二甲双胍对PCOS患者子宫内膜GLUT4及血清TNF-α、内分泌代谢的影响
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摘要
多囊卵巢综合征(polycystic ovarian syndrome, PCOS)是育龄妇女常见的内分泌紊乱性疾病,是育龄妇女不育的主要原因。近20年研究表明,PCOS患者不仅存在内分泌和生育功能的异常,还存在着代谢紊乱。胰岛素抵抗(insulin resistance, IR)及其继发的高胰岛素血症是PCOS病理生理的中心环节。
关于PCOS-IR的机理,目前的研究认为,胰岛素受体后缺陷是PCOS-IR的发病机制。最近有研究提示,炎性因子可能在PCOS-IR的发生中起一定作用。其中肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)可通过抑制胰岛素受体酪氨酸磷酸化引起IR, TNF-α与IR的关系日益受到人们的关注。
PCOS-IR使人们开始应用胰岛素增敏剂来治疗PCOS。最常用的药物为二甲双胍(metformin)。普遍研究结果表明,二甲双胍可降低肥胖PCOS患者体重及高胰岛素、高雄激素水平,改善月经周期,诱发排卵。对非肥胖患者,是否应用二甲双胍还存在争议。一些学者认为,肥胖与非肥胖患者与其年龄及体重匹配的对照组比较均有IR及高胰岛素血症,但肥胖因素加剧IR,非肥胖患者存在内在性的胰岛素抵抗。鉴于此,人们开始对非肥胖PCOS患者进行二甲双胍的治疗,但结果不尽相同。有些研究显示了二甲双胍治疗非肥胖PCOS患者的有效性,而有些研究认为对非肥胖PCOS患者应用二甲双胍治疗无效。二甲双胍在肥胖及非肥胖患者中的治疗效果到底如何,TNF-a是否和PCOS-IR存在相关性及二甲双胍对其的影响如何,值得我们进一步深入研究。
对于因PCOS排卵障碍引起不孕的治疗,其主要的手段是诱发排卵,但存在着高排卵率和低妊娠率的问题。推测PCOS的代谢异常可能影响子宫内膜的代谢和功能,造成子宫内膜的容受性缺陷,胚胎着床障碍,导致妊娠率低下。子宫内膜细胞的分化和成熟需要足够量的葡萄糖代谢,胰岛素介导的葡萄糖转运是以葡萄糖转运蛋白-4(glucose transporter-4, GLUT4)为载体的,葡萄糖转运蛋白减少而导致的子宫内膜IR可能是PCOS患者子宫内膜细胞代谢受损的原因。
二甲双胍可以降低PCOS患者血中高胰岛素水平,提高胰岛素敏感性。但二甲双胍治疗能否改善PCOS患者子宫内膜IR,PCOS患者子宫内膜组织是否存GLUT4表达异常及与IR的关系如何,二甲双胍治疗又怎样通过影响GLUT4的表达来改善子宫内膜IR,所有这些问题,目前尚无相应的研究做出明确的阐述。因此,有必要对上述问题进行深入的研究,以期为临床治疗提供新的理论依据。
第一部分：二甲双胍对PCOS患者子宫内膜GLUT4表达的影响
目的：
探讨GLUT4在多囊卵巢综合征患者子宫内膜的表达及其与IR的相关性,明确二甲双胍治疗对GLUT4在子宫内膜表达的影响。
方法：
收集胰岛素抵抗的肥胖PCOS患者(PCOS组)20例及同期因输卵管盆腔因素引起不孕的非PCOS肥胖患者(对照组)20例。测定两组患者的生殖激素：促卵泡生成素(follicle stimulating hormone, FSH)、促黄体生成素(luteinizing hormone, LH)、雌二醇(estradiol-2, E2)、睾酮(testosterone, T)、空腹血糖(fasting serum glucose, FSG)、空腹胰岛素水平(fasting serum insulin, FINS)、胰岛素敏感指数(insulin sensitivity index, ISI),并分别应用免疫组织化学法及逆转录聚合酶链式反应(reverse transcription polymerase chain reaction, RT-PCR)法测定两组患者子宫内膜GLUT4、胰岛素(insulin, INS)、胰岛素受体(insulin-receptor, INS-R)蛋白及GLUT4mRNA、INSmRNA、INS-RmRNA的表达。对PCOS组患者应用二甲双胍治疗(500mg/次,3次/d,连续3个月),比较该组患者治疗前后上述指标的改变。
结果：
PCOS组患者血清T、FINS水平明显高于对照组(P<0.01),ISI低于对照组(P<0.01)。PCOS组患者及对照组患者子宫内膜上皮细胞均存在GLUT4、INS、INS-R蛋白及GLUT4mRNA、INSmRNA、INS-RmRNA的表达。GLUT4蛋白及GLUT4mRNA的表达在PCOS组患者明显低于对照组(P<0.01),INS蛋白及INSmRNA表达明显高于对照组(P<0.01),INS-R蛋白、INS-RmRNA在两组患者子宫内膜上表达相似(P>0.05)。子宫内膜上皮细胞GLUT4蛋白及GLUT4mRNA的表达与ISI成正相关(P<0.01)。二甲双胍治疗后,子宫内膜GLUT4蛋白及GLUT4mRNA表达明显升高(P<0.01),INS蛋白、INS-RmRNA表达降低(P<0.01),INS-R蛋白、INS-RmRNA表达治疗前后无明显改变(P>0.05)。
结论：
PCOS患者子宫内膜上皮细胞存在GLUT4蛋白及GLUT4mRNA表达但水平较正常明显降低。PCOS患者子宫内膜存在IR。子宫内膜GLUT4蛋白及GLUT4mRNA的表达与ISI成正相关。二甲双胍可能通过上调PCOS患者子宫内膜GLUT4蛋白表达水平从而改善子宫内膜IR状况。
第二部分：二甲双胍对PCOS患者血清TNF-α、内分泌代谢的影响
目的：
了解肥胖及非肥胖PCOS患者血清中炎性风险因子TNF-α水平的表达及与PCOS-IR发病的相关性,二甲双胍治疗对肥胖及非肥胖PCOS患者TNF-α水平、生殖内分泌和糖脂代谢的影响,以探讨对上述两类人群的治疗作用。
方法：
24例肥胖PCOS患者,20例非肥胖PCOS患者应用二甲双胍500mg/次,3次/d,连续3个月。比较治疗前后两组临床症状：体重指数(body mass index, BMI)、腰臀比(waist to hip ratio, WHR)与排卵情况,血清TNF-α、FSH、LH、E2、T、FBS、FINS水平,OGTT后胰岛素曲线下面积(insulin area under the curve, IAUC)、ISI,以及脂代谢：总胆固醇(total cholesterol, TCH)、甘油三酯(triglycerides, TG)、高密度脂蛋白(low-density lipoprotein, HDL-c)、低密度脂蛋白(1ow-density lipoprotein, LDL-c)、载脂蛋白-A(apolipoprotein-A, ApoA)、载脂蛋白-B(apolipoprotein-B, ApoB)水平的改变。
结果：
44例PCOS患者二甲双胍治疗中,2例失访,4例因在治疗中妊娠而停药,共38例患者完成了三个月的治疗,其中肥胖组21例,非肥胖组17例。肥胖组患者TNF-α、FINS、IAUC显著高于非肥胖组患者(P<0.01), ISI、LH明显低于非肥胖组(P<0.01)。TNF-α与BMI成正相关(P<0.01),与ISI成负相关(P<0.01)。二甲双胍治疗后,两组患者血清TNF-α、LH、T、FINS、IAUC水平明显下降(P<0.05～P<0.01),ISI升高(P<0.05)；两组患者临床症状均得到了改善：肥胖组患者自主排卵率为52.17%,非肥胖组患者自主排卵率为52.63%。在血脂改善方面,肥胖组患者治疗后,TG、TCH、LDL-c、ApoB均明显下降(P<0.05-P<0.01)；非肥胖组中只有ApoB明显下降(P<0.01),余指标无明显改变。
结论：
肥胖与非肥胖PCOS患者内分泌特征不同,非肥胖组患者以LH水平升高为主,肥胖者组患者以胰岛素水平升高,胰岛素敏感指数降低为主。肥胖组患者血清TNF-α水平明显高于非肥胖组。TNF-α可能参与了PCOS-IR的发生。二甲双胍可改善肥胖及非肥胖PCOS患者的临床症状,降低TNF-α、LH、T水平,提高胰岛素的敏感性,对肥胖及非肥胖PCOS患者均有效,尤其适用于肥胖患者。
PCOS (polycystic ovarian syndrome) is one of the most common endocrinological disorders during reproductive age. Studies show PCOS patients not only have endocrine and reproductive dysfunction, but also have metabolic disorders. It is the main reason for infertility in women. IR (Insulin resistance) and hyperinsulinemia are the central links in the pathophysiology of PCOS.
It has been reported that mechanism of PCOS-IR is characterized by a receptor postbinding failure. Recent studies suggest that inflammatory factors may play a role in the occurrence of IR. TNF-α(tumor necrosis factor-α) can cause IR by inhibiting insulin receptor tyrosine phosphorylation. The relationship between IR and TNF-αare increasingly concerned by people.
People began using insulin sensitizers to treat PCOS-IR. Metformin is the most commonly used drug. Metformin can reduce body weight, insulin and androgen levels, improve menstrual cycle and induce ovulation. As for non-obese patients, it is still controversial on treating with metformin. Some scholars believe that both obese and non obese patients are IR and higher insulin levels with their age and weight matched control group. But obese exacerbate IR, non-obese patients have intrinsic IR.
In view of this, people began to treat non-obese PCOS patients with metformin, but the results varied. Some studies have shown that non-obese PCOS patients with metformin treatment are effectiveness, but some studies suggested ineffective. How are about the efficacy of metformin in obese and non-obese patients and whether TNF-αcorrelating with PCOS-IR are worth further exploration.
For the infertility, the main treatment is to induce ovulation, but there is a high ovulation rate and the problem of low pregnancy rate, suggesting that PCOS metabolic abnormalities may affect the metabolism and function of the endometrium. causing defects in endometrial receptivity, embryo implantation dysfunction, resulting in lower pregnancy rate. Differentiation and maturation of endometrial cell require an adequate amount of glucose metabolism. The GLUT4(glucose transporter protein-4) is the carrier of the insulin-mediated glucose transport. The reduction of the glucose transporter protein in endometrium of PCOS patients may be the reason of impaired cell metabolism.
Metformin can reduce high blood insulin and improve insulin sensitivity in PCOS patients. However, whether metformin can improve PCOS patients with endometrial IR and have the abnormal GLUT4 expression. The problems of what's the relationship between IR and GLUT4 expression and how does metformin effect the expression of GLUT4 to improve endometrial insulin sensitive are still having no clear explanation at present. Therefore, we need to further study in order to provide a new the theoretical basis for clinical treatment.
PartⅠ:Efficacy of Metformin in GLUT4 in endometriun of PCOS patients
Objective:
To study the expression of GLUT4 in the endometrium of PCOS patients and the relationship with IR, clarify the efficacy of metformin on the expression of GLUT4 in the endometrium.
Methods:
We enrolled 20 obses patients diagnosed PCOS with IR(PCOS group),20 obses non-PCOS patients with infertility caused by tubal or pelvic factors (control group). assayed the serum FSH (follicle stimulating hormone), LH(luteinizing hormone), E2 (estradiol-2), T (testosterone), FSG (fasting serum glucose), FINS(fasting insulin serum), ISI (insulin sensitivity index). Endometrial GLUT4, INS (insulin), INS-R (insulin-receptor) protein and GLUT4mRNA, INSmRNA, INS-RmRNA expression were measured by immunohistochemical and RT-PCR(reverse transcription polymerase chain reaction) respectively. These parameters were determined before and after oral administration of metfomin 500mg three times daily for three months in PCOS patients.
Results:
The levels of serum T, FINS were significantly higher in PCOS group than those in control group (P<0.01), while ISI level was lower in PCOS group than that in control group (P<0.01). There were expressions of GLUT4, INS, INS-R protein and GLUT4mRNA, INSmRNA, INS-R mRNA in endometrium of both two groups. The expression levels of GLUT4 protein and GLUT4mRNA in PCOS patients were significantly lower (P<0.01), INS protein and INS mRNA were significantly higher(P<0.01) than those in control group. The expression levels of INS-R protein and INS-R mRNA were similar in two groups (P>0.05). The expression levels of GLUT4 and GLUT4mRNA in endometrium had a positive correlation with ISI (p<0.01). After three months of treatment, a significant increasing occurred in GLUT4 protein and GLUT4mRNA expressions and a significant reduction occurred in INS protein and mRNA expressions in PCOS patients(P<0.01). There were no changes in INS-R protein and INS-R mRNA expression in PCOS patients (P>0.05).
Conclusion:
There were expressions of GLUT4 and GLUT4mRNA in endometrial epithelial cells of PCOS patients. But the levels of expression were significantly lower than normal patients. PCOS patients had endometrial IR. The expression levels of GLUT4 and GLUT4mRNA in endometrium had a positive correlation with ISI. Metformin therapy could upregulate the expression level of endometrial GLUT4 to improve the status of the endometrial IR in PCOS patients.
PartⅡ:Efficacy of Metformin in serum TNF-αlevels, endocrine and metabolic festures of PCOS patients
Objectives:
The aim of our study was to assess the serum TNF-αlevels, endocrine and metabolic festures of obese and non-obese polycystic ovary syndrome (PCOS) patients and the effects of metformin therapy.
Methods:
Forty-four diagnosed PCOS patients were recruited. The clinical signs, serum TNF-αlevels, endocrine and metabolic parameters were determined before and after oral administration of metfomin 500mg three times daily for three months.
Results:
The levels of TNF-α, FINS, IAUC were significantly higher in obese group than those in non-obese group (P<0.01), while LH and ISI levels were higher in non-obese group than those in obese group (P<0.01). TNF-αhad a positive correlation with BMI (P< 0.01), and had a negative correlation with ISI (P< 0.01). After three months of treatment, in obese women, a significant reduction occurred in BMI, WHR, TNF-α, LH, T, FINS, IAUC, TG, TCH, LDL-c, ApoB(P<0.05～P<0.01). A significant increasing occurred in ISI (P<0.05). In non-obese women, a significant reduction occurred in WHR, TNF-α, LH, T, FINS, IAUC, ApoB(P<0.05～P<0.01) and ISI increased significantly (P< 0.05). Clinical signs were improved in both two group. Ovulation rate was 52.17% in obese group and 52.63% in non-obese group.
Conclusion:
There were different endocrine characteristics between obese and non-obese PCOS patients. Non-obese PCOS patients showed mainly elevated levels of LH. Obese PCOS patients showed mainly elevated insulin level and decreased ISI. The level of TNF-αwas significantly higher in obese group than that in non-obese group. TNF-αmight be involved in the occurrence of PCOS-IR. Three months of metformin therapy improved in clinical signs, reduced the levels of TNF-α, LH, T, improved insulin sensitivity in both two groups. Metformin therapy was effective in both obese and non-obese PCOS patients, especially for obese patients.
关于PCOS-IR的机理,目前的研究认为,胰岛素受体后缺陷是PCOS-IR的发病机制。最近有研究提示,炎性因子可能在PCOS-IR的发生中起一定作用。其中肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)可通过抑制胰岛素受体酪氨酸磷酸化引起IR, TNF-α与IR的关系日益受到人们的关注。
PCOS-IR使人们开始应用胰岛素增敏剂来治疗PCOS。最常用的药物为二甲双胍(metformin)。普遍研究结果表明,二甲双胍可降低肥胖PCOS患者体重及高胰岛素、高雄激素水平,改善月经周期,诱发排卵。对非肥胖患者,是否应用二甲双胍还存在争议。一些学者认为,肥胖与非肥胖患者与其年龄及体重匹配的对照组比较均有IR及高胰岛素血症,但肥胖因素加剧IR,非肥胖患者存在内在性的胰岛素抵抗。鉴于此,人们开始对非肥胖PCOS患者进行二甲双胍的治疗,但结果不尽相同。有些研究显示了二甲双胍治疗非肥胖PCOS患者的有效性,而有些研究认为对非肥胖PCOS患者应用二甲双胍治疗无效。二甲双胍在肥胖及非肥胖患者中的治疗效果到底如何,TNF-a是否和PCOS-IR存在相关性及二甲双胍对其的影响如何,值得我们进一步深入研究。
对于因PCOS排卵障碍引起不孕的治疗,其主要的手段是诱发排卵,但存在着高排卵率和低妊娠率的问题。推测PCOS的代谢异常可能影响子宫内膜的代谢和功能,造成子宫内膜的容受性缺陷,胚胎着床障碍,导致妊娠率低下。子宫内膜细胞的分化和成熟需要足够量的葡萄糖代谢,胰岛素介导的葡萄糖转运是以葡萄糖转运蛋白-4(glucose transporter-4, GLUT4)为载体的,葡萄糖转运蛋白减少而导致的子宫内膜IR可能是PCOS患者子宫内膜细胞代谢受损的原因。
二甲双胍可以降低PCOS患者血中高胰岛素水平,提高胰岛素敏感性。但二甲双胍治疗能否改善PCOS患者子宫内膜IR,PCOS患者子宫内膜组织是否存GLUT4表达异常及与IR的关系如何,二甲双胍治疗又怎样通过影响GLUT4的表达来改善子宫内膜IR,所有这些问题,目前尚无相应的研究做出明确的阐述。因此,有必要对上述问题进行深入的研究,以期为临床治疗提供新的理论依据。
第一部分：二甲双胍对PCOS患者子宫内膜GLUT4表达的影响
目的：
探讨GLUT4在多囊卵巢综合征患者子宫内膜的表达及其与IR的相关性,明确二甲双胍治疗对GLUT4在子宫内膜表达的影响。
方法：
收集胰岛素抵抗的肥胖PCOS患者(PCOS组)20例及同期因输卵管盆腔因素引起不孕的非PCOS肥胖患者(对照组)20例。测定两组患者的生殖激素：促卵泡生成素(follicle stimulating hormone, FSH)、促黄体生成素(luteinizing hormone, LH)、雌二醇(estradiol-2, E2)、睾酮(testosterone, T)、空腹血糖(fasting serum glucose, FSG)、空腹胰岛素水平(fasting serum insulin, FINS)、胰岛素敏感指数(insulin sensitivity index, ISI),并分别应用免疫组织化学法及逆转录聚合酶链式反应(reverse transcription polymerase chain reaction, RT-PCR)法测定两组患者子宫内膜GLUT4、胰岛素(insulin, INS)、胰岛素受体(insulin-receptor, INS-R)蛋白及GLUT4mRNA、INSmRNA、INS-RmRNA的表达。对PCOS组患者应用二甲双胍治疗(500mg/次,3次/d,连续3个月),比较该组患者治疗前后上述指标的改变。
结果：
PCOS组患者血清T、FINS水平明显高于对照组(P<0.01),ISI低于对照组(P<0.01)。PCOS组患者及对照组患者子宫内膜上皮细胞均存在GLUT4、INS、INS-R蛋白及GLUT4mRNA、INSmRNA、INS-RmRNA的表达。GLUT4蛋白及GLUT4mRNA的表达在PCOS组患者明显低于对照组(P<0.01),INS蛋白及INSmRNA表达明显高于对照组(P<0.01),INS-R蛋白、INS-RmRNA在两组患者子宫内膜上表达相似(P>0.05)。子宫内膜上皮细胞GLUT4蛋白及GLUT4mRNA的表达与ISI成正相关(P<0.01)。二甲双胍治疗后,子宫内膜GLUT4蛋白及GLUT4mRNA表达明显升高(P<0.01),INS蛋白、INS-RmRNA表达降低(P<0.01),INS-R蛋白、INS-RmRNA表达治疗前后无明显改变(P>0.05)。
结论：
PCOS患者子宫内膜上皮细胞存在GLUT4蛋白及GLUT4mRNA表达但水平较正常明显降低。PCOS患者子宫内膜存在IR。子宫内膜GLUT4蛋白及GLUT4mRNA的表达与ISI成正相关。二甲双胍可能通过上调PCOS患者子宫内膜GLUT4蛋白表达水平从而改善子宫内膜IR状况。
第二部分：二甲双胍对PCOS患者血清TNF-α、内分泌代谢的影响
目的：
了解肥胖及非肥胖PCOS患者血清中炎性风险因子TNF-α水平的表达及与PCOS-IR发病的相关性,二甲双胍治疗对肥胖及非肥胖PCOS患者TNF-α水平、生殖内分泌和糖脂代谢的影响,以探讨对上述两类人群的治疗作用。
方法：
24例肥胖PCOS患者,20例非肥胖PCOS患者应用二甲双胍500mg/次,3次/d,连续3个月。比较治疗前后两组临床症状：体重指数(body mass index, BMI)、腰臀比(waist to hip ratio, WHR)与排卵情况,血清TNF-α、FSH、LH、E2、T、FBS、FINS水平,OGTT后胰岛素曲线下面积(insulin area under the curve, IAUC)、ISI,以及脂代谢：总胆固醇(total cholesterol, TCH)、甘油三酯(triglycerides, TG)、高密度脂蛋白(low-density lipoprotein, HDL-c)、低密度脂蛋白(1ow-density lipoprotein, LDL-c)、载脂蛋白-A(apolipoprotein-A, ApoA)、载脂蛋白-B(apolipoprotein-B, ApoB)水平的改变。
结果：
44例PCOS患者二甲双胍治疗中,2例失访,4例因在治疗中妊娠而停药,共38例患者完成了三个月的治疗,其中肥胖组21例,非肥胖组17例。肥胖组患者TNF-α、FINS、IAUC显著高于非肥胖组患者(P<0.01), ISI、LH明显低于非肥胖组(P<0.01)。TNF-α与BMI成正相关(P<0.01),与ISI成负相关(P<0.01)。二甲双胍治疗后,两组患者血清TNF-α、LH、T、FINS、IAUC水平明显下降(P<0.05～P<0.01),ISI升高(P<0.05)；两组患者临床症状均得到了改善：肥胖组患者自主排卵率为52.17%,非肥胖组患者自主排卵率为52.63%。在血脂改善方面,肥胖组患者治疗后,TG、TCH、LDL-c、ApoB均明显下降(P<0.05-P<0.01)；非肥胖组中只有ApoB明显下降(P<0.01),余指标无明显改变。
结论：
肥胖与非肥胖PCOS患者内分泌特征不同,非肥胖组患者以LH水平升高为主,肥胖者组患者以胰岛素水平升高,胰岛素敏感指数降低为主。肥胖组患者血清TNF-α水平明显高于非肥胖组。TNF-α可能参与了PCOS-IR的发生。二甲双胍可改善肥胖及非肥胖PCOS患者的临床症状,降低TNF-α、LH、T水平,提高胰岛素的敏感性,对肥胖及非肥胖PCOS患者均有效,尤其适用于肥胖患者。
PCOS (polycystic ovarian syndrome) is one of the most common endocrinological disorders during reproductive age. Studies show PCOS patients not only have endocrine and reproductive dysfunction, but also have metabolic disorders. It is the main reason for infertility in women. IR (Insulin resistance) and hyperinsulinemia are the central links in the pathophysiology of PCOS.
It has been reported that mechanism of PCOS-IR is characterized by a receptor postbinding failure. Recent studies suggest that inflammatory factors may play a role in the occurrence of IR. TNF-α(tumor necrosis factor-α) can cause IR by inhibiting insulin receptor tyrosine phosphorylation. The relationship between IR and TNF-αare increasingly concerned by people.
People began using insulin sensitizers to treat PCOS-IR. Metformin is the most commonly used drug. Metformin can reduce body weight, insulin and androgen levels, improve menstrual cycle and induce ovulation. As for non-obese patients, it is still controversial on treating with metformin. Some scholars believe that both obese and non obese patients are IR and higher insulin levels with their age and weight matched control group. But obese exacerbate IR, non-obese patients have intrinsic IR.
In view of this, people began to treat non-obese PCOS patients with metformin, but the results varied. Some studies have shown that non-obese PCOS patients with metformin treatment are effectiveness, but some studies suggested ineffective. How are about the efficacy of metformin in obese and non-obese patients and whether TNF-αcorrelating with PCOS-IR are worth further exploration.
For the infertility, the main treatment is to induce ovulation, but there is a high ovulation rate and the problem of low pregnancy rate, suggesting that PCOS metabolic abnormalities may affect the metabolism and function of the endometrium. causing defects in endometrial receptivity, embryo implantation dysfunction, resulting in lower pregnancy rate. Differentiation and maturation of endometrial cell require an adequate amount of glucose metabolism. The GLUT4(glucose transporter protein-4) is the carrier of the insulin-mediated glucose transport. The reduction of the glucose transporter protein in endometrium of PCOS patients may be the reason of impaired cell metabolism.
Metformin can reduce high blood insulin and improve insulin sensitivity in PCOS patients. However, whether metformin can improve PCOS patients with endometrial IR and have the abnormal GLUT4 expression. The problems of what's the relationship between IR and GLUT4 expression and how does metformin effect the expression of GLUT4 to improve endometrial insulin sensitive are still having no clear explanation at present. Therefore, we need to further study in order to provide a new the theoretical basis for clinical treatment.
PartⅠ:Efficacy of Metformin in GLUT4 in endometriun of PCOS patients
Objective:
To study the expression of GLUT4 in the endometrium of PCOS patients and the relationship with IR, clarify the efficacy of metformin on the expression of GLUT4 in the endometrium.
Methods:
We enrolled 20 obses patients diagnosed PCOS with IR(PCOS group),20 obses non-PCOS patients with infertility caused by tubal or pelvic factors (control group). assayed the serum FSH (follicle stimulating hormone), LH(luteinizing hormone), E2 (estradiol-2), T (testosterone), FSG (fasting serum glucose), FINS(fasting insulin serum), ISI (insulin sensitivity index). Endometrial GLUT4, INS (insulin), INS-R (insulin-receptor) protein and GLUT4mRNA, INSmRNA, INS-RmRNA expression were measured by immunohistochemical and RT-PCR(reverse transcription polymerase chain reaction) respectively. These parameters were determined before and after oral administration of metfomin 500mg three times daily for three months in PCOS patients.
Results:
The levels of serum T, FINS were significantly higher in PCOS group than those in control group (P<0.01), while ISI level was lower in PCOS group than that in control group (P<0.01). There were expressions of GLUT4, INS, INS-R protein and GLUT4mRNA, INSmRNA, INS-R mRNA in endometrium of both two groups. The expression levels of GLUT4 protein and GLUT4mRNA in PCOS patients were significantly lower (P<0.01), INS protein and INS mRNA were significantly higher(P<0.01) than those in control group. The expression levels of INS-R protein and INS-R mRNA were similar in two groups (P>0.05). The expression levels of GLUT4 and GLUT4mRNA in endometrium had a positive correlation with ISI (p<0.01). After three months of treatment, a significant increasing occurred in GLUT4 protein and GLUT4mRNA expressions and a significant reduction occurred in INS protein and mRNA expressions in PCOS patients(P<0.01). There were no changes in INS-R protein and INS-R mRNA expression in PCOS patients (P>0.05).
Conclusion:
There were expressions of GLUT4 and GLUT4mRNA in endometrial epithelial cells of PCOS patients. But the levels of expression were significantly lower than normal patients. PCOS patients had endometrial IR. The expression levels of GLUT4 and GLUT4mRNA in endometrium had a positive correlation with ISI. Metformin therapy could upregulate the expression level of endometrial GLUT4 to improve the status of the endometrial IR in PCOS patients.
PartⅡ:Efficacy of Metformin in serum TNF-αlevels, endocrine and metabolic festures of PCOS patients
Objectives:
The aim of our study was to assess the serum TNF-αlevels, endocrine and metabolic festures of obese and non-obese polycystic ovary syndrome (PCOS) patients and the effects of metformin therapy.
Methods:
Forty-four diagnosed PCOS patients were recruited. The clinical signs, serum TNF-αlevels, endocrine and metabolic parameters were determined before and after oral administration of metfomin 500mg three times daily for three months.
Results:
The levels of TNF-α, FINS, IAUC were significantly higher in obese group than those in non-obese group (P<0.01), while LH and ISI levels were higher in non-obese group than those in obese group (P<0.01). TNF-αhad a positive correlation with BMI (P< 0.01), and had a negative correlation with ISI (P< 0.01). After three months of treatment, in obese women, a significant reduction occurred in BMI, WHR, TNF-α, LH, T, FINS, IAUC, TG, TCH, LDL-c, ApoB(P<0.05～P<0.01). A significant increasing occurred in ISI (P<0.05). In non-obese women, a significant reduction occurred in WHR, TNF-α, LH, T, FINS, IAUC, ApoB(P<0.05～P<0.01) and ISI increased significantly (P< 0.05). Clinical signs were improved in both two group. Ovulation rate was 52.17% in obese group and 52.63% in non-obese group.
Conclusion:
There were different endocrine characteristics between obese and non-obese PCOS patients. Non-obese PCOS patients showed mainly elevated levels of LH. Obese PCOS patients showed mainly elevated insulin level and decreased ISI. The level of TNF-αwas significantly higher in obese group than that in non-obese group. TNF-αmight be involved in the occurrence of PCOS-IR. Three months of metformin therapy improved in clinical signs, reduced the levels of TNF-α, LH, T, improved insulin sensitivity in both two groups. Metformin therapy was effective in both obese and non-obese PCOS patients, especially for obese patients.
引文
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