van der Linden Michelle, Buckingham Karen, Farquhar Cindy, Kremer Jan A M, Metwally Mostafa
Department of Obstetrics and Gynaecology, Radboud University Medical Center, PO Box 9101, Nijmegen, Netherlands, 6500 HB.
Cochrane Database Syst Rev. 2015 Jul 7;2015(7):CD009154. doi: 10.1002/14651858.CD009154.pub3.
Progesterone prepares the endometrium for pregnancy by stimulating proliferation in response to human chorionic gonadotropin(hCG) produced by the corpus luteum. This occurs in the luteal phase of the menstrual cycle. In assisted reproduction techniques(ART), progesterone and/or hCG levels are low, so the luteal phase is supported with progesterone, hCG or gonadotropin-releasing hormone (GnRH) agonists to improve implantation and pregnancy rates.
To determine the relative effectiveness and safety of methods of luteal phase support provided to subfertile women undergoing assisted reproduction.
We searched databases including the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and trial registers. We conducted searches in November 2014, and further searches on 4 August 2015.
Randomised controlled trials (RCTs) of luteal phase support using progesterone, hCG or GnRH agonist supplementation in ART cycles.
Three review authors independently selected trials, extracted data and assessed risk of bias. We calculated odds ratios (ORs) and 95%confidence intervals (CIs) for each comparison and combined data when appropriate using a fixed-effect model. Our primary out come was live birth or ongoing pregnancy. The overall quality of the evidence was assessed using GRADE methods.
Ninety-four women RCTs (26,198 women) were included. Most studies had unclear or high risk of bias in most domains. The main limitations in the evidence were poor reporting of study methods and imprecision due to small sample sizes.1. hCG vs placebo/no treatment (five RCTs, 746 women)There was no evidence of differences between groups in live birth or ongoing pregnancy (OR 1.67, 95% CI 0.90 to 3.12, three RCTs,527 women, I2 = 24%, very low-quality evidence, but I2 of 61% was found for the subgroup of ongoing pregnancy) with a random effects model. hCG increased the risk of ovarian hyperstimulation syndrome (OHSS) (1 RCT, OR 4.28, 95% CI 1.91 to 9.6, low quality evidence).2. Progesterone vs placebo/no treatment (eight RCTs, 875 women)Evidence suggests a higher rate of live birth or ongoing pregnancy in the progesterone group (OR 1.77, 95% CI 1.09 to 2.86, five RCTs, 642 women, I2 = 35%, very low-quality evidence). OHSS was not reported.3. Progesterone vs hCG regimens (16 RCTs, 2162 women)hCG regimens included comparisons of progesterone versus hCG and progesterone versus progesterone + hCG. No evidence showed differences between groups in live birth or ongoing pregnancy (OR 0.95, 95% CI 0.65 to 1.38, five RCTs, 833 women, I2 = 0%, low quality evidence) or in the risk of OHSS (four RCTs, 615 women, progesterone vs hCG OR 0.54, 95% CI 0.22 to 1.34; four RCTs,678 women; progesterone vs progesterone plus hCG, OR 0.34, 95% CI 0.09 to 1.26, low-quality evidence).4. Progesterone vs progesterone with oestrogen (16 RCTs, 2577 women)No evidence was found of differences between groups in live birth or ongoing pregnancy (OR 1.12, 95% CI 0.91 to 1.38, nine RCTs,1651 women, I2 = 0%, low-quality evidence) or OHSS (OR 0.56, 95% CI 0.2 to 1.63, two RCTs, 461 women, I2 = 0%, low-quality evidence).5. Progesterone vs progesterone + GnRH agonist (seven RCTs, 1708 women)Live birth or ongoing pregnancy rates were lower in the progesterone-only group and increased in women who received progester one and one or more GnRH agonist doses (OR 0.62, 95% CI 0.48 to 0.81, nine RCTs, 2861 women, I2 = 55%, random effects, low quality evidence). Statistical heterogeneity for this comparison was high because of unexplained variation in the effect size, but the direction of effect was consistent across studies. OHSS was reported in one study only (OR 1.00, 95% CI 0.33 to 3.01, 1 RCT, 300 women, very low quality evidence).6. Progesterone regimens (45 RCTs, 13,814 women)The included studies reported nine different comparisons between progesterone regimens. Findings for live birth or ongoing pregnancy were as follows: intramuscular (IM) versus oral: OR 0.71, 95% CI 0.14 to 3.66 (one RCT, 40 women, very low-quality evidence);IM versus vaginal/rectal: OR 1.24, 95% CI 1.03 to 1.5 (seven RCTs, 2309 women, I2 = 71%, very low-quality evidence); vaginal/rectal versus oral: OR 1.19, 95% CI 0.83 to 1.69 (four RCTs, 857 women, I2 = 32%, low-quality evidence); low-dose versus high-dose vaginal: OR 0.97, 95% CI 0.84 to 1.11 (five RCTs, 3720 women, I2 = 0%, moderate-quality evidence); short versus long protocol:OR 1.04, 95% CI 0.79 to 1.36 (five RCTs, 1205 women, I2 = 0%, low-quality evidence); micronised versus synthetic: OR 0.9, 95%CI 0.53 to 1.55 (two RCTs, 470 women, I2 = 0%, low-quality evidence); vaginal ring versus gel: OR 1.09, 95% CI 0.88 to 1.36 (oneRCT, 1271 women, low-quality evidence); subcutaneous versus vaginal gel: OR 0.92, 95% CI 0.74 to 1.14 (two RCTs, 1465 women,I2 = 0%, low-quality evidence); and vaginal versus rectal: OR 1.28, 95% CI 0.64 to 2.54 (one RCT, 147 women, very low-quality evidence). OHSS rates were reported for only two of these comparisons: IM versus oral, and low versus high-dose vaginal. No evidence showed a difference between groups.7. Progesterone and oestrogen regimens (two RCTs, 1195 women)The included studies compared two different oestrogen protocols. No evidence was found to suggest differences in live birth or ongoing pregnancy rates between a short and a long protocol (OR 1.08, 95% CI 0.81 to 1.43, one RCT, 910 women, low-quality evidence) or between a low dose and a high dose of oestrogen (OR 0.65, 95% CI 0.37 to 1.13, one RCT, 285 women, very low-quality evidence).Neither study reported OHSS.
AUTHORS' CONCLUSIONS: Both progesterone and hCG during the luteal phase are associated with higher rates of live birth or ongoing pregnancy than placebo.The addition of GnRHa to progesterone is associated with an improvement in pregnancy outcomes. OHSS rates are increased with hCG compared to placebo (only study only). The addition of oestrogen does not seem to improve outcomes. The route of progester one administration is not associated with an improvement in outcomes.
孕酮通过响应黄体产生的人绒毛膜促性腺激素（hCG）刺激子宫内膜增殖，为妊娠做好准备。这发生在月经周期的黄体期。在辅助生殖技术（ART）中，孕酮和/或hCG水平较低，因此使用孕酮、hCG或促性腺激素释放激素（GnRH）激动剂来支持黄体期，以提高着床率和妊娠率。
确定为接受辅助生殖的亚生育力女性提供黄体期支持方法的相对有效性和安全性。
我们检索了多个数据库，包括Cochrane月经紊乱与亚生育力小组（MDSG）专业注册库、Cochrane对照试验中央注册库（CENTRAL）、MEDLINE、EMBASE、PsycINFO以及试验注册库。我们在2014年11月进行了检索，并于2015年8月4日进行了进一步检索。
ART周期中使用孕酮、hCG或GnRH激动剂补充进行黄体期支持的随机对照试验（RCT）。
三位综述作者独立选择试验、提取数据并评估偏倚风险。我们计算了每个比较的比值比（OR）和95%置信区间（CI），并在适当情况下使用固定效应模型合并数据。我们的主要结局是活产或持续妊娠。使用GRADE方法评估证据的总体质量。
纳入了94项女性RCT（26,198名女性）。大多数研究在大多数领域的偏倚风险不明确或较高。证据的主要局限性在于研究方法报告不佳以及样本量小导致的不精确性。
采用随机效应模型时，未发现两组在活产或持续妊娠方面存在差异（OR 1.67，95%CI 0.90至3.12，3项RCT，527名女性，I² = 24%，极低质量证据，但持续妊娠亚组的I²为61%）。hCG增加了卵巢过度刺激综合征（OHSS）的风险（1项RCT，OR 4.28，95%CI 1.91至9.6，低质量证据）。
证据表明孕酮组的活产或持续妊娠率更高（OR 1.77，95%CI 1.09至2.86，5项RCT，642名女性，I² = 35%，极低质量证据）。未报告OHSS情况。
hCG方案包括孕酮与hCG以及孕酮与孕酮 + hCG的比较。未发现两组在活产或持续妊娠方面存在差异（OR 0.95，95%CI 0.65至1.38，5项RCT，833名女性，I² = 0%，低质量证据），也未发现OHSS风险存在差异（4项RCT，615名女性，孕酮与hCG，OR 0.54，95%CI 0.22至1.34；4项RCT（678名女性）；孕酮与孕酮加hCG，OR 0.34，95%CI 0.09至1.26，低质量证据）。
未发现两组在活产或持续妊娠方面存在差异（OR 1.12，95%CI 0.91至1.38，9项RCT，1651名女性，I² = 0%，低质量证据）或OHSS方面存在差异（OR 0.56，95%CI 0.2至1.63，2项RCT，461名女性，I² = 0%，低质量证据）。
仅接受孕酮治疗的组活产或持续妊娠率较低，而接受孕酮和一剂或多剂GnRH激动剂的女性活产或持续妊娠率增加（OR 0.62，95%CI 0.48至0.81，9项RCT，2861名女性，I² = 55%，随机效应，低质量证据）。由于效应大小存在无法解释的差异，该比较的统计异质性较高，但各研究的效应方向一致。仅在一项研究中报告了OHSS情况（OR 1.00，95%CI 0.33至3.01，1项RCT，300名女性，极低质量证据）。
纳入的研究报告了孕酮方案之间的九种不同比较。活产或持续妊娠的结果如下：肌肉注射（IM）与口服：OR 0.71，95%CI 0.14至3.66（1项RCT，40名女性，极低质量证据）；IM与阴道/直肠：OR 1.24，95%CI 1.03至1.5（7项RCT，2309名女性，I² = 71%，极低质量证据）；阴道/直肠与口服：OR 1.19，95%CI 0.83至1.69（4项RCT，857名女性，I² = 32%，低质量证据）；低剂量与高剂量阴道：OR 0.97，95%CI 0.84至1.11（5项RCT，3720名女性，I² = 0%，中等质量证据）；短方案与长方案：OR 1.04，95%CI 0.79至1.36（5项RCT，1205名女性，I² = 0%，低质量证据）；微粒化与合成：OR 0.9，95%CI 0.53至1.55（2项RCT，470名女性，I² = 0%，低质量证据）；阴道环与凝胶：OR 1.09，95%CI 0.88至1.36（1项RCT，1271名女性，低质量证据）；皮下与阴道凝胶：OR 0.92，95%CI 0.74至1.14（2项RCT，1465名女性，I² = 0%，低质量证据）；阴道与直肠：OR 1.28，95%CI 0.64至2.54（1项RCT，147名女性，极低质量证据）。这些比较中仅两项报告了OHSS发生率。未发现两组之间存在差异。
纳入的研究比较了两种不同的雌激素方案。未发现短方案和长方案之间（OR 1.08，95%CI 0.81至1.43，1项RCT，910名女性，低质量证据）或低剂量和高剂量雌激素之间（OR 0.65，95%CI 至1.13，1项RCT，285名女性，极低质量证据）在活产或持续妊娠率方面存在差异。两项研究均未报告OHSS情况。
黄体期使用孕酮和hCG与比安慰剂更高的活产或持续妊娠率相关。在孕酮中添加GnRHa与妊娠结局改善相关。与安慰剂相比，hCG会增加OHSS发生率（仅一项研究）。添加雌激素似乎并未改善结局。孕酮的给药途径与结局改善无关。
