摘要
目的：系统分析二甲双胍联合克罗米芬(Clomiphene,CC)治疗多囊卵巢综合征(Polycystic ovary syndrome,PCOS)的有效性、安全性,以期做出客观、可信的评价,指导临床用药,提出临床研究中存在的问题,拟采取的对策。
方法：采用循证医学(Evidence-based medicine,EBM)的方法,全面检索国内二甲双胍联合克罗米芬治疗多囊卵巢综合征的随机对照试验(Randomized controlled trial,RCT)文献资料并进行系统评价(Systematic review,SR),按文献可靠性的分级、试验分配的隐藏方案和JADAD量表评价文献的质量。采用Cochrane协作网提供的Revman4.2软件进行统计分析。
结果：二甲双胍联合克罗米芬治疗多囊卵巢综合征临床排卵率(P<0.00001)、妊娠率(P<0.00001与单独克罗米芬组比较有显著意义；与单独二甲双胍组比较排卵率(P=0.0009<0.05=,高于单独应用二甲双胍组,妊娠率(P=0.02<0.05=显著高于单独应用二甲双胍组,二甲双胍联合克罗米芬治疗多囊卵巢综合征总体疗效肯定,为指导以后的临床用药提供了理论支持。倒漏斗图显示不对称,可能与发表偏倚及临床试验设计有关。
结论：二甲双胍联合克罗米芬治疗多囊卵巢综合征是一种有效的方法。但临床随机对照试验的方法学质量较低,存在潜在的发表偏倚,其临床疗效及安全性有待今后随机对照、多中心的临床试验加以证实和重新评估。
Purpose:To make the systematic review of "combinded treatment of clomiphene and metformin" in treating Polycystic ovary syndrome so that clinical treating decision can be made based on objective believable evaluation of the treatment to Polycystic ovary syndrome by the method, put forward the existent problem in the clinical research, draw up the methods to solve them.
Method:All the randomized controlled trails about the research work of combinded treatment of metformin and clomiphene in treating Polycystic ovary syndrome in China were searched based on the methods of evidence-based medicine. All the articles were evaluated based on reliability classification, concealment of research allocation and JADAD scale review.Articles were analysised with Revman4.2 sofeware.
Result:The ovulation rates and pregnancy rates of the group of combined treatment of metformin and clomiphene have conspicuous significance when compared with the clomiphene group (P<0.00001, P<0.00001)The ovulation rates and pregnancy rates of the group of combined treatment of metformin and clomiphene are conspicuous precede to the metformin group (P=00009<0.05, P=0.02<0.05).The therapeutic effect of the treatment method of combined metformin and clomiphene indicated for PCOS is ascertain, which provides the theory evidence for guiding the usage of medicine clinically. Asymmetry showed in "Funel Plot" may be related to the publication bias and the design of clinical experiment.
Conclusion:Polycystic ovary syndrome in metformin and clomiphene is an efficical method.Because of the general poor methodological quality and potential publication bias,the efficacy and safety of metformin and clomiphene in the treatment of polycystic ovary syndrome should be evaluated by more rigorously designed, randmized, multiply-center trails.
引文
1.PORETSKYL,CATALDONA,ROSEN WAKSZ,e tal.The insulin-related ovarian regulatory system in health and disease[J].Endocr Rev,1999,20(4):535-582.
2.Siegel S,Futterweit W, DaviesT F,etal.A A/T sing nucleotide polymorphism at the tyrosine kinase domain of the insulin receptor gene is associated with polycystic ovar syndrome [J].FertilSteril,2002,78(6):1240-1243.
3.Tucci S,Futterweit W, Concepcion E S,etal. Evidence for associateion of polycystic ovary syndrome in Caucasian wome with a marker at the insulin receptor gene locus[J].J Cli Endocrinol Metab,2001,86:446-449.
4.Villuendas G, Escobar M H F, Tosi F,etal. Association between the D19S884 marker at the insulin receptor geng locus and polycystic ovary syndrome [J].Fertil Steril,2003,79(1):219-220.
5.HolteJ.Polycystic Ovary Syndrome and insulin resistance thrifty genes struggling with over-feeding and sedentary life style[J]?J Endo Invest,1998,21 (9):589-601.
6.Nestler J E. Role of hyperinsulinemia in the path ologenesis of Polycystic Ovary Syndrome and its clinical implichtion [J]. Semia Reprod Endocrinol,1997, 15(2):111-122.
7.Romualdi D, Guido M, Clampelli M, etal. Selective effects of Pioglitazone on insulin and androgen abnormallyties in norm and hyperinsulineaemic obese patients with polycystic ovary syndrome [J]. HumPeprod,2003,18(6):1210-1218.
8.Baranowska B, Radzikowska M, Wasilewska D E,etal Neuropeptide Y, leptin, galanin and insulin in women with polycystic ovary syndrome [J].Gynecol Endocrinol, 1999,13 (5):344-351.
9.la M A,Morgante G, Palumbo M,etal. 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.
10.Yasuda N,Inoue T,Nagakura T, et al,Enhanced secretion of glucagons-like peptide 1 by biguanide compounds [J],Biochem Biophys Res Commum,2002,298(5):779.
11.Stefanovic V, Antic S, Mitic-Zlatkovic M.et al.Reversal of increased lymphocyte PC-1 activity in patients with type 2 diabetes treated with metformin [J] Diabetes Metab Res Rev,1999,15(6):400
12.Meuillet EJ,Wiemsperger N. Mama-Famell B, et al.Metformin.modulates insulin receptor stgnahng in normal and cholesteol-treated human hepatoma cells (HepG2) [J].Eur J Pharmacol,1999.377(2-3):241
13.Yuau L, Rrudmnl Z,,Amlreas H, et al.Metformin in modulates insulin post-receptor signaling transduction in chronically insulin-treated Hep G2 cells[J]. Acta Pharmacol Sin,2003,24(1):55.
14.Gunton JE, Delhanty PJ. Takahasht S,et al.Metformin rapidly mcreases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2[J].J Clm Endocrinol Metab,2003,88(3):1323
15.李益明,段文澜,朱禧星等.二甲双胍对糖尿病大鼠骨骼肌GLUT4基因表达的影响[J].上海医科大学学报,1998,25(6)：409.
16.Stolar MW.Insulin resistance,diabetes, and the adipocyte[J].Am J Health Syst Pharm,2002,59(Suppl 9):S3.
17.李长贵,宁光,陈家伦.胰岛素抵抗状态下HepG2细胞纤维蛋白溶解酶原激活物抑制物—1基因的表达[J]中华内分泌代谢杂志,2000,1(4)：239.
18.Nestler JE, Jakubowicz DJ.Decreases in ovarian cytochrome P450c17alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome[J].N Engl J Med,1996,335(9):617.
19.Diamanti Kandarakia E,Kouli C,Tsianateli T,et al.Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome [J].Eur J Endocrinol,1998,138(3):269.
20.Glueck CJ,Wang P,Fontaine R,et al.Metformin-induced resumption of normal menses in 39 of 43(91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism,1999,48:511-519.
21.Velazquez BM et al. Metabolism,1994,43(5):647-654.
22.Kolodziejczyk B,Duleba AJ,Spaczynski RZ,et al.Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome [J]. Fertil Steril,2000,73(6):1149.
23.Paolo M,Roberto C,Carlo N,et al.Metformin effects on clinical features, endocrine and metabolic profiles and insulin sensitivity in polycystic ovary syndrome:A randomized, double-blind,placebo-controlled 6-month trial,followed by open, long-term clinical evaluation [J]. The Journal of Clinical Endocrinology & Metabolism,2000,85(1):139-146.
24.Irina K,Maciej K,Marek S,et al.Insulin,Leptin,IGF-1 an Insulin-dependent protein concerntrations after insulin-sensitizing therapy in obse women with Polycystic Ovary Syndrome [J].European Journal If Endocrinology,2001,144:509-515.
25.Ghazeeri G,Kutteh W H,Bryer-Ash M,et al.Effect of roaiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome.Fertil Steri 1,2003,79:562-566.
26.Lord JM, Flighe IH, Norman RJ. Metformin in polycystic ovary syndrome:systematic review and meta-analysis[J] BMJ,2003,327(7421):951
27.康白,韩慧蓉,李广宙等二甲双胍对小鼠血清雌二醇、孕酮含量的影响[J].中国药理学通报.2003.19(2)：237.
28.Shegem NS, Nasir AM Jhour AK, et al. Effects of short term metformin adminishation on androgens in normal men [J],Saudi Med J,2002,23(8):934.
29.沈山梅,朱大龙,田成功,等.二甲双胍对假性黑棘皮病胰岛素抵抗及高胰岛素血症的作用[J].中华内分泌代谢杂志,2001,17(5)：285.
30.Harbome L,Fleming R,Lyall H,et al Metformin in or antiand in the treatment of hirsutism inpolycystic ovary syndrome.J Clin Endocrinol Metab,2005,88(4):4116-4123.
31.Kelly CJ, Cordon D. The effect of metformin on hirsutism in polycystic ovary syndrome. Eur J Endocrinol,2002,147(2):217-221.
32.Velazquez EM, Mendoza SG,Wang P,et al.Metformin therapy is associated with decrease in plasma plasminogen activato rinhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome.Metabolism,1997,46:454-457.
33.Ehrmann DA, Cavaghan M,Imperial J,et al.Effects of metformin on insulin secretion,insulin action and ovarian steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab,1997,82:524-530.
34.Pirwany I R, Yates R W S, Cameron 1 T, et al. Effects of the insulin sensitizing drug metformin on ovarian function,follicular growth and ovulation rate in obese with oligomenorrhea. Hum Reprod,1999,14,2963-2968
35.Nestler JE,Jakubowicz DJ. Decreases in ovarian cytochrome P450cl7alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome.N Engl J Med,1996,335:617-623.
36.Morin-Papunen L C, Koiwnen R M, Ruokonen A, et al.Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycyatic ovary syndrome. Fertil Steril,1998,69:691-696.
37.Jakubowicz D J, Luorno M J, Jakubowicz S, et al. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. Clin Endocrinol Metab,2002, 87(2):524-529.
38.Batukan C, Baysal B. Metformin improves ovulation and pregnancy rates in patients with polycystic ovary syndrome. Arch Gynecol Obstet,2001,265(3):124-127.
39.Kashyap S,Wells GA, Rosenwaks Z.Insulin-sesitizing agents as primary therapy for patients with polycystic ovatian syndrome.Hum Repros,2004,19(6):2474-2483.
40.Barbieri RL.Metformin for the treatment of polycyctic ovany syndrome [J].Bstet Gynecol,2003,101:785-793.
41.Daniela J,Maria J,luorno A,e tal. Effects of metformin on early pregnancy loss in the polycystic ovar ysyndrome[J].The Jonrnal of Clinical Endocrinology & Metabolism,2002,87(2):2524-2529.
42.Glueck C J,Goldenberg N,Wang P,et al.Metformin during pregnancy reduces insulin,insulin resistance,insulin secretion,weight,testosterone and development of gestational diabetes:Prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy [J].Hum Reprod,2004,19(3):510-521.
43.Glueck C J,Wang P,Goldenberg N,et al.Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin [J].Hum Reprod,2002,17(11):2858-2864.
44.Nestler J E. Metformin and the polycystic ovary syndrome.J Clin Endocrinol Meltab,2001,86:1430.
45.Vanky E,Salvesen KA,Heimstad R,et al.Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women:results of a randomized study.HumReprod,2004,19(6):1734-1740.
46.Glueck CJ,Phillips H,Cameron D,et al.Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion:a pilot study.Fertil Steril,2001,75(1):46-52.
47.Glueck CJ,Goldenberg N,Pranikoff J,et al.Height,weight,andmotor-social development during the first 18 months of lifes in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy.Hum Reprod,2004,19(6):1323-1330.
48.Glueck CJ,Wang P,Kobayashi S,et al.Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome [J].Fertil Steril,2002,77:520-525.
49.Morin-Papnnen L, Rautin K, Ruokonen A,et al,Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome.[J].J Clin Endocrinol Metab,2003,88 (10):4649.
50.Loverro G, Lorusso F, De Pergola G, et al. Clinical and endocrinological effects of 6 months of metformin treatment in young hyperinsulinemic patients affected by polycystic ovary syndrome. Gynecol Endocrinol,2002,16(3):217-224.
51.Moghetti P,Castello R,Negri C,et al.Metformin effects on clinical features,endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome:a randomized,double-blind,placebo-controlled 6-month trial, followed by open,long-term clinical evaluation.J Clin Endocrinol Metab,2000,85:139-146.
52.Acbay O,Gundogdu S.Can metformin reduce insulinresistance in polycystic ovary syndrome? Fertil Steril,1996,65:946-949.
53.Diamanti-Kandarakis E, Spins G, Kouli C, et al. Increased endothelin-I levels in women with polycystic ovary syndrome and the beneficial of metformin therapy.J Clin Endocrinol Metab,2001,86:4666-4673.
54.Marfella R,Acampora R,Verrazzo G,et al.Metformin improves hemodynamic and rheological responses to L-argininein NIDDM patients[J].Diabetes Care,1996,19:934.
55.Ibanez L,Valls C,Ferrer A,et al. Sensitization to insulin induces ovulation in nonobese adolescents with anovulatory hyperandrogenism.J Clin Endocrinol Metab,2001,86:3595-3598.
56.Checa MA,Requena A,Salvador c,et al.Insulin-sensitizing agents:use in pregnancy and as therapy in polycystic ovary syndrome.Hum Reprod Update,2005,11(4):375-390.
57.彭丹红,鲁荣绥.多囊卵巢综合征患者应用二甲双胍增强氯米酚的促排卵效果观察.东南大学学报,2004,23(6)：414—417.
58.周晓也,张建云.二甲双胍对多囊卵巢综合征促排卵治疗的疗效分析.中国药物与临床2004,4(8)：635—636.
59.徐玉伟,王元芳等.二甲双胍联合促排卵药物治疗多囊卵巢综合征的临床观察.滨州医学院学报,2005,28(2)：131.
60.顾正田,黄燕冰等二甲双胍联合促排卵药治疗多囊卵巢综合征的疗效观察.中国误诊学杂志,2004,4(3)：360—362.
61.郑峥.二甲双胍用于多囊卵巢综合征患者促排卵周期的疗效观察.中国优生与遗传杂志,2004,12(5)：117-118.
62.韩美英,马建爽等.二甲双胍在PCOS胰岛素抵抗、高胰岛素血症中促排卵中的疗效观察.中国初级卫生保健,2004,18(8)：89-91.
63.张玮,刘芳.二甲双胍治疗多囊卵巢综合征26例临床分析.临沂医学专科学校学报,2003,25,98-99.
64.杨纯等.二甲双胍治疗多囊卵巢综合征38例疗效分析.医学信息,2007,20(1)：96—97.
65.李云,钱丽明等.二甲双胍治疗多囊卵巢综合征58例疗效观察.中原医 刊,2006,33(9)：45—46.
66.郭郁郁,隋春华等.二甲双胍治疗多囊卵巢综合征的疗效.上海医学,2006,29(7)：442-444.
67.李永华.二甲双胍治疗克罗米芬抵抗的多囊卵巢综合征56例疗效观察.医学信息,2006,19(5)：829—831.
68.胡亚林.克罗米酚联合二甲双胍治疗多囊卵巢综合征疗效观察.现代医药卫生,2006,22(19)：2939—2940.
69.郑建淮,曹缵孙等.罗格列酮和二甲双胍治疗多囊卵巢综合征患者的临床疗效比较.实用妇产科杂志,2005,2(9)：541—544.
70.李彩球,周毅等.他莫西芬结合二甲双胍治疗多囊卵巢综合征效果观察.浙江临床医学,2007,9(1)：62.
71.周旭毓,等。Meta-分析的常见偏倚[J].循证医学,2002；2(4)：216-220
72.唐雪春,罗翌.对双黄连粉针剂治疗急性呼吸道感染研究文献的质量评价.广州中医药大学学报,2002,19(2)：149-153
73.Schulz KF,Chalmers I, Hayes R, Altman D. Empirical evidence of bias JAMA, 1995:27(3):408-12