BACKGROUND Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALE We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODS We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMES IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06). WIDER IMPLICATIONS In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.

中文翻译：

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多囊卵巢综合征的一线排卵诱导：个体参与者数据荟萃分析。

背景技术多囊卵巢综合征（PCOS）是无排卵性不孕的最常见原因。对于患有PCOS的女性，有效的排卵诱导是无排卵性不孕症的重要一线治疗。个体参与者数据（IPD）荟萃分析被认为是证据综合的金标准，它可以提供对主要随机对照试验（RCT）的结果的准确评估，并允许对事件至事件的时间进行其他分析。它还有助于进行治疗-协变量相互作用分析，因此为个性化医学提供了机会。目的和理由我们的目的是评估与单独使用CC相比，不同的排卵诱导剂，特别是单独的来曲唑和柠檬酸克罗米芬（CC）加二甲双胍的有效性，作为PCOS和不育症女性排卵诱导的一线选择，并探讨治疗与参与者水平基线特征之间的相互作用。搜索方法我们搜索了截至2018年12月20日的电子数据库，包括MEDLINE，EMBASE和Cochrane对照试验中心登记册。纳入的RCT比较了以下干预措施或安慰剂/不治疗PCOS和不育女性的以下干预措施：CC，二甲双胍，CC加上二甲双胍，来曲唑，促性腺激素和他莫昔芬。我们排除了对抗药性女性的研究。主要结局是活产。我们联系了符合条件的RCT的研究人员，以共享IPD并进行了IPD荟萃分析。我们通过对RCT使用Cochrane偏倚风险工具评估了偏倚风险。获得了包括3962名PCOS妇女在内的20项RCT的结果IPD。六个RCT比较了1284名妇女的来曲唑和CC。与CC相比，来曲唑提高了活产率（3例RCT，1043名妇女，风险比[RR] 1.43，95％置信区间[CI] 1.17-1.75，中度确定性证据）和临床妊娠率（6例RCT，1284名妇女， RR 1.45，95％CI 1.23-1.70，中等确定性证据）和缩短怀孕时间（6例RCT，1235名女性，危险比[HR] 1.72，95％CI 1.38-2.15，中等确定性证据）。效果修改的荟萃分析显示，基线血清总睾丸激素水平与活产的治疗效果之间存在正相关（交互作用RR 1.29，95％CI 1.01-1.65）。八个RCT比较了1039名妇女的CC和二甲双胍与单纯CC的比较。与CC相比，CC加二甲双胍可能会提高临床妊娠率（8例RCT，1039名妇女，RR 1.18，95％CI 1.00-1.39，低确定性证据），并可能缩短怀孕时间（7例RCT，898例女性，HR 1.25，95％ CI 1.00-1.57，低确定性证据），但没有足够的证据表明活产率存在差异（5个RCT，907名妇女，RR 1.08，95％CI 0.87-1.35，低确定性证据）。效果改善的荟萃分析显示，在CC加二甲双胍和CC之间的比较中，基线胰岛素水平与活产的治疗效果之间存在正相互作用（相互作用RR 1.03，95％CI 1.01-1.06）。对PCOS患者的影响与CC相比，来曲唑改善了活产和临床妊娠率，缩短了怀孕时间，因此可被推荐作为PCOS和不育症患者的首选一线治疗。与单独使用CC相比，CC加二甲双胍可能会增加临床妊娠并可能缩短怀孕时间，而没有足够的证据表明活产有差异。来曲唑的治疗效果受血清总睾丸激素水平的影响，而CC加二甲双胍的治疗效果受胰岛素血清水平的影响。高雄激素血症和胰岛素抵抗的治疗方法和生物标志物之间的这些相互作用为了解与PCOS相关的无排卵性不孕症的个性化治疗方法提供了进一步的见解。而CC加二甲双胍的那些则受基线血清胰岛素水平的影响。高雄激素血症和胰岛素抵抗的治疗方法和生物标志物之间的这些相互作用为了解与PCOS相关的无排卵性不孕症的个性化治疗方法提供了进一步的见解。而CC加二甲双胍的那些则受基线血清胰岛素水平的影响。高雄激素血症和胰岛素抵抗的治疗方法和生物标志物之间的这些相互作用为了解与PCOS相关的无排卵性不孕症的个性化治疗方法提供了进一步的见解。