 case in study group.But there were no significant differences of them between two groups(p>0.05).
Conclusions: 1 the clinical manifestation and endocrine disturbance of PCOS patients with IR, but the study group has more significant effect. 2 Both treatments can improve the glycometabolism disturbance, but the study group has more significant effect. And indicate that Pioglitazone can defend the function of beta Cell of islet in the therapy of HI. 3 In the study group, the level of HDL-C and APN were increased, and the level of TC, TG and LDL-C were decreased. But in the control group those levels had no difference. It indicates that Pioglitazone can improve lipid metabolism and preclude metabolism syndrome. 4 Negative correlation was found between APN and IR. It indicates that decreasing of APN coincidents with increasing of IR and decresing of insulin sensitivity. It suggested that there were some linkage between PCOS and DIDMOAD. 5 Pioglitazone compared with Metformin has fewer side effects and adverse reaction, and can be well accepted by the patients.
引文
1 Cagnacci A, Paoletti AM, Renzi A. Glucose metabolism and insulin resistance in women with polycystic ovary syndrome during therapy with oral contraceptives containing cyproterone acetate or desogest rel. Clin Endocrinol Metab, 2003, 88 (8): 3621~3625
2 Albertini DF, Rider V. Patterns of intercellular connectivity in the mammalian cumulus-oocyte complex. Microsc Res Tech, 1994, 27(2):125~133
3 Almahbobi G, Anderiesz C, Hutchinson P, et al. Functional integrity of granulosa cells from polycystic ovaries. Clin Endocrinol (Oxf), 1996, 44(5): 571~580
4 Amirikia H, Savoy-Moore RT, Sundareson AS, et al. The effects of long-term androgen treatment on the ovary. Fertil Steril, 1986, 45(2): 202~208
5 Amsterdam A, Rotmensch S. Structure-function relationships during granulosa cell differentiation. Endocr Rev, 1987, 8(3): 309~337
6 Tarlatzis, Fauser J, Chang et al. Revised 2003 consensus ondiagnostic and long-term health risks related to polycystic ovary syndrome. Fertil Steril, 2004, (1): 20~25
7 Bonora E, Kiechl S, Willeit J, et al.Prevalence of insulin resistance in metabolic disorders: the Bruneck Study. Diabetes, 1998, 47(10): 1643~1649
8 李美芝.多囊卵巢综合征的研究现状.中华妇产科杂志,2000,35(10):581~582
9 Mather KJ, Kwan F, Corenblum B. Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity. Fertil Steril, 2000, 73(1): 150~156
10 Ghazeeri G, Kutteh WH, Bryer-Ash M, Haas D, Ke . Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. Fertil Steril, 2003, 79(3): 562~566
11 Arlt W, Auchus RJ, Miller WL. Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 36 eta-hydroxysteroid dehydrogenase. J Biol Chem, 2001, 276(20): 16767~16771
12 Mitwally MF, Witchel SF, Casper RF. Trogl itazone: a possible modulator of ovarian steroidogenesis. J Soc Gynecol Investig, 2002, 9(3): 163~167
13 Olefsky, Saltiel AR. PPAR gamma and the treatment of insulin resistance. Trends Endocrinol Metab, 2000, 11(9): 362~368
14 Seli E, Duleba AJ. Should patients with polycystic ovariansyndrome be treated with metformin? Hum Reprod, 2002, 17 (9): 2230~2236
15 Pirwany IR, Yates RW, Cameron IT, et al. Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea. Hum Reprod, 1999, 14(12): 2963~2968
16 Hward BV , Schneiderman N , Falkner B , et al . Insulin , healthbehaviors and lipid metabolismJ. Metabolism, 1993, 42(9 supple1): 25~29
17 全菊英,余叶蓉.噻唑烷二酮类药物对2型糖尿病大血管病变的影响及其机制.中国糖尿病杂志,2003, 11(4): 285~287
18 Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. NarMed, 2001, 7(8): 941~946
19 Osei K, Gaillard T, SchusterD, et al. Plasma adiponectin levels in high risk African and Americans with normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes. Obesity Res, 2005, 13(1): 179~185
20 Belcowski J. Adiponectin and resistin-new hormones of white adipose tissue. Med SciMonit, 2003, 9(2): 55~61
21 Matsuda M , Shimomum L , Sata M , et al. Bole of adiponectin in preventing vascular stenosis, the missing link of adipo-vascular axis. Biol Chem, 2002, 277(40): 37487~37491
22 Tartagn M, Schonauer LM, Salvia MAD, et al. Comparison of Diane 35 and Diane 35 plus finasteride in the treatment of hirsutism. Fertil Steril, 2000, 73(4): 718~723
1 Burghen GA,Givens JR,Kitabchi AE.Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease[J].Clin Endocrin Metab, 1980, 50(1):113
2 Fernando O ,Ricardo A. Insulin resistance, polycystic ovary syndrome ,and type 2 diabetes mellitus[J].Fertil Steril,2002,77 (6):1095~1105
3 Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications forp athogenesis,Endocrine Rev,1997,18(6):774~800
4 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.Fertil Steril, 2004,81(1):19~25
5 Carey AH, Chan KL, Short F, et al. Evidence for a single gene efect causing polycystic ovaries and male pattern baldness.Clin Endocrinol,1993,38 (4):653
6 Franks S, Charani N, McCarthy M. Candidate genes in polycystic ovary syndrome. HumReprod Update, 2001, 7(4): 405~410
7 李美芝主编.妇科内分泌学〔M〕.第一版, 北京:人民军医出版社, 2001,197
8 张丽珠主编.临床生殖内分泌与不育症〔M〕.第一版, 北京:科学出版社, 2001,367
9 李秀钧主编.胰岛素抵抗综合征〔M〕.第一版, 北京: 人民卫生出版社, 2001,168
10 World Health Organization (WHO). Definition, diagnosis and classification of diabetes mellitus and its comp lication-report of a WHO consultation, part 1: diagnosis and classification of diabetes mellitus.Geneva, Switzerland:WHO, 19991
11 Fruzzetti F , Bersi C , Parrini D , et al . Effect of long-term naltrex one treatment on endocrine , profile , clinical fearures ,and insulin sensitivity in obese women with polycystic ovary syndrome [ J ] . Fertil Steril ,2002 ,77 (5) :936~944
12 Tucci S , Fut terweit W , Concepcion E S , et al . Evidence for associateion of polycystic ovary syndrome in Caucasian women with a marker at the insulin recept or gene locus [ J ] . J Clin Endocrinol Metab ,2001 ,86 :446~449
13 Villuendas G , Escobar M H F , Tosi F , et al . Association between t he D19S884 marker at the insulin recept or geng locus and polycystic ovary syndrome [ J ] . Fertil Steril , 2003 , 79 ( 1) :219~220
14 Siegel S , Fut terweit W , Davies T F , et al . A A/T single nucleotide polymorphism at the tyrosine kinase domain of the insulin recept or gene is associated with polycystic ovary syndrome [J] . Fertil Steril ,2002 ,78 (6) :1240~1243
15 Remsberg KE , Talbott EO , Zborowski JV , et al . Evidence for competing effect s of body mass , hyperinsulinemia , insulin resistance , and androgens on leptin levels among lean , overweight , and obese women with polycystic ovary syndrome [J ] . Fertil Steril ,2002 ,78 (3) :479~486
16 Acien P , Quereda F , Matallin P , et al . Insulin , androgens , and obesity in women with and without polycystic ovary syndrome : a heterogeneous group of disorders[J ] . Fertil Steril ,1999 ,72 (1) :32~40
17 Nestler JE ,Barlasani CO ,Matt DW, et al . Suppression of serum insulin by diazoxide redudes testosterone levels in obese woman with polycystic ovarian syndrome [ J ] . J Clin Endocrinol Metab , 1989 , 68 (5) :1027~1032
18 La-Marca A, Egbe TO, Morgante G,et al. Metformin treatment reduces ovarian cytochrome P450c17α response to human chorionicg onadotrophin in women with insulin resistance-related polycystic ovary syndrome. Hum Reprod, 2000,15:21~23
19 Nestler JE ,Jakubowicz DJ , de Vargas AF , et al . Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system [J]. J Clin Endocrinol Metab , 1998 ,83 (6) :2001
20 Nestler JE, Jakubowicz DJ, de Vargas AF, et al. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system.J Clin Endocrinol Metab,1998,83:2001~2005
21 Nestler JE. Role of hyperinsulinemia in the pathogenesis of polycystic ovary syndrome, and its clinical implication. Semin Report Endocrinol, 1997, 15:111~122
22 王治鸿.多囊卵巢综合征高雄激素血症的形成,国外医学 妇产科学分册, 2001, 28 (3) : 167
23 黄荷凤,郦美根.多囊卵巢综合征和高雄激素血症,中国实用妇产科与产科杂志, 2002, 18 (11) : 648
24 Azziz R,Rittmaster RS,Fox LM,et a l.Role of the ovary in the adrenal excess of hyperandrogenic women.Fertil Steril, 1998, 69:691~696
25 Marshall JC, Eagleson CA, McCartney CR. Hypothalamic dysfunction. Mol Cell Endocrino1,2001, 183(1-2): 29~32
26 R Jeffrey Change,Seth E Katz.Polycystic ovary syndrome. Endocrinol Metab Clin North Am,1999, 28: 397~408
27 Cordon CM. Menstrual disorders in adolescents. Excess androgens and the polycystic ovary syndrome.Pediatr Clin North Am,1999,46(3):519~543
28 Marshall JC, Eagleson CA. Neuroendocrine aspects of ovary syndrome.Endocrinol & Metab Clin North Am,1999,28(2):295~324
29 Nestler JE,Jakubowicz DJ.Lean woman with polycystic ovary syndrome respond to insulin reduce with decrease in ovarian P450c17α activity and serum androgens.J Clin Endocrinol Metab, 1997,82(12):4075~4079
30 Lockwood GM,Muttakrishna S,Grome NP.Mid follicularphase pulse of inhibin B are absent in polycystic ovary syndrome and are initiated by successful laparoscopic ovarian diathermy: a possible mechanism regulatinge mergence of the dominant follicle.J Clin Endocrinol Metab,1998,83:1730~1735
31 Ia M A ,Morgante G ,Palumbo M ,et al.Insulin-lowering treatment reduces aromatase activeity in response to follicle-stimulating hormone in women with polycystic ovary syndrome [J ].Fertil Steril, 2002, 78 (6) :1234~1239
32 Diamanti-Kandarakis E,Dunaif A. New perspectives in polycystic ovary syndrome.Trends Endocrinol Metab, 1996,7:267~271
33 Con JJ, Jacobs HS, Conway CS. The prevalence of polycystic ovaries in women with 2 type diabetes mellitus.ClinE ndocrinol(Oxf),2000,52(1):81~86
34 Baranowska B , Radzikowska M , Wasilewska D E , et al . Neuropeptide Y, leptin , galanin and insulin in women with polycystic ovary syndrome [ J ] . Gynecol Endocrinol , 1999 , 13(5):344~351
35 Kaushal R , Parchure N , Bano G, et al . Insulin resistance and endothelial dysfunction in the brothers of Indian subcontinent Asian women with polycystic ovaries[J ] . Clin Endocrinol (Oxf) ,2004 ,60 (3) :322~328
36 Reaven GM.Pathophysiology of insulin resistance in human disease [J].Physiol Rev,1995,75(3):473
37 Duaif A.Hyperandrogenic anovulation(PCOS):a unrquicdisorder of insulin action associated with an increased risk of non insulind enpendent diabetes mellitus.Am J Med,1995,98:33~39
38 Pelusi B , Gambineri A , Pasquali R. Type 2 diabetes and the polycystic ovary syndrome [ J ] . Minerva Ginecol , 2004 , 56 (1) : 41~51
39 吴效科,周珊英,苏延华.多囊卵巢综合征患者的胰岛素抵抗.中华妇产科杂志,1999,34:698~701
40 Strowitzki T, Halser B. Demant body fat distribution, insuline sensitivity, ovarian dysfunction and serum lipoproteins in patients with polycystic ovary syndrome.Gynecol Endocrinol,2002,16(1):45~51
41 Ibanez L,Aulesa C,Potau N,et al. Plasminogen activator inhibitor-1 in girls with precocious pubarche: a premenarcheal marker for polycystic ovary syndrome?Pediatr Res,2002,51(2):244~248
42 Paradisi G, Steinberg HO. Polycystic ovary syndrome is associated with endothelial dysfuction. Circulation. 2001, 103 (10):1410~1405
2 Albertini DF, Rider V. Patterns of intercellular connectivity in the mammalian cumulus-oocyte complex. Microsc Res Tech, 1994, 27(2):125~133
3 Almahbobi G, Anderiesz C, Hutchinson P, et al. Functional integrity of granulosa cells from polycystic ovaries. Clin Endocrinol (Oxf), 1996, 44(5): 571~580
4 Amirikia H, Savoy-Moore RT, Sundareson AS, et al. The effects of long-term androgen treatment on the ovary. Fertil Steril, 1986, 45(2): 202~208
5 Amsterdam A, Rotmensch S. Structure-function relationships during granulosa cell differentiation. Endocr Rev, 1987, 8(3): 309~337
6 Tarlatzis, Fauser J, Chang et al. Revised 2003 consensus ondiagnostic and long-term health risks related to polycystic ovary syndrome. Fertil Steril, 2004, (1): 20~25
7 Bonora E, Kiechl S, Willeit J, et al.Prevalence of insulin resistance in metabolic disorders: the Bruneck Study. Diabetes, 1998, 47(10): 1643~1649
8 李美芝.多囊卵巢综合征的研究现状.中华妇产科杂志,2000,35(10):581~582
9 Mather KJ, Kwan F, Corenblum B. Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity. Fertil Steril, 2000, 73(1): 150~156
10 Ghazeeri G, Kutteh WH, Bryer-Ash M, Haas D, Ke . Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. Fertil Steril, 2003, 79(3): 562~566
11 Arlt W, Auchus RJ, Miller WL. Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 36 eta-hydroxysteroid dehydrogenase. J Biol Chem, 2001, 276(20): 16767~16771
12 Mitwally MF, Witchel SF, Casper RF. Trogl itazone: a possible modulator of ovarian steroidogenesis. J Soc Gynecol Investig, 2002, 9(3): 163~167
13 Olefsky, Saltiel AR. PPAR gamma and the treatment of insulin resistance. Trends Endocrinol Metab, 2000, 11(9): 362~368
14 Seli E, Duleba AJ. Should patients with polycystic ovariansyndrome be treated with metformin? Hum Reprod, 2002, 17 (9): 2230~2236
15 Pirwany IR, Yates RW, Cameron IT, et al. Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea. Hum Reprod, 1999, 14(12): 2963~2968
16 Hward BV , Schneiderman N , Falkner B , et al . Insulin , healthbehaviors and lipid metabolismJ. Metabolism, 1993, 42(9 supple1): 25~29
17 全菊英,余叶蓉.噻唑烷二酮类药物对2型糖尿病大血管病变的影响及其机制.中国糖尿病杂志,2003, 11(4): 285~287
18 Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. NarMed, 2001, 7(8): 941~946
19 Osei K, Gaillard T, SchusterD, et al. Plasma adiponectin levels in high risk African and Americans with normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes. Obesity Res, 2005, 13(1): 179~185
20 Belcowski J. Adiponectin and resistin-new hormones of white adipose tissue. Med SciMonit, 2003, 9(2): 55~61
21 Matsuda M , Shimomum L , Sata M , et al. Bole of adiponectin in preventing vascular stenosis, the missing link of adipo-vascular axis. Biol Chem, 2002, 277(40): 37487~37491
22 Tartagn M, Schonauer LM, Salvia MAD, et al. Comparison of Diane 35 and Diane 35 plus finasteride in the treatment of hirsutism. Fertil Steril, 2000, 73(4): 718~723
1 Burghen GA,Givens JR,Kitabchi AE.Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease[J].Clin Endocrin Metab, 1980, 50(1):113
2 Fernando O ,Ricardo A. Insulin resistance, polycystic ovary syndrome ,and type 2 diabetes mellitus[J].Fertil Steril,2002,77 (6):1095~1105
3 Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications forp athogenesis,Endocrine Rev,1997,18(6):774~800
4 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.Fertil Steril, 2004,81(1):19~25
5 Carey AH, Chan KL, Short F, et al. Evidence for a single gene efect causing polycystic ovaries and male pattern baldness.Clin Endocrinol,1993,38 (4):653
6 Franks S, Charani N, McCarthy M. Candidate genes in polycystic ovary syndrome. HumReprod Update, 2001, 7(4): 405~410
7 李美芝主编.妇科内分泌学〔M〕.第一版, 北京:人民军医出版社, 2001,197
8 张丽珠主编.临床生殖内分泌与不育症〔M〕.第一版, 北京:科学出版社, 2001,367
9 李秀钧主编.胰岛素抵抗综合征〔M〕.第一版, 北京: 人民卫生出版社, 2001,168
10 World Health Organization (WHO). Definition, diagnosis and classification of diabetes mellitus and its comp lication-report of a WHO consultation, part 1: diagnosis and classification of diabetes mellitus.Geneva, Switzerland:WHO, 19991
11 Fruzzetti F , Bersi C , Parrini D , et al . Effect of long-term naltrex one treatment on endocrine , profile , clinical fearures ,and insulin sensitivity in obese women with polycystic ovary syndrome [ J ] . Fertil Steril ,2002 ,77 (5) :936~944
12 Tucci S , Fut terweit W , Concepcion E S , et al . Evidence for associateion of polycystic ovary syndrome in Caucasian women with a marker at the insulin recept or gene locus [ J ] . J Clin Endocrinol Metab ,2001 ,86 :446~449
13 Villuendas G , Escobar M H F , Tosi F , et al . Association between t he D19S884 marker at the insulin recept or geng locus and polycystic ovary syndrome [ J ] . Fertil Steril , 2003 , 79 ( 1) :219~220
14 Siegel S , Fut terweit W , Davies T F , et al . A A/T single nucleotide polymorphism at the tyrosine kinase domain of the insulin recept or gene is associated with polycystic ovary syndrome [J] . Fertil Steril ,2002 ,78 (6) :1240~1243
15 Remsberg KE , Talbott EO , Zborowski JV , et al . Evidence for competing effect s of body mass , hyperinsulinemia , insulin resistance , and androgens on leptin levels among lean , overweight , and obese women with polycystic ovary syndrome [J ] . Fertil Steril ,2002 ,78 (3) :479~486
16 Acien P , Quereda F , Matallin P , et al . Insulin , androgens , and obesity in women with and without polycystic ovary syndrome : a heterogeneous group of disorders[J ] . Fertil Steril ,1999 ,72 (1) :32~40
17 Nestler JE ,Barlasani CO ,Matt DW, et al . Suppression of serum insulin by diazoxide redudes testosterone levels in obese woman with polycystic ovarian syndrome [ J ] . J Clin Endocrinol Metab , 1989 , 68 (5) :1027~1032
18 La-Marca A, Egbe TO, Morgante G,et al. Metformin treatment reduces ovarian cytochrome P450c17α response to human chorionicg onadotrophin in women with insulin resistance-related polycystic ovary syndrome. Hum Reprod, 2000,15:21~23
19 Nestler JE ,Jakubowicz DJ , de Vargas AF , et al . Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system [J]. J Clin Endocrinol Metab , 1998 ,83 (6) :2001
20 Nestler JE, Jakubowicz DJ, de Vargas AF, et al. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system.J Clin Endocrinol Metab,1998,83:2001~2005
21 Nestler JE. Role of hyperinsulinemia in the pathogenesis of polycystic ovary syndrome, and its clinical implication. Semin Report Endocrinol, 1997, 15:111~122
22 王治鸿.多囊卵巢综合征高雄激素血症的形成,国外医学 妇产科学分册, 2001, 28 (3) : 167
23 黄荷凤,郦美根.多囊卵巢综合征和高雄激素血症,中国实用妇产科与产科杂志, 2002, 18 (11) : 648
24 Azziz R,Rittmaster RS,Fox LM,et a l.Role of the ovary in the adrenal excess of hyperandrogenic women.Fertil Steril, 1998, 69:691~696
25 Marshall JC, Eagleson CA, McCartney CR. Hypothalamic dysfunction. Mol Cell Endocrino1,2001, 183(1-2): 29~32
26 R Jeffrey Change,Seth E Katz.Polycystic ovary syndrome. Endocrinol Metab Clin North Am,1999, 28: 397~408
27 Cordon CM. Menstrual disorders in adolescents. Excess androgens and the polycystic ovary syndrome.Pediatr Clin North Am,1999,46(3):519~543
28 Marshall JC, Eagleson CA. Neuroendocrine aspects of ovary syndrome.Endocrinol & Metab Clin North Am,1999,28(2):295~324
29 Nestler JE,Jakubowicz DJ.Lean woman with polycystic ovary syndrome respond to insulin reduce with decrease in ovarian P450c17α activity and serum androgens.J Clin Endocrinol Metab, 1997,82(12):4075~4079
30 Lockwood GM,Muttakrishna S,Grome NP.Mid follicularphase pulse of inhibin B are absent in polycystic ovary syndrome and are initiated by successful laparoscopic ovarian diathermy: a possible mechanism regulatinge mergence of the dominant follicle.J Clin Endocrinol Metab,1998,83:1730~1735
31 Ia M A ,Morgante G ,Palumbo M ,et al.Insulin-lowering treatment reduces aromatase activeity in response to follicle-stimulating hormone in women with polycystic ovary syndrome [J ].Fertil Steril, 2002, 78 (6) :1234~1239
32 Diamanti-Kandarakis E,Dunaif A. New perspectives in polycystic ovary syndrome.Trends Endocrinol Metab, 1996,7:267~271
33 Con JJ, Jacobs HS, Conway CS. The prevalence of polycystic ovaries in women with 2 type diabetes mellitus.ClinE ndocrinol(Oxf),2000,52(1):81~86
34 Baranowska B , Radzikowska M , Wasilewska D E , et al . Neuropeptide Y, leptin , galanin and insulin in women with polycystic ovary syndrome [ J ] . Gynecol Endocrinol , 1999 , 13(5):344~351
35 Kaushal R , Parchure N , Bano G, et al . Insulin resistance and endothelial dysfunction in the brothers of Indian subcontinent Asian women with polycystic ovaries[J ] . Clin Endocrinol (Oxf) ,2004 ,60 (3) :322~328
36 Reaven GM.Pathophysiology of insulin resistance in human disease [J].Physiol Rev,1995,75(3):473
37 Duaif A.Hyperandrogenic anovulation(PCOS):a unrquicdisorder of insulin action associated with an increased risk of non insulind enpendent diabetes mellitus.Am J Med,1995,98:33~39
38 Pelusi B , Gambineri A , Pasquali R. Type 2 diabetes and the polycystic ovary syndrome [ J ] . Minerva Ginecol , 2004 , 56 (1) : 41~51
39 吴效科,周珊英,苏延华.多囊卵巢综合征患者的胰岛素抵抗.中华妇产科杂志,1999,34:698~701
40 Strowitzki T, Halser B. Demant body fat distribution, insuline sensitivity, ovarian dysfunction and serum lipoproteins in patients with polycystic ovary syndrome.Gynecol Endocrinol,2002,16(1):45~51
41 Ibanez L,Aulesa C,Potau N,et al. Plasminogen activator inhibitor-1 in girls with precocious pubarche: a premenarcheal marker for polycystic ovary syndrome?Pediatr Res,2002,51(2):244~248
42 Paradisi G, Steinberg HO. Polycystic ovary syndrome is associated with endothelial dysfuction. Circulation. 2001, 103 (10):1410~1405