International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou 310014, China.
Hum Reprod Update. 2020 Feb 28;26(2):247-263. doi: 10.1093/humupd/dmz046.
Despite great advances in assisted reproductive technology, poor ovarian response (POR) is still considered as one of the most challenging tasks in reproductive medicine.
The aim of this systemic review is to evaluate the role of different adjuvant treatment strategies on the probability of pregnancy achievement in poor responders undergoing IVF. Randomized controlled trials (RCTs) comparing 10 adjuvant treatments [testosterone, dehydroepiandrosterone (DHEA), letrozole, recombinant LH, recombinant hCG, oestradiol, clomiphene citrate, progesterone, growth hormone (GH) and coenzyme Q10 (CoQ10)] were included.
Relevant studies published in the English language were comprehensively selected using PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) until 11 July 2018. We included studies that investigated various adjuvant agents, including androgen and androgen-modulating agents, oestrogen, progesterone, clomiphene citrate, GH and CoQ10, during IVF treatment and reported subsequent pregnancy outcomes. The administration of GnRH analogs and gonadotrophins without adjuvant treatment was set as the control. We measured study quality based on the methodology and categories listed in the Cochrane Collaboration Handbook. This review protocol was registered with PROSPERO (CRD42018086217).
Of the 1124 studies initially identified, 46 trials reporting on 6312 women were included in this systematic review, while 19 trials defining POR using the Bologna criteria reporting 2677 women were included in the network meta-analysis. Compared with controls, DHEA and CoQ10 treatments resulted in a significantly higher chance of clinical pregnancy [odds ratio (OR) 2.46, 95% CI 1.16 to 5.23; 2.22, 1.08-4.58, respectively]. With regard to the number of retrieved oocytes, HCG, oestradiol and GH treatments had the highest number of oocytes retrieved [weighted mean difference (WMD) 2.08, 0.72 to 3.44; 2.02, 0.23 to 3.81; 1.72, 0.98 to 2.46, compared with controls, respectively]. With regard to the number of embryos transferred, testosterone and GH treatment led to the highest number of embryos transferred (WMD 0.72, 0.11 to 1.33; 0.67, 0.43 to 0.92; compared with controls, respectively). Moreover, GH resulted in the highest oestradiol level on the HCG day (WMD 797.63, 466.45 to 1128.81, compared with controls). Clomiphene citrate, letrozole and GH groups used the lowest dosages of gonadotrophins for ovarian stimulation (WMD 1760.00, -2890.55 to -629.45; -1110.17, -1753.37 to -466.96; -875.91, -1433.29 to -282.52; compared with controls, respectively). CoQ10 led to the lowest global cancelation rate (OR 0.33, 0.15 to 0.74, compared with controls).
For patients with POR, controlled ovarian stimulation protocols using adjuvant treatment with DHEA, CoQ10 and GH showed better clinical outcomes in terms of achieving pregnancy, and a lower dosage of gonadotrophin required for ovulation induction. Furthermore, high-level RCT studies using uniform standards for POR need to be incorporated into future meta-analyses.
尽管辅助生殖技术取得了巨大进展，但卵巢反应不良（POR）仍然被认为是生殖医学中最具挑战性的任务之一。
本系统评价的目的是评估在接受 IVF 的 POR 患者中，使用不同辅助治疗策略对妊娠成功率的影响。纳入了 10 种辅助治疗方法（睾酮、脱氢表雄酮（DHEA）、来曲唑、重组 LH、重组 hCG、雌二醇、枸橼酸氯米酚、孕酮、生长激素（GH）和辅酶 Q10（CoQ10））的随机对照试验（RCT）。
全面检索了 PubMed、Embase 和 Cochrane 中心对照试验注册库（CENTRAL），直到 2018 年 7 月 11 日，检索了用英语发表的相关研究。纳入了研究各种辅助药物的研究，包括雄激素和雄激素调节剂、雌激素、孕酮、枸橼酸氯米酚、GH 和 CoQ10，在 IVF 治疗中，并报告了随后的妊娠结局。将 GnRH 类似物和促性腺激素的给药作为对照。我们根据 Cochrane 协作手册中的方法和类别来衡量研究质量。本研究方案已在 PROSPERO（CRD42018086217）上注册。
最初确定的 1124 项研究中，有 46 项试验（6312 名女性）纳入本系统评价，19 项试验（2677 名女性）采用博洛尼亚标准定义 POR 纳入网络荟萃分析。与对照组相比，DHEA 和 CoQ10 治疗显著增加了妊娠的机会[优势比（OR）2.46，95%置信区间（CI）1.16 至 5.23；2.22，1.08 至 4.58]。在取卵数量方面，HCG、雌二醇和 GH 治疗取卵数量最多[加权均数差（WMD）2.08，0.72 至 3.44；2.02，0.23 至 3.81；1.72，0.98 至 2.46，与对照组相比，分别]。在胚胎移植数量方面，睾酮和 GH 治疗导致胚胎移植数量最高（WMD 0.72，0.11 至 1.33；0.67，0.43 至 0.92；与对照组相比，分别）。此外，GH 导致 HCG 日雌二醇水平最高（WMD 797.63，466.45 至 1128.81，与对照组相比）。氯米酚、来曲唑和 GH 组使用的促性腺激素剂量最低（WMD 1760.00，-2890.55 至-629.45；-1110.17，-1753.37 至-466.96；-875.91，-1433.29 至-282.52；与对照组相比，分别）。CoQ10 导致全球取消率最低（OR 0.33，0.15 至 0.74，与对照组相比）。
对于 POR 患者，使用 DHEA、CoQ10 和 GH 进行控制性卵巢刺激方案可提高妊娠成功率，并降低促排卵所需的促性腺激素剂量。此外，需要纳入使用统一 POR 标准的高质量 RCT 研究进行未来的荟萃分析。
