STUDY QUESTION Does ultra-long downregulation with a GnRH agonist (triptorelin depot) in previously operated patients with endometriosis improve the rate of clinical pregnancy with positive fetal heart beat (CPHB) in the subsequent initiated fresh ART cycle? SUMMARY ANSWER Ultra-long downregulation with a GnRH agonist prior to ART did not improve the rate of CPHB in the subsequent fresh ART cycle in previously completely operated patients but the trial was underpowered due to early termination. WHAT IS KNOWN ALREADY Administration of GnRH agonists for a period of 3–6 months prior to ART in women with endometriosis may increase the odds of clinical pregnancy. However, the quality of the studies on which this statement is based is questionable, so these findings need confirmation. STUDY DESIGN, SIZE, DURATION A controlled, randomized, open label trial was performed between 1 June 2013 and 31 December 2016 (start and end of recruitment, respectively). Patients with prior complete laparoscopic treatment of any type or stage of endometriosis and an indication for ART were randomized (by a computer-generated allocation sequence) into two groups: the control group underwent ART stimulation in a classical long agonist protocol using preparation with oral contraceptives, the ultra-long group first underwent at least 3 months downregulation followed by a long agonist protocol for ART stimulation. The sample size was calculated to detect a superiority of the ultra-long downregulation protocol, based on the hypothesis that baseline CPHB rate in the control group of 20% would increase to 40% in the ultra-long group. For a power of 20% at a significance level of 5%, based on two-sided testing, including 5% of patients lost to follow-up, the necessary sample size was 172 patients (86 per group). PARTICIPANTS/MATERIALS, SETTING, METHODS This trial was conducted at the Leuven University Fertility Center, a tertiary care center for endometriosis and infertility, and a total of 42 patients were randomized (21 in the control group and 21 in the ultra-long group). MAIN RESULTS AND THE ROLE OF CHANCE Baseline characteristics were similar in both groups. The primary outcome studied—CPHB after the initiated ART treatment—did not differ and was 25% (5/20) in the control group, and 20% (4/20) in the ultra-long group (P > 0.999; relative risk (RR) 1.25, 95% CI 0.41–3.88). Cumulative (fresh + associated frozen) CPHB rates were also similar in the control versus ultra-long group (8/20, 40% vs 6/20, 30%, P = 0.7411; RR = 1.33, 95% CI 0.57–3.19). When other secondary outcomes were compared with the ultra-long group, patients from the control group had a shorter duration of stimulation (mean 11.8 days (SD ± 2.4) versus 13.2 days (SD ± 1.5), P = 0.0373), a lower total dose of gonadotrophins used (mean 1793 IU/d (SD ± 787) vs 2329 (SD ± 680), P = 0.0154), and a higher serum estradiol concentration (ng/ml) at the end of ovarian stimulation on the day of ovulation triggering or cycle cancellation (mean1971 (SD ± 1495) vs 929 (± 548); P = 0.0326), suggesting a better ovarian response in the control group. LIMITATIONS, REASONS FOR CAUTION Due to a strong patient preference, nearly exclusively against ultra-long downregulation (even though patients were thoroughly informed of the potential benefits), the targeted sample size could not be achieved and the trial was stopped prematurely. WIDER IMPLICATIONS OF THE FINDINGS Conditional power analysis revealed that the probability of confirming the study hypothesis if the study were completed would be low. We hypothesize that in patients with prior complete surgical treatment of endometriosis, the ultra-long protocol does not enhance ART-CPHB rates. Patient’s concerns and preferences regarding possible side-effects, and delay of ART treatment start with the ultra-long protocol should be taken into account when considering this type of treatment in women with endometriosis. STUDY FUNDING/COMPETING INTEREST(S) C.T. was during 2 years funded by a grant from the Clinical research Foundation of UZ Leuven (KOF) and during 2 years by the Research Foundation—Flanders (FWO grant number: 1700816N). C.T. reports grants from Clinical Research Foundation of the University Hospitals of Leuven (KOF), grants from Fund for Scientific Research Flanders (FWO), during the conduct of the study; grants, non-financial support and other from Merck SA, non-financial support and other from Gedeon Richter, non-financial support from Ferring Pharmaceuticals, outside the submitted work. T.D. is vice president and head of Global Medical Affairs Fertility, Research and Development, Merck KGaA, Darmstadt, Germany. He is also a professor in Reproductive Medicine and Biology at the Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium and an adjunct professor at the Department of Obstetrics and Gynecology in the University of Yale, New Haven, USA. Neither his corporate role nor his academic roles represent a conflict of interest with respect to the work done by him for this study. A.C. reports personal fees from Merck S.p.A., outside the submitted work. The other co-authors have no conflict of interest. TRIAL REGISTRATION NUMBER UZ Leuven trial registry SS55300, EudraCT number 2013-000993-32, clinicaltrials.gov NCT02400801. TRIAL REGISTRATION DATE Registration for EudraCT on 1 March 2013. DATE OF FIRST PATIENT’S ENROLMENT 4 September 2013.

中文翻译：

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超长研究：一项评估子宫内膜异位症女性在 ART 前长期 GnRH 下调的随机对照试验

研究问题 在先前接受过手术的子宫内膜异位症患者中使用 GnRH 激动剂（曲普瑞林长效制剂）进行超长下调是否会提高随后启动的新 ART 周期中胎儿心跳阳性 (CPHB) 的临床妊娠率？总结 答案 在 ART 之前使用 GnRH 激动剂进行超长时间下调并没有提高先前完全手术患者在随后的新鲜 ART 周期中 CPHB 的发生率，但由于提前终止，该试验的效力不足。已知情况 ART 前 3-6 个月在子宫内膜异位症女性中使用 GnRH 激动剂可能会增加临床妊娠的几率。然而，该声明所依据的研究质量值得怀疑，因此这些发现需要确认。研究设计、规模、持续时间 开放标签试验于 2013 年 6 月 1 日至 2016 年 12 月 31 日期间进行（分别为招募开始和结束）。先前接受过任何类型或阶段的子宫内膜异位症的完整腹腔镜治疗并有 ART 适应症的患者被随机分为两组（通过计算机生成的分配顺序）：对照组接受 ART 刺激，采用经典的长激动剂方案，使用口服避孕药制剂，超长组首先经历了至少 3 个月的下调，然后是长期的 ART 刺激激动剂方案。样本量的计算是为了检测超长下调方案的优越性，这是基于对照组中 20% 的基线 CPHB 率将在超长组中增加到 40% 的假设。对于 20% 的功效，显着性水平为 5%，根据包括 5% 失访患者在内的双边测试，必要的样本量为 172 名患者（每组 86 名）。参与者/材料、地点、方法 本试验在鲁汶大学生育中心进行，该中心是子宫内膜异位症和不孕症的三级护理中心，共有 42 名患者被随机分组​​（对照组 21 名，超长组 21 名） . 主要结果和机会的作用 两组的基线特征相似。研究的主要结果——开始 ART 治疗后的 CPHB——没有差异，对照组为 25% (5/20)，超长组为 20% (4/20)（P > 0.999；相对风险 (RR) 1.25, 95% CI 0.41–3.88)。对照组与超长组的累积（新鲜 + 相关冷冻）CPHB 率也相似（8/20, 40% vs 6/20, 30%, P = 0.7411; RR = 1.33, 95% CI 0.57–3.19)。当其他次要结局与超长组进行比较时，对照组患者的刺激持续时间较短（平均 11.8 天 (SD ± 2.4) 对比 13.2 天 (SD ± 1.5)，P = 0.0373），总刺激时间较短使用的促性腺激素剂量（平均 1793 IU/d (SD ± 787) vs 2329 (SD ± 680)，P = 0.0154），以及排卵日卵巢刺激结束时更高的血清雌二醇浓度 (ng/ml)触发或周期取消（平均 1971 (SD ± 1495) vs 929 (± 548)；P = 0.0326），表明对照组的卵巢反应更好。限制，谨慎的原因由于患者强烈的偏好，几乎完全反对超长时间下调（即使患者被彻底告知潜在的好处），无法达到目标样本量，试验提前终止。研究结果的更广泛意义 条件功效分析表明，如果研究完成，确认研究假设的可能性很低。我们假设在先前接受过子宫内膜异位症完全手术治疗的患者中，超长方案不会提高 ART-CPHB 率。在考虑对患有子宫内膜异位症的女性进行此类治疗时，应考虑患者对可能的副作用的担忧和偏好，以及从超长方案开始 ART 治疗的延迟。研究资助/竞争兴趣 CT 在 2 年内由 UZ Leuven (KOF) 临床研究基金会资助，在 2 年内由研究基金会 - 法兰德斯 (FWO 资助号：1700816N) 资助。电脑断层扫描 在研究进行期间报告鲁汶大学医院 (KOF) 临床研究基金会的赠款，法兰德斯科学研究基金 (FWO) 的赠款；Merck SA 的赠款、非财务支持和其他、Gedeon Richter 的非财务支持和其他、Ferring Pharmaceuticals 的非财务支持，在提交的工作之外。TD 是德国达姆施塔特默克公司的副总裁兼全球医疗事务生育、研发负责人。他还是比利时鲁汶大学（鲁汶大学）发育与再生、集团生物医学科学系生殖医学和生物学教授，以及纽黑文耶鲁大学妇产科兼职教授， 美国。就他为本研究所做的工作而言，他的公司角色和学术角色均不代表利益冲突。AC 报告 Merck SpA 提交的工作之外的个人费用。其他合著者没有利益冲突。试验注册号 UZ Leuven 试验注册 SS55300，EudraCT 号 2013-000993-32，clinicaltrials.gov NCT02400801。试用注册日期 EudraCT 的注册日期为 2013 年 3 月 1 日。第一位患者的注册日期为 2013 年 9 月 4 日。