Weiss Nienke S, Kostova Elena, Nahuis Marleen, Mol Ben Willem J, van der Veen Fulco, van Wely Madelon
Center for Reproductive Medicine, Amsterdam UMC, Free Medical University, De Boelelaan 1105, Amsterdam, Netherlands, 1081 HV.
Cochrane Database Syst Rev. 2019 Jan 16;1(1):CD010290. doi: 10.1002/14651858.CD010290.pub3.
Ovulation induction with follicle stimulating hormone (FSH) is a second-line treatment in women with polycystic ovary syndrome (PCOS) who do not ovulate or conceive on clomiphene citrate.
To compare the effectiveness and safety of gonadotrophins as a second-line treatment for ovulation induction in women with clomiphene citrate-resistant polycystic ovary syndrome (PCOS), and women who do not ovulate or conceive after clomiphene citrate.
In January 2018, we searched the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, the World Health Organisation clinical trials register, Clinicaltrials.gov, LILACs, and PubMed databases, and Google Scholar. We checked references of in all obtained studies. We had no language restrictions.
All randomised controlled trials reporting data on clinical outcomes in women with PCOS who did not ovulate or conceive on clomiphene citrate, and undergoing ovulation induction with urinary-derived gonadotrophins, including urofollitropin (uFSH) in purified FSH (FSH-P) or highly purified FSH (FSH-HP) form, human menopausal gonadotropin (HMG) and highly purified human menopausal gonadotrophin (HP-HMG), or recombinant FSH (rFSH), or continuing clomiphene citrate. We included trials reporting on ovulation induction followed by intercourse or intrauterine insemination. We excluded studies that described co-treatment with clomiphene citrate, metformin, luteinizing hormone, or letrozole.
Three review authors (NW, EK, and MvW) independently selected studies for inclusion, assessed risk of bias, and extracted study data. Primary outcomes were live birth rate per woman and multiple pregnancy per woman. Secondary outcomes were clinical pregnancy, miscarriage, incidence of ovarian hyperstimulation syndrome (OHSS) per woman, total gonadotrophin dose, and total duration of stimulation per woman. We combined data using a fixed-effect model to calculate the risk ratio (RR). We summarised the overall quality of evidence for the main outcomes using GRADE criteria.
The review included 15 trials with 2387 women. Ten trials compared rFSH with urinary-derived gonadotrophins (three compared rFSH with human menopausal gonadotrophin, and seven compared rFSH with FSH-HP), four trials compared FSH-P with HMG. We found no trials that compared FSH-HP with FSH-P. One trial compared FSH with continued clomiphene citrate.Recombinant FSH (rFSH) versus urinary-derived gonadotrophinsThere may be little or no difference in the birth rate between rFSH and urinary-derived gonadotrophins (RR 1.21, 95% confidence interval (CI) 0.83 to 1.78; five trials, N = 505; I² = 9%; low-quality evidence). This suggests that for the observed average live birth per woman who used urinary-derived FSH of 16%, the chance of live birth with rFSH is between 13% and 28%. There may also be little or no difference between groups in incidence of multiple pregnancy (RR 0.86, 95% CI 0.46 to 1.61; eight trials, N = 1368; I² = 0%; low-quality evidence), clinical pregnancy rate (RR 1.05, 95% CI 0.88 to 1.27; eight trials, N = 1330; I² = 0; low-quality evidence), or miscarriage rate (RR 1.20, 95% CI 0.71 to 2.04; seven trials, N = 970; I² = 0; low-quality evidence). We are uncertain whether rFSH reduces the incidence of OHSS (RR 1.48, 95% CI 0.82 to 2.65, ten trials, n=1565, I² = 0%, very low-quality evidence).Human menopausal gonadotrophin (HMG) or HP-HMG versus uFSHWhen compared to uFSH, we are uncertain whether HMG or HP-HMG improves live birth rate (RR 1.28, 95% CI 0.65 to 2.52; three trials, N = 138; I² = 0%; very low quality evidence), or reduces multiple pregnancy rate (RR 2.13, 95% CI 0.51 to 8.91; four trials, N = 161; I² = 0%; very low quality evidence). We are also uncertain whether HMG or HP-HMG improves clinical pregnancy rate (RR 1.31, 95% CI 0.66 to 2.59; three trials, N = 102; I² = 0; very low quality evidence), reduces miscarriage rate (RR 0.33, 95% CI 0.06 to 1.97; two trials, N = 98; I² = 0%; very low quality evidence), or reduces the incidence of OHSS (RR 7.07, 95% CI 0.42 to 117.81; two trials, N = 53; very low quality evidence) when compared to uFSH.Gonadotrophins versus continued clomiphene citrateGonadotrophins resulted in more live births than continued clomiphene citrate (RR 1.24, 95% CI 1.05 to 1.46; one trial, N = 661; I² = 0%; moderate-quality evidence). This suggests that for a woman with a live birth rate of 41% with continued clomiphene citrate, the live birth rate with FSH was between 43% and 60%. There is probably little or no difference in the incidence of multiple pregnancy between treatments (RR 0.89, 95% CI 0.33 to 2.44; one trial, N = 661; I² = 0%; moderate-quality evidence). Gonadotrophins resulted in more clinical pregnancies than continued clomiphene citrate (RR 1.31, 95% CI 1.13 to 1.52; one trial, N = 661; I² = 0%; moderate-quality evidence), and more miscarriages (RR 2.23, 95% CI 1.11 to 4.47; one trial, N = 661; I² = 0%; moderate-quality evidence). None of the women developed OHSS.
AUTHORS' CONCLUSIONS: There may be little or no difference in live birth, incidence of multiple pregnancy, clinical pregnancy rate, or miscarriage rate between urinary-derived gonadotrophins and recombinant follicle stimulating hormone in women with polycystic ovary syndrome. For human menopausal gonadotropin or highly purified human menopausal gonadotrophin versus urinary follicle stimulating hormone we are uncertain whether one or the other improves or lowers live birth, incidence of multiple pregnancy, clinical pregnancy rate, or miscarriage rate. We are uncertain whether any of the interventions reduce the incidence of ovarian hyperstimulation syndrome. We suggest weighing costs and convenience in the decision to use one or the other gonadotrophin. In women with clomiphene citrate failure, gonadotrophins resulted in more live births than continued clomiphene citrate without increasing multiple pregnancies.
对于使用枸橼酸氯米芬后仍不排卵或未受孕的多囊卵巢综合征（PCOS）女性，使用促卵泡生成素（FSH）进行促排卵是二线治疗方法。
比较促性腺激素作为二线治疗药物，对枸橼酸氯米芬抵抗的多囊卵巢综合征（PCOS）女性以及使用枸橼酸氯米芬后不排卵或未受孕女性进行促排卵的有效性和安全性。
2018年1月，我们检索了Cochrane妇科和生育组专业对照试验注册库、CENTRAL、MEDLINE、Embase、PsycINFO、CINAHL、世界卫生组织临床试验注册库、Clinicaltrials.gov、LILACs和PubMed数据库以及谷歌学术。我们检查了所有纳入研究的参考文献。我们没有语言限制。
所有随机对照试验，报告了使用枸橼酸氯米芬后不排卵或未受孕的PCOS女性，使用尿源性促性腺激素进行促排卵的数据，包括纯化FSH（FSH-P）或高度纯化FSH（FSH-HP）形式的尿促卵泡素（uFSH）、人绝经期促性腺激素（HMG）和高度纯化人绝经期促性腺激素（HP-HMG）、重组FSH（rFSH），或继续使用枸橼酸氯米芬。我们纳入了报告促排卵后进行性交或宫内人工授精的试验。我们排除了描述与枸橼酸氯米芬、二甲双胍、促黄体生成素或来曲唑联合治疗的研究。
三位综述作者（NW、EK和MvW）独立选择纳入研究、评估偏倚风险并提取研究数据。主要结局是每位女性的活产率和每位女性的多胎妊娠率。次要结局是临床妊娠、流产、每位女性卵巢过度刺激综合征（OHSS）的发生率、促性腺激素总剂量以及每位女性的总刺激持续时间。我们使用固定效应模型合并数据以计算风险比（RR）。我们使用GRADE标准总结主要结局的总体证据质量。
该综述纳入了15项试验，共2387名女性。10项试验比较了rFSH与尿源性促性腺激素（3项试验比较了rFSH与人绝经期促性腺激素，7项试验比较了rFSH与FSH-HP），4项试验比较了FSH-P与HMG。我们未发现比较FSH-HP与FSH-P的试验。1项试验比较了FSH与继续使用枸橼酸氯米芬。重组FSH（rFSH）与尿源性促性腺激素相比rFSH与尿源性促性腺激素之间的出生率可能几乎没有差异或无差异（RR 1.21，95%置信区间（CI）0.83至1.78；5项试验；N = 505；I² = 9%；低质量证据）。这表明，对于观察到的使用尿源性FSH的女性平均活产率为16%，使用rFSH的活产机会在13%至28%之间。两组在多胎妊娠发生率（RR 0.86，95% CI 0.46至1.61；8项试验；N = 1368；I² = 0%；低质量证据）、临床妊娠率（RR 1.05，95% CI 0.88至1.27；8项试验；N = 1330；I² = 0；低质量证据）或流产率（RR 1.20，95% CI 0.71至2.04；7项试验；N = 970；I² = 0；低质量证据）方面可能也几乎没有差异或无差异。我们不确定rFSH是否会降低OHSS的发生率（RR 1.48，95% CI 0.82至2.65；10项试验；n = 1565；I² = 0%；极低质量证据）。人绝经期促性腺激素（HMG）或HP-HMG与uFSH相比与uFSH相比，我们不确定HMG或HP-HMG是否能提高活产率（RR 1.28，95% CI 0.65至2.52；3项试验；N = 138；I² = 0%；极低质量证据），或降低多胎妊娠率（RR 2.13，95% CI 0.51至8.91；4项试验；N = 161；I² = 0%；极低质量证据）。我们也不确定HMG或HP-HMG与uFSH相比是否能提高临床妊娠率（RR 1.31，95% CI 0.66至2.59；3项试验；N = 102；I² = 0；极低质量证据），降低流产率（RR 0.33，95% CI从0.06至1.97；2项试验；N = 98；I² = 0%；极低质量证据），或降低OHSS的发生率（RR 7.07，95% CI 0.42至117.81；2项试验；N = 53；极低质量证据）。促性腺激素与继续使用枸橼酸氯米芬相比促性腺激素导致的活产数比继续使用枸橼酸氯米芬更多（RR 1.24，95% CI 1.05至1.46；1项试验；N = 661；I² = 0%；中等质量证据）。这表明，对于继续使用枸橼酸氯米芬活产率为41%的女性，使用FSH的活产率在43%至60%之间。各治疗组之间的多胎妊娠发生率可能几乎没有差异或无差异（RR 0.89，95% CI 0.33至2.44；1项试验；N = 661；I² = 0%；中等质量证据）。促性腺激素导致的临床妊娠比继续使用枸橼酸氯米芬更多（RR 1.31，95% CI 1.13至1.52；一项试验；N = 661；I² = 0%；中等质量证据），流产也更多（RR 2.23，95% CI 1.11至4.47；一项试验；N = 661；I² = 0%；中等质量证据）。没有女性发生OHSS。
在多囊卵巢综合征女性中，尿源性促性腺激素与重组促卵泡生成素在活产率、多胎妊娠发生率、临床妊娠率或流产率方面可能几乎没有差异或无差异。对于人绝经期促性腺激素或高度纯化人绝经期促性腺激素与尿促卵泡素相比，我们不确定哪一种能提高或降低活产率、多胎妊娠发生率、临床妊娠率或流产率。我们不确定任何一种干预措施是否能降低卵巢过度刺激综合征的发生率。我们建议在决定使用哪种促性腺激素时权衡成本和便利性。在枸橼酸氯米芬治疗失败的女性中，促性腺激素比继续使用枸橼酸氯米芬导致更多活产，且不增加多胎妊娠。
