Metform for ovarian stimulation 二甲双胍用于卵巢刺激

　　Meta-analysis of five randomized clinical trials with adjunctive use of metformin (Met) in women with PCOS having ovarian stimulation for IVF has shown a dramatic reduction of ovarian hyperstimulation syndrome (OHSS) (OR 0.21, CL 0.11-0.41, p<0.00001) (1). Insulin, which is elevated in PCOS and markedly reduced by Met, is one of the factors that stimulate luteinized granulosa cells to produce vascular endothelial growth factor (2), the principle cause of the increased vascular permeability responsible for the major manifestations of OHSS. Because OHSS can be associated with severe complications and even death, this finding alone makes the use of metformin essential whenever ovarian stimulation in PCOS patients is expected to be accompanied by a significant risk of OHSS.

　　通过对五项多囊卵巢综合征(PCOS)患者随机临床试验进行元分析后发现，这些患者在服用二甲双胍辅助药物后发生卵巢过度刺激综合征(OHSS)的几率显著降低(比值比0.21，置信水平0.11-0.41，p<0.00001)(1)。PCOS患者的胰岛素水平高，胰岛素能刺激黄体化颗粒细胞产生血管内皮生长因素，进而导致PCOS患者血管通透性增加，这是造成卵巢过度刺激综合征的主要原因。由于卵巢过度刺激综合征可能导致严重的并发症甚至死亡，当发现二甲双胍能降低胰岛素水平后，二甲双胍已经成为PCOS并伴有过度刺激综合征高风险患者必不可少的辅助药物。

　　Metformin also appears to improve the odds of pregnancy with ovarian stimulation in women with PCOS. Meta-analysis of 17 randomized clinical trials in POCS women has shown both increased ovulation (OR 4.39, CL 1.94-9.96) and pregnancy (OR 2.67, CL 1.54-4.94) when Met was added to clomiphene citrate (3). The effect was found to be statistically significant in obese women with PCOS (OR 10.9), whereas it failed to reach significance in non-obese women with this condition. It therefore seems logical to routinely use Met with clomiphene citrate in obese women with PCOS. Met has also been associated with an improved pregnancy rate in PCOS women having IVF (4), but when all randomized clinical trials were combined, the 29% higher pregnancy rate (only approximately 200 cycles total in each group) was not statistically significant (1). Because individual trials have achieved statistical significance, it is assumed that Met also improves the odds of pregnancy in PCOS women having IVF.

　　二甲双胍似乎还可以提高PCOS女性卵巢促排后的妊娠几率。对卵巢过度刺激综合征患者的17项随机临床试验的元分析发现，在克罗米芬的用药基础上添加二甲双胍后，促排结果(比值比4.39，置信水平1.96-9.96)和妊娠率(比值比2.67，置信水平1.54-4.94)都会增加(3)，这个差异在患有PCOS的肥胖女性中具有统计意义(比值比10.9)，但在非肥胖女性中却没有显著性。因此，对于PCOS肥胖患者，常规使用克罗米芬和二甲双胍是合理的。二甲双胍可能会提高PCOS患者的IVF妊娠率(4)，但结合所有随机临床试验结果看，妊娠率高出29%(每组总共仅约200个周期)却没有统计意义(1)。由于个别试验已经取得统计学意义，因此我们还是认为二甲双胍可以提高PCOS患者的IVF妊娠率。

　　The increased chance of implantation in PCOS women having ovarian stimulation is supported by studies showing decreased glycodelin, uterine blood flow, and HOXA-10 in women with PCOS, with significant improvement of these parameters with Met (5). These findings also may explain the increased rate of miscarriage in these women and the reduced fetal loss reported with Met. However, there are no randomized clinical trials in women continuing Met during early pregnancy to verify this latter benefit.

　　研究数据表明，PCOS女性在服用二甲双胍后，其糖蛋白、子宫血流和HOXA-10显著降低，说明她们胚胎着床的概率增加(5)。这些发现也可以解释为什么这些患者的流产率增加，但在服用二甲双胍后报告的流产率降低了。但是，目前还没有随机临床试验验证妊娠早期继续服用二甲双胍对降低流产率的益处。

　　Intraovarian androgen increases ovarian response by increasing FSH receptors on granulosa cells. Therefore Met may produce a more controlled ovarian response in PCOS women by reducing insulin stimulation of ovarian androgen production. In women who were clomiphene citrate-resistant, who also tend to be hyperinsulinemic, Met did reduce ovarian stimulation response for IVF (4). Also, in PCOS women receiving low-dose FSH, Met reduced the number of mature follicles (6). Recent studies have confirmed a relatively low incidence of ovulation and pregnancy with Met as a single agent, leading many to conclude that clomiphene citrate alone should be used in preference to a trial of Met alone. This approach may not take into account potential long-term benefits in reducing the sensitivity of the PCO ovary to stimulation.

　　卵巢内雄激素通过增加颗粒细胞上的FSH受体来增加卵巢反应。因此，二甲双胍可能通过减少胰岛素对卵巢雄激素产生的刺激，在PCOS患者中产生更可控的卵巢反应。对克罗米芬耐药的患者往往也伴有高胰岛素血症，二甲双胍确实降低了她们在IVF过程中的卵巢刺激反应(4)。另外，在接受低剂量FSH给药的PCOS患者中，二甲双胍减少了成熟卵泡的数量(6)。最新的研究证明，在促排过程中使用二甲双胍单一辅助药物后排卵和妊娠率相对较低，导致许多人得出结论，应优先使用克罗米芬，而不是单独使用二甲双胍。这种方法可能没有考虑到二甲双胍对降低多囊的卵巢对刺激敏感性的潜在长期益处。

　　References

　　参考文献

　　1.Castello MF, Chapman M, Conway U. A systematic review and meta-analysis of randomized controlled trials on metformin co-administration during gonadotrophin ovulation induction or IVF in women with polycystic ovary syndrome. Hum Reprod 2006;21:1387-1399.

　　2. Agrawal R, Jacobs H, Payne N, Conway G. Concentration of vascular endothelial growth factor released by cultured human luteinized granulosa cells is higher in women with polycystic ovaries than in women with normal ovaries. Fertil Steril 2002;78:1164-1169.

　　3. Creanga AA, Bradley HM, McCormick C, Witkop CT. Use of metformin in polycystic ovary syndrome: a meta-analysis. Obstet Gynecol 2008;111:959-968.

　　4. Stadtmauer LA, Toma SK, Riehl RM. Talbert LM. Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilization improves outcomes and is associated with modulation of insulin-like growth factors. Fertil Steril 2001;75:505-509.

　　5. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, Nestler JE. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:524-529.

　　6. De Leo V, Marca A, Ditto A, Morgante G, Cianci A. Effects of metformin on gonadotropin-inducedovulation in women with polycystic ovary syndrome. Fertil Steril 1999;72:282-285.