{"paper_id":"734fbf76-643b-441a-ac6a-5d83d712dbe9","body_text":"ARTICLE IN PRESS\nArticle in Press\nEfficacy of different pretreatments in IVF \noutcomes in patients with endometriosis: A \nsystematic review and network meta‑analysis\nScientific Reports\nReceived: 20 November 2025\nAccepted: 8 May 2026\nCite this article as: Li D., Zheng L., \nZhang X. et al. Efficacy of different \npretreatments in IVF outcomes \nin patients with endometriosis: \nA systematic review and network \nmeta‑analysis. Sci Rep (2026). https://\ndoi.org/10.1038/s41598‑026‑52918‑5\nDan Li, Lianwen Zheng, Xueying Zhang, Wei Wang, Jingshun Zhang & Lulu Fu\nWe are providing an unedited version of this manuscript to give early access to its \nfindings. Before final publication, the manuscript will undergo further editing. Please \nnote there may be errors present which affect the content, and all legal disclaimers \napply.\nIf this paper is publishing under a Transparent Peer Review model then Peer \nReview reports will publish with the final article.\nhttps://doi.org/10.1038/s41598-026-52918-5\n© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International \nLicense, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit \nto the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do \nnot have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this \narticle are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the \narticle’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain \npermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.\n\n1Efficacy of different pretreatments in IVF\n2outcomes in patients with endometriosis: a systematic review \n3and network meta‑analysis \n4\n5Dan Li 1, Lianwen Zheng1, Xueying Zhang1, Wei Wang2, Jingshun Zhang1, Lulu Fu1* \n6\n7 1Reproductive Medicine Centre, Jilin Provincial KeyLaboratory of Reproductive \n8Biology（The Second Hospital of Jilin University, Changchun Jilin Province, China\n9 2Department of Breast Surgery Two, Jilin Provincial Cancer Hospital, Changchun \n10130000, Jilin, China\n11Corresponding author: Lulu Fu lulufu@jlu.edu.cn\n12\n13\n1            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n14Abstract \n15Background: To investigate the efficacy of different pretreatment protocols for women \n16with endometriosis undergoing IVF.\n17Methods: We systematically searched the Cochrane Library, PubMed, Medline, and \n18Embase from inception to April 30, 2025, to identify randomized controlled trials \n19(RCTs) evaluating different pretreatment protocols in women with endometriosis \n20undergoing IVF. The primary outcomes were live birth rate and clinical pregnancy rate. \n21Secondary outcomes included miscarriage rate, fertilization rate, implantation rate, \n22gonadotropin dose, and number of retrieved oocytes.\n23Results: This network meta-analysis included 11 randomized controlled trials \n24involving 1,435 women with endometriosis undergoing IVF. No clear improvement in \n25clinical pregnancy rate was observed among the pretreatment protocols compared with \n26the general protocol. For live birth rate, limited evidence from four RCTs suggested a \n27higher rate in the general protocol than in the GnRH-a protocol (RR [95% CI], 2.12 \n28[1.05, 4.31]), but this finding should be interpreted cautiously because of imprecision. \n29Some differences were observed in secondary or intermediate outcomes. The number \n30of retrieved oocytes was significantly higher in the general protocol than in the DNG \n31protocol (MD [95% CI], 0.60 [0.24, 0.97]). The GnRH-a protocol (MD [95% CI], −2.11 \n32[−2.94, −1.28]) and the general protocol (MD [95% CI], −2.45 [−3.50, −1.40]) were \n33associated with lower gonadotropin doses than the DNG protocol. However, these \n34secondary findings did not translate into clear improvements in the prespecified primary \n35clinical outcomes.\n2            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n36Conclusion: The results of this network meta-analysis suggest that, compared with the \n37general protocol, pretreatment with GnRH-a or DNG was not associated with clear \n38improvements in the primary clinical IVF outcomes, namely clinical pregnancy rate \n39and live birth rate, in patients with endometriosis. However, the evidence for live birth \n40rate was limited to four RCTs and imprecise; therefore, this finding should be \n41interpreted cautiously. Although some differences were observed in secondary or \n42intermediate outcomes, these findings did not establish the clinical superiority of \n43pretreatment protocols. PROSPERO under identifier: (CRD42024606775).\n44Keywords: GnRH-a, Dienogest, Endometriosis, IVF-ET, Network meta-analysis\n45Introduction\n46Endometriosis（EMs（, an estrogen-driven, persistent gynecological disorder, is \n47identified by the existence of functional endometrial tissue located outside the uterine \n48cavity 1. Previous studies have shown that a pro-inflammatory microenvironment, \n49driven by hormonal and immune factors, promotes the persistence of EMs. These \n50mechanisms are associated with the two primary symptoms of the disease: pain and \n51infertility 2. It is predicted that approximately 40% of women suffering EMs experience \n52infertility 3. The mechanisms through which EMs contributes to infertility are \n53multifactorial, involving distortion of pelvic anatomy, inflammatory responses, and \n54oxidative stress that impair oocyte quality and embryo implantation 4 5 6.\n55In Vitro Fertilization (IVF) has become a critical strategy in the management of \n56infertility associated with EMs. However, the success rates of IVF in women suffering \n57from EMs are considerably lower than those in women free of the condition 7 8, posing \n3            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n58a significant clinical challenge. Various pretreatment protocols have been investigated, \n59including the use of GnRH-a, dienogest (DNG), and other hormonal therapies, all aimed \n60at improving IVF outcomes for women diagnosed with EMs 9. However, the findings \n61across studies have been inconsistent. Some studies suggest that prolonged GnRH-a \n62therapy may significantly enhance clinical pregnancy rates in women with advanced-\n63stage EMs 10, 11,  potentially through the reduction of inflammation and endometrial \n64lesions. Additionally, progestins such as DNG are thought to offer a more favorable \n65side-effect profile, while still contributing to clinical improvements, including higher \n66pregnancy rates and a reduction in recurrence risk 12. However, after further \n67investigation, researchers such as Anna, Xueying, Ektoras, and Becker discovered that \n68pretreatment with DNG or GnRH-a does not significantly impact IVF outcomes in \n69patients with EMs 13 14 15 16 . Given these conflicting findings, our study intends to \n70perform a comprehensive review and assess the efficiency of various pretreatment \n71protocols on outcomes of IVF in women suffering from EMs, providing evidence-based \n72recommendations to guide clinicians in customizing fertility treatments for these \n73patients. \n74Methods \n75We conducted this network meta-analysis in full compliance with the PRISMA \n76Extension guidelines for Systematic Reviews and Meta-Analyses. PROSPERO \n77registration was obtained for the study (registration no. CRD42024606775).\n78Search strategy\n79PubMed, Cochrane Library, Medline, and Embase were systematically and \n4            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n80exhaustively searched for relevant articles until Apr 30, 2025. English search terms \n81were ‘Endometriosis’ OR ‘EMs’ OR ‘Endometrioma’ OR ‘Endometriomas’ AND \n82‘GnRH’ OR ‘Gonadotropin-Releasing Hormone’ OR ‘Luliberin OR Gonadorelin’ OR \n83‘Gonadoliberin’ OR ‘dienogest’ OR ‘DNG’ AND ‘Fertilization in Vitro’ OR \n84‘Fertilizations in Vitro’.\n85Clinical trial registries (ClinicalTrials.gov and australianclinicaltrials.gov.au) were also \n86searched, and the reference lists of relevant reviews and eligible studies were manually \n87screened to identify additional potentially relevant articles. According to the predefined \n88eligibility criteria, only randomized controlled trials (RCTs) evaluating pretreatment \n89protocols in women with endometriosis undergoing IVF were included in the final \n90analysis. The study protocol was specified in advance, with prespecified procedures for \n91data identification, extraction, and analysis. \n92Inclusion and exclusion criteria\n93The inclusion criteria were as follows: (1) studies involving women with endometriosis \n94undergoing IVF or IVF/ICSI; (2) The study groups received different pre-treatment \n95protocols, which primarily included: GnRH-a protocol, with 3 to 6 months of \n96administration prior to IVF; DNG protocol, with at least 3 months of administration \n97prior to IVF; other pre-treatment protocols. The control group followed the general \n98protocol, which was defined as conventional IVF/ICSI treatment without ≥3 months \n99of endometriosis-directed hormonal pretreatment before controlled ovarian \n100hyperstimulation. In this comparator category, patients proceeded directly to assisted \n101reproductive technology according to the standard IVF/ICSI practice used in each \n5            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n102original study, typically involving standard controlled ovarian stimulation with a \n103conventional long GnRH agonist protocol, followed by gonadotropin stimulation, hCG \n104triggering, oocyte retrieval, and IVF/ICSI-embryo transfer; (3) studies reporting at least \n105one of the outcomes as follows: re0trieved oocytes, r-FSH levels, duration of \n106stimulation, rates of fertilization, implantation, miscarriage, live birth and clinical \n107pregnancy; (4) randomized controlled trials (RCTs). Endometriosis was defined \n108according to the diagnostic criteria reported in the original studies. Where available, \n109information on surgical confirmation, histopathological findings, imaging-based \n110diagnosis, clinical diagnosis, and disease stage was extracted.\n111The exclusion criteria were as follows: (1) studies involving infertility mainly \n112attributable to other major factors, such as severe male-factor infertility; (2) non-\n113randomized studies, retrospective studies, prospective observational studies, case \n114reports, reviews, conference abstracts, and duplicate publications; (3) studies with \n115insufficient data for extraction or analysis.\n116Data collection and quality evaluation\n117 Two independent reviewers extracted data from the eligible studies, assessed study \n118eligibility, and evaluated the methodological quality of the included trials. \n119Disagreements were resolved through discussion or, when necessary, consultation with \n120a third reviewer. Extracted data included study characteristics, intervention protocols, \n121sample size, patient age, and outcome indicators. In addition, whenever reported, \n122information on the diagnostic basis of endometriosis was collected, including surgical \n123confirmation, histopathological findings, imaging-based diagnosis, clinical diagnosis, \n6            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n124and disease stage. The Cochrane Collaboration’s tool was employed to assess bias risk \n125in the RCTs 17. The bias risk was rated as low, unclear, or high. The certainty of \n126evidence for key outcomes was additionally assessed using the GRADE framework. \n127The assessment considered risk of bias, inconsistency, indirectness, imprecision, and \n128publication bias. The certainty of evidence was rated as high, moderate, low, or very \n129low.\n130Clinical Outcomes  \n131Primary outcomes: live birth rate and clinical pregnancy rate. Secondary outcomes: (1) \n132miscarriage rate; (2) fertilization rate; (3) implantation rate; (4) dose of gonadotropin;\n133(5) number of oocytes collected. \n134Statistical analyses\n135We first used the network map command in STATA 17.0 to assess the network \n136configuration of the available data, evaluating all pretreatment protocols before IVF for \n137patients with EMs 18. When feasible, pooled effect estimates were computed from direct \n138comparisons of each treatment pair using a random-effects REML model to account for \n139expected between-study variability. Effect measures were reported as risk ratios (RRs) \n140with 95% confidence intervals (CIs) for dichotomous variables and as mean differences \n141(MDs) for continuous variables. Clinical and methodological heterogeneity was \n142assessed qualitatively by examining reported differences in diagnostic criteria, \n143endometriosis stage, prior surgical history, embryo transfer type, pretreatment duration, \n144and IVF/ICSI protocols. Because these potential effect modifiers were incompletely \n145and inconsistently reported across studies, formal subgroup analyses, sensitivity \n146analyses, or network meta-regression could not be performed reliably. To assess \n7            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n147inconsistency, the node-splitting method was applied, comparing direct and indirect \n148evidence within the network. This approach incorporates both types of evidence to \n149determine the relative effects and rankings 19. Surface Under the Cumulative Ranking \n150Curve (SUCRA) was used to summarize the relative ranking probabilities of different \n151protocols within the treatment network. SUCRA rankings were interpreted together \n152with the corresponding effect estimates, 95% confidence intervals, risk of bias, and \n153certainty of evidence, rather than as standalone evidence of clinical superiority. The \n154comparison-adjusted funnel plot was utilized to assess publication bias.\n155Results\n156Study selection and Characteristics of included studies\n157A total of 743 records were identified from four databases, and 11 RCTs were \n158ultimately included in the quantitative analysis 12 20 21 22 23 24  25 26 27  28 29 (Figure 1). \n159Overall, 1,435 patients were included, with 810 in the pretreatment protocols and 625 \n160in the general protocol. The characteristics of the included studies are summarized in \n161Table 1. The distribution of reported potential effect modifiers across treatment nodes \n162is summarized in Supplementary Table 1, including diagnostic basis of endometriosis, \n163disease stage or phenotype, prior surgical history, pretreatment duration, embryo \n164transfer type, IVF/ICSI protocol, and age where available. Because these variables were \n165not uniformly reported across all trials, their distribution could only be assessed \n166qualitatively.\n8            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n167\n168Quality assessment of the studies included\n169Risk-of-bias assessment showed that several studies were rated as having low or unclear \n170risk in domains such as random sequence generation, incomplete outcome data, and \n171selective reporting. However, eight of the eleven included trials were judged to be at \n172high risk of bias in the blinding of participants and personnel domain, mainly because \n173blinding was difficult to implement given the nature of the interventions. In addition, \n174five studies were rated as high risk in the blinding of outcome assessment domain. Only \n175one study was considered to have a high risk of bias due to incomplete outcome data, \n176one study due to selective reporting, and one study due to allocation concealment. \n177Overall, performance bias and detection bias were the most common methodological \n178concerns among the included studies (Figure 2). The high risk of bias in the blinding \n9            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n179domain reduced confidence in the synthesized estimates. Lack of blinding may have \n180introduced performance bias, particularly for cycle-related or management-dependent \n181outcomes, such as gonadotropin dose, stimulation management, and treatment \n182adherence. Although live birth rate and clinical pregnancy rate are relatively objective \n183outcomes and may be less susceptible to detection bias, the overall certainty of evidence \n184was downgraded for several outcomes because of risk of bias, imprecision, and clinical \n185heterogeneity. The GRADE certainty assessment for the key outcomes is presented in \n186Supplementary Table 2.\n187\n10            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n188Network Meta-Analyses\n189Results of the network meta-analysis: No statistically significant inconsistency was \n190detected in the inconsistency tests (P > 0.05), and the consistency model was therefore \n191used for the main analyses. The node-splitting method was applied to assess local \n192inconsistency, with all P-values > 0.05, suggesting no significant disagreement between \n193direct and indirect evidence for the evaluated outcomes. However, the absence of \n194statistical inconsistency should not be interpreted as evidence of clinical homogeneity, \n195given the incomplete reporting of key patient- and treatment-level characteristics across \n196the included trials. The network relationship diagram for the web meta-analysis is \n197shown in Supplementary Figure 1. We evaluated four treatment regimens within the \n198network: (A) DNG, (B) GnRH-a, (C) general protocol, and (D) ethinylestradiol + DNG.\n199The comparison focused on rates of clinical pregnancy, live birth, miscarriage, \n200fertilization, and implantation, r-FSH levels, and the count of oocytes collected.\n201\n202Clinical Pregnancy Rate\n203The analysis of seven RCTs showed the following SUCRA ranking probabilities for \n204clinical pregnancy rate: GnRH-a group, general protocol, DNG group, and \n205ethinylestradiol + DNG group (Figure 3a). However, the interval plot comparing effect \n206estimates showed no statistically significant differences among the four groups (Figure \n2074a). Specifically, the comparisons were as follows: DNG group vs. GnRH-a protocol \n208(RR [95% CI], 1.55 [0.56, 4.30]); DNG group vs. general protocol (RR [95% CI], 1.12 \n209[0.44, 2.88]); DNG group vs. ethinylestradiol + DNG protocol (RR [95% CI], 0.84 \n210[0.20, 3.58]); GnRH-a protocol vs. general protocol (RR [95% CI], 0.73 [0.35, 1.49]); \n11            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n211GnRH-a protocol vs. ethinylestradiol + DNG group (RR [95% CI], 0.54 [0.11, 2.61]); \n212and general protocol vs. ethinylestradiol + DNG protocol (RR [95% CI], 0.54 [0.11, \n2132.61]). Therefore, these SUCRA rankings should be interpreted cautiously and should \n214not be considered evidence of clinical superiority.\n215Live Birth Rate\n216Four RCTs reported live birth rate. The SUCRA ranking indicated the following order, \n217from most to least favorable: general protocol, DNG group, and GnRH-a group (Figure \n2183b). The interval plot suggested a higher live birth rate in the general protocol than in \n219the GnRH-a protocol (RR [95% CI], 2.12 [1.05, 4.31]). However, no statistically \n220significant differences were observed between the DNG protocol and the GnRH-a \n221protocol (RR [95% CI], 0.96 [0.41, 2.28]) or between the DNG protocol and the general \n222protocol (RR [95% CI], 2.05 [0.82, 5.14]) (Figure 4b). Because only four RCTs \n223contributed data to this outcome and several confidence intervals were wide, these \n224findings should be interpreted cautiously.\n225Miscarriage Rate\n226For miscarriage rate, a lower rate was considered more favorable. According to SUCRA ranking \n227probabilities, the general protocol ranked most favorably, followed by the GnRH-a group and the \n228DNG group (Figure 3c). However, no statistically significant differences were observed among the \n229GnRH-a protocol, DNG protocol, and general protocol. Specifically, the risk ratios were as follows: \n230DNG protocol vs. general protocol (RR [95% CI], 0.92 [0.23, 3.70]) and GnRH-a protocol vs. \n231general protocol (RR [95% CI], 0.93 [0.38, 2.31]) (Figure 4c). Therefore, the SUCRA ranking for \n232miscarriage rate should be interpreted cautiously.\n233Fertilization Rate\n12            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n234According to SUCRA ranking probabilities, the order for fertilization rate was GnRH-\n235a group, general protocol, and DNG group (Figure 3d). The interval plot showed that \n236fertilization rate was higher in the GnRH-a protocol than in the DNG protocol (RR [95% \n237CI], 2.69 [1.11, 6.51]). However, no statistically significant differences were observed \n238between the pretreatment groups and the general protocol. Specifically, the risk ratios \n239were as follows: DNG group vs. general protocol (RR [95% CI], 2.32 [0.87, 6.17]) and \n240GnRH-a group vs. general protocol (RR [95% CI], 0.86 [0.57, 1.31]) (Figure 4d). \n241Therefore, although a protocol-specific difference was observed, this secondary \n242outcome should not be interpreted as evidence of overall clinical superiority unless it \n243translates into improved primary clinical outcomes.\n244Implantation Rate\n245According to SUCRA ranking probabilities, the order was DNG group, GnRH-a group, \n246and general protocol (Figure 3e). No meaningful differences were found among the \n247three intervention groups. DNG protocol VS GnRH-a protocol (RR [95%CI]; 0.72 \n248[0.28, 1.81]); DNG protocol VS General protocol (RR [95%CI]; 0.61 [0.26, 1.42]); \n249GnRH-a protocol VS General protocol (RR [95%CI]; 0.85 [0.58, 1.25]) (Figure 4e).\n250Dose of Gonadotropin\n251For gonadotropin dose, a lower dose was considered more favorable. According to \n252SUCRA ranking probabilities, the order was general protocol, GnRH-a group, and \n253DNG group (Figure 3f). The interval plot showed that both the GnRH-a group (MD [95% \n254CI], −2.11 [−2.94, −1.28]) and the general protocol group (MD [95% CI], −2.45 [−3.50, \n255−1.40]) had significantly lower gonadotropin doses than the DNG group (Figure 4f). \n256However, no statistically significant difference was observed between the GnRH-a \n13            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n257group and the general protocol (MD [95% CI], −0.34 [−0.98, 0.30]) (Figure 4f). \n258Because gonadotropin dose is a cycle-related outcome, this finding should be \n259interpreted as reflecting differences in ovarian stimulation requirements rather than \n260direct evidence of improved clinical reproductive outcomes.\n261Number of Retrieved Oocytes\n262According to SUCRA ranking probabilities, the order was general protocol, GnRH-a \n263group, and DNG group (Figure 3g). The interval plot comparing the effect sizes for \n264collected oocytes numbers revealed that the GnRH-a protocol (MD [95% CI]; 0.39 \n265[0.09, 0.69]) and the general protocol (MD [95% CI]; 0.60 [0.24, 0.97]) had slightly \n266higher collected oocytes numbers compared to the DNG group. However, no \n267meaningful difference was found between the GnRH-a protocol and the general \n268protocol (MD [95% CI]; 0.21 [-0.13, 0.55]) (Figure 4g). The more information of the \n269network side-split and the cumulative probability network rank test are shown in \n270Supplementary Figure 2,3\n271\n14            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n272\n273Risk of Bias Across Studies\n274Publication bias was assessed using funnel plots (Figure 5), which plot individual study \n275effect sizes against their standard errors. Asymmetry in the plots may suggest the \n276presence of unpublished small studies with negative results. It should be noted, however, \n277that funnel plot asymmetry may also arise from heterogeneity or differences in study \n278quality.\n15            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n279\n280Discussion\n281To the best of our knowledge, this is the first network meta-analysis to assess the \n282efficacy and safety of different pretreatment protocols before IVF in women with \n283endometriosis. Network meta-analysis allows simultaneous comparison of multiple \n284interventions by integrating direct and indirect evidence across trials with different \n285comparison groups 30. \n286Overall, we included 11 randomized controlled trials involving 1,435 patients. The \n287findings of individual studies were not fully consistent. Among studies evaluating DNG \n288pretreatment, one trial suggested that pretreatment may benefit patients with stage II–\n289III endometriosis by improving IVF success rates 20, whereas Tamura et al 21. reported \n290that DNG pretreatment was associated with less favorable IVF outcomes. Another \n291study found no significant differences between DNG and GnRH-a pretreatment in \n292ovarian stimulation, response parameters, or pregnancy outcomes 12. Similarly, among \n293studies evaluating GnRH-a, some trials suggested that prolonged GnRH-a pretreatment \n294for 3–6 months may improve IVF outcomes in women with endometriosis-related \n16            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n295infertility 20 22 25 27 29, whereas other trials did not support the effectiveness of an ultra-\n296long GnRH-a protocol in improving IVF outcomes 23 24 28.\n297These mixed findings highlight the importance of interpreting the results according to \n298the prespecified outcome hierarchy. In this review, the main conclusions were based on \n299the primary clinical outcomes, namely live birth rate and clinical pregnancy rate. \n300Although some secondary or intermediate outcomes differed between protocols, these \n301findings mainly reflect laboratory, ovarian response, or cycle-related parameters and \n302should be regarded as supportive rather than definitive evidence of clinical benefit.\n303To better understand these mixed clinical findings, it is necessary to consider the \n304biological effects of GnRH-a and DNG. Undoubtedly, GnRH-a is recognized for its \n305proliferation-suppressing and inflammation-reducing effects, which help modulate the \n306hormonal environment in patients with Ems 31. And it could make pituitary cells \n307unresponsive to endogenous GnRH-a to achieve desensitization, reduce the secretion \n308of FSH and luteinizing hormone (LH), inhibit ovarian activity, reduce the level of \n309estradiol, and promote atrophy of ectopic foci to favor embryo implantation 32. The \n310ultra-long protocol, by extensively inhibiting ovarian function through receptor \n311downregulation, reduces pituitary sensitivity, which often results in a prolonged \n312duration and increased dosage of gonadotropins, leading to a poor ovarian response, \n313fewer follicles, smaller follicular diameters, reduced oocyte retrieval, and a lower \n314number of embryos 33. Haouzi and van claim that long-duration GnRH-a therapy during \n315ovarian stimulation cycles may impair endometrial receptivity, with animal studies \n316indicating that the ultra-long protocol downregulates the expression of key molecules \n17            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n317such as CDH1, CTNNB1, Meis1 and Hoxa11, further affecting endometrial receptivity \n318 34 35 36 37.\n319Currently, the effect of pretreatment on live birth rate remains inconsistent across \n320studies. In our network meta-analysis, although 11 RCTs were included overall, live \n321birth rate was reported by only four RCTs. The available evidence suggested a higher \n322live birth rate in the general protocol than in the GnRH-a protocol; however, because \n323only four RCTs contributed data and the confidence intervals were relatively wide, this \n324estimate should be interpreted cautiously. This finding contrasts with a previous review \n325 38. Their meta-analysis included only three trials 22 25 29, comprising data from 165 cases \n326and 78 pregnancies, and suggested that prolonged GnRH-a pretreatment might improve \n327pregnancy outcomes despite no increase in the number of retrieved oocytes. The authors \n328attributed this potential benefit to improved oocyte quality or enhanced endometrial \n329receptivity. The Cochrane meta-analysis conducted by Georgiou et al. 15 included eight \n330parallel-design RCTs involving 640 participants, but the quality of evidence was rated \n331as very low to low, primarily because seven of the eight studies lacked adequate \n332blinding. In turn, a recent review encompassing 16 studies, including 10 RCTs, 3 \n333retrospective cohorts, and 3 comparative studies, concluded that GnRH-a \n334administration did not have a statistically significant effect on follicle count, total or \n335mature oocyte count, embryo count, embryo quality, or miscarriage rate. Given the lack \n336of updated evidence and the limitations of existing studies, including small sample sizes, \n337insufficient statistical power, unequal study-group matching, and limited data on \n338complications or live birth rate, the authors did not recommend GnRH-a pretreatment \n18            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n339before IVF as a strategy to improve clinical pregnancy rates 39.\n340Similarly, pretreatment with DNG may face comparable challenges 40. DNG exerts its \n341effects through negative feedback regulation of the hypothalamic-pituitary-ovarian axis, \n342alleviating dysmenorrhea, suppressing ovulation, reducing estrogen levels, and \n343shrinking ovarian endometriotic cysts. Notably, the reduction in cyst size becomes \n344more pronounced with longer treatment duration 41. Additionally, DNG is known to \n345suppress follicular growth and promote follicular atresia, further contributing to its \n346therapeutic effects in EMs management 42. One study involving 568 women with EMs \n347in 5 studies (2 RCTs and 3 cohort studies) suggested that pregnancy outcomes with the \n348DNG protocol were significantly better than with no hormonal treatment. Subgroup \n349analysis showed higher clinical pregnancy and live birth rates in the DNG group for \n350fresh embryo transfer 43.  However, in our review, we found no significant trend \n351favoring DNG therapy for improving clinical pregnancy or live birth rates. Our results \n352align with those of a recent review, which also found that pretreatment with DNG did \n353not improve live birth or clinical pregnancy rates in females with EMs undergoing IVF \n354 44. The reason for this could be that DNG can lessen the recruitment of primordial \n355follicles, which could further reduce the number of follicles that are growing. This is \n356often clinically reflected in a higher proportion of immature oocytes and lower \n357fertilization rates 45. This discrepancy may also stem from the inclusion of more recent \n358randomized controlled trials in our analysis, and the exclusion of cohort studies. The \n359RCTs we included used modern stimulation protocols, randomized larger sample sizes, \n360and incorporated more rigorous study designs—such as placebo controls and \n19            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n361comparisons between females suffering from EMs and females affected by other \n362infertility etiologies—making them more methodologically robust than earlier studies. \n363 These mechanisms may explain why the DNG pretreatment group did not show \n364superior outcomes compared to the general protocol. Additionally, the extended \n365duration of stimulation and higher gonadotropin requirements led to increased patient \n366inconvenience, higher medical costs, and delayed conception, without a corresponding \n367improvement in clinical outcomes. Based on these findings, the currently available \n368evidence does not support a robust additional benefit of pretreatment protocols for \n369improving the primary reproductive outcomes in patients with EMs undergoing IVF, \n370although differences in some secondary or cycle-related outcomes may warrant further \n371investigation.\n372These findings are also consistent with a recent network meta-analysis evaluating \n373hormone pretreatment before ART in infertile women with endometriosis, which \n374likewise failed to demonstrate clear superiority of hormonal suppression over \n375immediate ART for improving key reproductive outcomes 46. This external consistency \n376supports a cautious interpretation of the current evidence base. Likewise, comparative \n377work examining IVF/ICSI versus surgery as the initial approach for endometriosis-\n378associated infertility highlights that disease-directed interventions should not \n379automatically be assumed to improve reproductive outcomes simply because they are \n380biologically or surgically plausible 47. More broadly, similar issues have been observed \n381with endocrine or adjunctive strategies in reproductive medicine. Recent literature \n382suggests that biologically plausible interventions may affect intermediate, laboratory, \n20            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n383or cycle-related outcomes, yet such effects do not necessarily translate into consistent \n384improvements in live birth outcomes 48 49 50. Therefore, in women with endometriosis \n385undergoing IVF, mechanistic plausibility and protocol-level changes should be \n386interpreted cautiously unless supported by robust evidence of benefit in patient-\n387important outcomes such as live birth and clinical pregnancy.\n388The interpretation of these pooled estimates should also consider the clinical and \n389methodological heterogeneity of the included trials. Differences in disease stage, \n390diagnostic criteria, prior surgical history, embryo transfer strategy, pretreatment \n391duration, and IVF/ICSI protocols may have influenced treatment effects. Although \n392statistical inconsistency was not detected, the limited number of studies and incomplete \n393reporting of potential effect modifiers restricted our ability to formally explore these \n394sources of heterogeneity. Therefore, the pooled estimates should be regarded as overall \n395average effects across heterogeneous trial populations rather than as effects directly \n396applicable to every clinical subgroup. \n397The risk-of-bias assessment in our study also affected the interpretation of the pooled \n398estimates. Blinding of participants and personnel was difficult to implement in most \n399included IVF trials because pretreatment protocols differed in drug type, duration, and \n400administration schedule. This may have introduced performance bias, particularly for \n401outcomes influenced by clinical management or cycle decisions, such as gonadotropin \n402dose, stimulation duration, and cycle planning. Although the primary outcomes, \n403including live birth rate and clinical pregnancy rate, are relatively objective and may be \n404less vulnerable to detection bias, the high risk of bias in the blinding domain still \n21            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n405reduces confidence in the overall evidence.\n406Limitation\n407First, the number of eligible studies available for analysis was limited. In particular, \n408although live birth rate was prespecified as a primary outcome, only four RCTs reported \n409this endpoint. This limited evidence base resulted in imprecise estimates, as reflected \n410by the wide confidence intervals in several comparisons. Therefore, conclusions \n411regarding live birth rate should be considered exploratory and interpreted with caution. \n412Second, important clinical details, including diagnostic criteria for endometriosis, \n413disease stage, prior surgical history, embryo transfer type, pretreatment duration, and \n414IVF/ICSI protocols, were incompletely and inconsistently reported across studies. \n415Because individual patient-level data were unavailable and several outcome networks \n416were sparse, subgroup analyses, sensitivity analyses, or covariate adjustments could not \n417be performed reliably. Therefore, the generalizability of the pooled estimates may be \n418limited, and the results should be interpreted as overall average effects rather than as \n419effects applicable to all clinical subgroups. Third, the certainty of evidence was limited \n420by methodological concerns, particularly the high risk of bias in the blinding domain. \n421Although blinding is inherently challenging in IVF trials comparing different \n422pretreatment regimens, this limitation may have affected treatment implementation, co-\n423interventions, and cycle management, thereby reducing confidence in the synthesized \n424estimates. The GRADE assessment indicated that the certainty of evidence for several \n425key outcomes was low to moderate, mainly because of risk of bias, imprecision, and \n426clinical heterogeneity. Future large-scale, multicenter randomized controlled trials with \n22            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n427standardized and comprehensive reporting of key clinical and treatment-related factors \n428are needed to improve the reliability, interpretability, and clinical applicability of the \n429evidence.\n430Conclusion\n431To the best of our knowledge, this is the first network meta-analysis to compare the \n432efficacy of different pretreatment protocols before IVF/ICSI in women with \n433endometriosis. Based on the currently available evidence, pretreatment protocols were \n434not associated with clear improvements in the primary clinical IVF outcomes, namely \n435live birth rate and clinical pregnancy rate, compared with the general protocol. \n436Although some secondary outcomes and SUCRA rankings suggested protocol-specific \n437differences, these findings did not establish the clinical superiority of pretreatment \n438protocols. This conclusion should be interpreted cautiously because of the limited \n439number of eligible trials, clinical heterogeneity, risk of bias, and imprecision of some \n440estimates, particularly for live birth rate. Pretreatment may still be considered for \n441selected patient-centered indications, such as symptom control or cycle planning, but \n442routine use solely to improve IVF success rates is not strongly supported by current \n443evidence. Further large-scale, well-designed randomized controlled trials with \n444standardized reporting of diagnostic criteria, disease stage, prior surgical history, \n445embryo transfer type, and pretreatment duration are needed to confirm these findings.\n446Abbreviations\n447EMs Endometriosis\n448IVF In Vitro Fertilization\n23            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n449GnRH-a                 Gonadotropin-Releasing Hormone agonist\n450DNG Dienogest\n451RCT Randomized Controlled Trial\n452CI Confidence Interval\n453RR Risk Ratio\n454MD Mean Difference\n455SUCRA Surface Under the Cumulative Ranking Curve\n456PRISMA Preferred Reporting Items for Systematic Reviews and \n457Meta-Analyses\n458FSH Follicle-Stimulating Hormone\n459r-FSH Recombinant Follicle-Stimulating Hormone\n460ET Embryo Transfer\n461CPR Clinical Pregnancy Rate\n462ART Assisted Reproductive Technology\n463LH Luteinizing Hormone\n464MII Metaphase II (oocytes)\n465REML Restricted Maximum Likelihood\n466ICSI Intracytoplasmic Sperm Injection\n467Author Contributions\n468DL performed the experiments, analyzed the data, prepared figures and table and \n469approved the final draft. LWZ conceived and designed the experiments, authored and \n470reviewed drafts of the article, and approved the final draft. XYZ conceived and \n24            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n471designed the experiments, authored and reviewed drafts of the article, and approved the \n472final draft. WW conceived and designed the experiments, authored and reviewed drafts \n473of the article, and approved the final draft. JSZ conceived and designed the experiments, \n474authored and reviewed drafts of the article, and approved the final draft. LLF conceived \n475and designed the experiments, authored and reviewed drafts of the article, and approved \n476the final draft.\n477Funding\n478The author(s) declare financial support was received for the research, authorship, \n479and/or publication of this article. This research was supported by the Natural Science \n480Foundation of Jilin Province (YDZJ202301ZYTS434)\n481Data availability statement\n482No datasets were generated or analysed during the current study.\n483Declarations\n484 Consent for publication\n485 Not applicable.\n486Competing interests\n487 The authors declare no competing interests.\n488Ethical approval and consent to participate\n489 This study was a meta-analysis of previously published data. Therefore, no \n490additional ethical approval or patient consent was required.\n491 Clinical trial number\n492 Not applicable.\n493\n494Reference\n4951. Vercellini, P., Viganò, P., Somigliana, E. & Fedele, L. Endometriosis: \n496pathogenesis and treatment. Nature reviews. Endocrinology 10, 261-275 \n25            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n497(2014).\n4982. Gupta, S. et al. Pathogenic mechanisms in endometriosis-associated \n499infertility. Fertility and Sterility 90, 247-257 (2008).\n5003. Leone Roberti Maggiore, U. et al. Epidemiology of infertility in women with \n501endometriosis. Best Practice & Research Clinical Obstetrics & Gynaecology \n50292, 102454 (2024).\n5034. de Ziegler, D., Borghese, B. & Chapron, C. Endometriosis and infertility: \n504pathophysiology and management. Lancet (London, England) 376, 730-738 \n505(2010).\n5065. Edgardo, S. et al. Management of Endometriosis in the Infertile Patient. \n507Semin Reprod Med 35 (2016).\n5086. Paolo, V. et al. Association of endometriosis and adenomyosis with \n509pregnancy and infertility. Fertil Steril 119 (2023).\n5107. Sallwa M, A., Brenda F, N., Mark A, F. & Mostafa, M. The impact of \n511endometrioma on in vitro fertilisation/intra-cytoplasmic injection IVF/ICSI \n512reproductive outcomes: a systematic review and meta-analysis. Arch \n513Gynecol Obstet 303 (2020).\n5148. Hamdan, M., Dunselman, G., Li, T.C. & Cheong, Y. The impact of \n515endometrioma on IVF/ICSI outcomes: a systematic review and meta-analysis. \n516Hum Reprod Update 21, 809-825 (2015).\n5179. Klaas, H. et al. Safety of Dienogest and Other Hormonal Treatments for \n518Endometriosis in Real-World Clinical Practice (VIPOS): A Large \n519Noninterventional Study. Adv Ther 37 (2020).\n52010. Zhong, C. et al. Analysis of IVF/ICSI Outcomes in Endometriosis Patients With \n521Recurrent Implantation Failure: Influence on Cumulative Live Birth Rate. \n522Front Endocrinol (Lausanne) 12, 640288 (2021).\n52311. Ma, C., Qiao, J., Liu, P. & Chen, G. Ovarian suppression treatment prior to in-\n524vitro fertilization and embryo transfer in Chinese women with stage III or IV \n525endometriosis. Int J Gynaecol Obstet 100, 167-170 (2008).\n52612. Khalifa, E. et al. Role of suppression of endometriosis with progestins before \n527IVF-ET: a non-inferiority randomized controlled trial. BMC Pregnancy and \n528Childbirth 21 (2021).\n52913. Anna, R., Jacques, B., Elias M, D. & Johnny T, A. The Effects of Long-Term \n530Dienogest Therapy on In Vitro Fertilization Outcomes in Women with \n531Endometriosis: A Systematic Review and Meta-Analysis. J Obstet Gynaecol \n532Can 46 (2024).\n53314. Xueying, L., Jinli, L., Linhao, Z. & Yao, L. Pretreatment of Dienogest for \n534Women with Endometriosis in in vitro Fertilization: A Systematic Review and \n535Meta-Analysis. Gynecol Obstet Invest 88 (2023).\n53615. Ektoras X, G. et al. Long-term GnRH agonist therapy before in vitro \n537fertilisation (IVF) for improving fertility outcomes in women with \n538endometriosis. Cochrane Database Syst Rev 2019 (2019).\n53916. Becker, C. et al. ESHRE guideline: endometriosis. Human reproduction open \n5402022, hoac009 (2022).\n26            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n54117. Julian P T, H. et al. The Cochrane Collaboration's tool for assessing risk of \n542bias in randomised trials. BMJ 343 (2011).\n54318. Shim, S., Yoon, B.H., Shin, I.S. & Bae, J.M. Network meta-analysis: application \n544and practice using Stata. Epidemiol Health 39, e2017047 (2017).\n54519. Dias, S., Welton, N.J., Caldwell, D.M. & Ades, A.E. Checking consistency in \n546mixed treatment comparison meta-analysis. Statistics in Medicine 29, 932-\n547944 (2010).\n54820. Aksenenko, A.A., Gus, A.I., Mishieva, N.G. & Senina, D.N. Pre-treatment \n549before in vitro fertilization and its effectiveness in patients with diffuse \n550adenomyiosis. Akusherstvo i Ginekologiya (Russian Federation) 2021, 113-\n551120 (2021).\n55221. Tamura, H. et al. The clinical outcome of Dienogest treatment followed by \n553in vitro fertilization and embryo transfer in infertile women with \n554endometriosis. Journal of Ovarian Research 12 (2019).\n55522. Rickes, D., Nickel, I., Kropf, S. & Kleinstein, J. Increased pregnancy rates after \n556ultralong postoperative therapy with gonadotropin-releasing hormone \n557analogs in patients with endometriosis. Fertil Steril 78, 757-762 (2002).\n55823. Kaponis, A. et al. Ultralong administration of gonadotropin-releasing \n559hormone agonists before in vitro fertilization improves fertilization rate but \n560not clinical pregnancy rate in women with mild endometriosis: a prospective, \n561randomized, controlled trial. Fertil Steril 113, 828-835 (2020).\n56224. Rodríguez-Tárrega, E. et al. Effect of GnRH agonist before IVF on outcomes \n563in infertile endometriosis patients: a randomized controlled trial. Reprod \n564Biomed Online 41, 653-662 (2020).\n56525. Surrey, E.S., Silverberg, K.M., Surrey, M.W. & Schoolcraft, W.B. Effect of \n566prolonged gonadotropin-releasing hormone agonist therapy on the outcome \n567of in vitro fertilization-embryo transfer in patients with endometriosis. \n568Fertility and sterility 78, 699-704 (2002).\n56926. Decleer, W., Osmanagaoglu, K., Verschueren, K., Comhaire, F. & Devroey, P. \n570RCT to evaluate the influence of adjuvant medical treatment of peritoneal \n571endometriosis on the outcome of IVF. Hum Reprod 31, 2017-2023 (2016).\n57227. Ahmed Mohamed, M. et al. Effect of Prolonged GnRH Agonist \n573Downregulation on ICSI Outcome in Patients With Endometriomas of Less \n574Than 5 cm: A Randomized Controlled Trial. Reprod Sci 25 (2018).\n57528. Tomassetti, C. et al. The ultra-long study: A randomized controlled trial \n576evaluating long-term GnRH downregulation prior to ART in women with \n577endometriosis. Human Reproduction 36, 2676-2686 (2021).\n57829. Dicker, D., Goldman, J.A., Levy, T., Feldberg, D. & Ashkenazi, J. The impact \n579of long-term gonadotropin-releasing hormone analogue treatment on \n580preclinical abortions in patients with severe endometriosis undergoing in \n581vitro fertilization-embryo transfer. Fertil Steril 57, 597-600 (1992).\n58230. Salanti, G. Indirect and mixed-treatment comparison, network, or multiple-\n583treatments meta-analysis: many names, many benefits, many concerns for \n584the next generation evidence synthesis tool. Research Synthesis Methods 3, \n27            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n58580-97 (2012).\n58631. Lan, J. et al. Ultra-Long GnRH Agonist Protocol During IVF/ICSI Improves \n587Pregnancy Outcomes in Women With Adenomyosis: A Retrospective Cohort \n588Study. Front Endocrinol (Lausanne) 12, 609771 (2021).\n58932. Lessey, B.A. Medical management of endometriosis and infertility. Fertil \n590Steril 73, 1089-1096 (2000).\n59133. Hou, X. et al. The effect of adenomyosis on IVF after long or ultra-long GnRH \n592agonist treatment. Reprod Biomed Online 41, 845-853 (2020).\n59334. Haouzi, D. et al. Controlled ovarian hyperstimulation for in vitro fertilization \n594alters endometrial receptivity in humans: protocol effects. Biology of \n595reproduction 82, 679-686 (2010).\n59635. van der Houwen, L. et al. Efficacy and safety of IVF/ICSI in patients with \n597severe endometriosis after long-term pituitary down-regulation. \n598Reproductive biomedicine online 28, 39-46 (2014).\n59936. Xiong, M. et al. Association of controlled ovarian hyperstimulation treatment \n600with down-regulation of key regulators involved in embryonic implantation \n601in mice. Journal of Huazhong University of Science and Technology. Medical \n602sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = \n603Huazhong keji daxue xuebao. Yixue Yingdewen ban 31, 535 (2011).\n60437. Tian, Y. et al. Efficacy of long-term pituitary down-regulation pretreatment \n605prior to in vitro fertilization in infertile patients with endometriosis: A meta-\n606analysis. Journal of Gynecology Obstetrics and Human Reproduction 52, \n607102541 (2023).\n60838. Sallam, H.N., Garcia-Velasco, J.A., Dias, S. & Arici, A. Long-term pituitary \n609down-regulation before in vitro fertilization (IVF) for women with \n610endometriosis. Cochrane Database Syst Rev 2006, Cd004635 (2006).\n61139. Panagodimou, E.K., Kalogeropoulos, S., Adonakis, G. & Kaponis, A. Does \n612Gonadotropin-Releasing Hormone Agonist Administration Before Assisted \n613Reproduction Techniques Improve Pregnancy Rates in Women With \n614Endometriosis? Obstet Gynecol Surv 79, 421-428 (2024).\n61540. Klipping, C. et al. Ovulation-inhibiting effects of dienogest in a randomized, \n616dose-controlled pharmacodynamic trial of healthy women. J Clin Pharmacol \n61752, 1704-1713 (2012).\n61841. Tang, M., Yang, W. & Zhang, H. Comparison of the efficacy of dienogest and \n619GnRH-a after endometriosis surgery. BMC women's health 23, 85 (2023).\n62042. Manikkam, M. & Rajamahendran, R. Progesterone-induced atresia of the \n621proestrous dominant follicle in the bovine ovary: changes in diameter, \n622insulin-like growth factor system, aromatase activity, steroid hormones, and \n623apoptotic index. Biology of reproduction 57, 580-587 (1997).\n62443. Shao, W., Li, Y. & Wang, Y. Impact of dienogest pretreatment on IVF-ET \n625outcomes in patients with endometriosis: a systematic review and meta-\n626analysis. Journal of Ovarian Research 16 (2023).\n62744. Li, J. et al. Analysis of cumulative live birth rate outcomes of three ovarian \n628stimulation protocols in patients after laparoscopic cystectomy of ovarial \n28            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\n629endometrioma: a retrospective cohort study. Reproductive Health 20 (2023).\n63045. Tsuyoshi, H. et al. Protective effect of dienogest on chemotherapy-induced \n631reduced fertility in female rats. Steroids 93, 1-7 (2015).\n63246. Riemma, G. et al. Efficacy of hormone pre-treatment before ART to improve \n633reproductive outcomes in infertile women with endometriosis: Network \n634meta-analysis of randomized controlled trials. Int J Gynaecol Obstet 170, \n6351001-1013 (2025).\n63647. Riemma, G. et al. IVF/ICSI or surgery as first approach for the treatment of \n637infertility associated with ovarian and deep infiltrating endometriosis? A \n638systematic review and meta-analysis. Reproductive BioMedicine Online 52 \n639(2026).\n64048. Etrusco, A. et al. Effectiveness of hormone add-on strategies in ovarian \n641stimulation for women with poor ovarian response: a systematic review and \n642network meta-analysis of randomized controlled trials. J Assist Reprod Genet \n64342, 3231-3252 (2025).\n64449. Zhu, F. et al. TEAS, DHEA, CoQ10, and GH for poor ovarian response \n645undergoing IVF-ET: a systematic review and network meta-analysis. Reprod \n646Biol Endocrinol 21, 64 (2023).\n64750. Zhang, Y. et al. Adjuvant treatment strategies in ovarian stimulation for poor \n648responders undergoing IVF: a systematic review and network meta-analysis. \n649Hum Reprod Update 26, 247-263 (2020).\n29            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\nTable 1 The basic characteristics of the included studies\nAuthor Year Group Interventions N Age\n(years) Outcomes\nDienogest A 3-month treatment with DNG (2 \nmg daily) before IVF\n67 36.1±2.7Khalifa 2021\nGnRH-a A 3-month treatment with GnRH-a \n(3.75mg monthly) before IVF\n36 35.6±3.5\nThe number of oocytes retrieved, the \nnumber of mature oocytes, fertilization rate, \nClinical pregnancy rate （Miscarriage rate（\nNo. of transferrable embryos（Total dose of \nFSH (IU)\nDienogest A 3- month treatment with DNG (2 \nmg daily) before IVF\n30 34.2±3.4Tamura 2019\nGeneral \nprotocol\nStandard controlled ovarian \nhyperstimulation\n34 33.6±3.6\nThe numbers of mature follicles, retrieved \noocytes, and fertilized oocytes, the \nfertilization rates, implantation rates, and \nclinical pregnancy rates\nDienogest A 3-month treatment with DNG (2 \nmg daily) before IVF\n45 22-38\nGnRH-a A 3-month treatment with GnRH-a \n(3.75mg monthly) before IVF\n38 22-38\nCOCs and \nDienogest\nA 3-month treatment with \nEthinylestradiol (30mcg daily) and \nDNG (2 mg daily) before IVF\n45 22-38\nAksenenko 2021\nGeneral \nprotocol\nDirect IVF 70 22-38\nMedication tolerance, clinical and \nlaboratory characteristics, the state of the \nuterus depending on the stage of EMs \n(confirmed by ultrasound), and pregnancy \nrate\nGnRH-a A 6-month treatment with GnRH-a \n(3.75mg monthly) before IVF\n28 23-40Rickes 2002\nGeneral \nprotocol\nDirect IVF 19 23-40\nPregnancy rate at the end of the treatment \n(without considering the number of cycles)\nGnRH-a A 3-month treatment with GnRH-a \n(3.75mg monthly) before IVF\n200 34.8±3.8Kaponis 2020\nGeneral \nprotocol\nIVF without GnRH-a 200 32.8±2.9\nFollicular fluid (FF) levels of tumor \nnecrosis factor a (TNF-a), interleukin-1b \n(IL-1b), IL-6, IL-8, and IL-1 receptor \nantagonist; fertilization rate (FR), \nimplantation rate (IR), quality of embryos, \nand clinical pregnancy rate (PR)\nGnRH-a A 3-month treatment with GnRH-a \n(3.75mg monthly) before IVF\n100 33.86±3.08Elisabet 2020\nGeneral \nprotocol\nDirect IVF 100 33.72±3.25\nClinical pregnancy rate (CPR) per started \ncycle, cumulative CPR per patient, \nimplantation rate, miscarriage rate, \ncumulative live birth rate, multiple \npregnancy rate; and variables related to \ncontrolled ovarian stimulation: estradiol \nlevels, number of MII oocytes, number of \nembryos and embryo quality\nGnRH-a A 3-month treatment with GnRH-a \n(3.75mg monthly) before IVF\n25 33.12±0.67Surrey 2002\nGeneral \nprotocol\nStandard controlled ovarian \nhyperstimulation\n26 32.58±0.56\nResponse to controlled ovarian \nhyperstimulation, ongoing pregnancy rates \nper cycle, group implantation rates, and \nimplantation rate per embryo transfer \nprocedure.\nGnRH-a A 3-month treatment with GnRH-a \n(3.75mg monthly) before IVF\n61 30.3 ± 3.63Decleer 2016\nGeneral \nprotocol\nStandard controlled ovarian \nhyperstimulation\n59 31.7±4.28\nNumber of MII oocytes, pregnancy rate, \nembryo transfer, Total FSH dose (IU), days \nstimulation, embryo quality, pregnancy rate\nGnRH-a A 3-month treatment with GnRH-a \n(3.75mg monthly) before IVF\n45 30.8±1.2Maged 2018\nGeneral \nprotocol\nStandard controlled ovarian \nhyperstimulation\n45 31.2±1.4\nChemical and clinical pregnancy rates, \nongoing pregnancy, miscarriage, ectopic \npregnancy, and multiple pregnancy rates\nGnRH-a A 3-month treatment with GnRH-a \n(3.75mg monthly) before IVF\n21 31.4±3.9Tomassetti 2021\nGeneral \nprotocol\nStandard controlled ovarian \nhyperstimulation\n21 32.4± 3.7\nClinical pregnancy rate, cumulative \ndelivery rate, antral follicle count on the day \nof start of stimulation, cumulus oocyte \ncomplex retrieved, duration of stimulation, \nfertilization rate, embryo quality, embryo \nutilization rate, implantation rate, other \npregnancy outcomes (miscarriage, ectopic, \ndelivery, live birth)\n30            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS\n\nTable 1 The basic characteristics of the included studies（Continued（\nAuthor Year Group Interventions N Age\n(years) Outcomes\nGnRH-a A 6-month treatment with GnRH-a \n(3.2mg monthly) before IVF\n35 31 ± 5Dicker 1992\nGeneral \nprotocol\nFSH combined with human \nmenopausal gonadotrophin starting \non the 3rd day of the cycle with \nadministration of 3 ampules per day \nof either preparation.\n32 32 ± 4\nClinical pregnancy rate, the number of \noocytes, fertilization rate, cleavage rate, the \nnumber of transfers, the number of \npreclinical pregnancies, the number of \nclinical pregnancies\nFigure 1 Flow of studies through the review\nFigure 2 Risk of bias summary and graph\nFigure 3 SUCRA ranking probabilities of outcome indicators A, DNG group; B, GnRH-\na group; C, General protocol; D, Ethinylestradiol + DNG\nFigure 4 Forest plot for outcome indicators. a, Clinical pregnancy rate; b, live birth rate \nc, miscarriage rate; d, fertilization rate; e, implantation rate; f, dose of gonadotropin; g, \nnumber of retrieved oocytes. A, DNG group; B, GnRH-a group; C, General protocol; \nD, Ethinylestradiol + DNG\nFigure 5 Publication bias funnel plot. a, Clinical pregnancy rate; b, live birth rate; c, \nmiscarriage rate; d, fertilization rate; e, implantation rate; f, dose of gonadotropin; g, \nnumber of retrieved oocytes. A, DNG group; B, GnRH-a group; C, General protocol; \nD, Ethinylestradiol + DNG\n31            \nACCEPTED MANUSCRIPTARTICLE IN PRESS\nARTICLE IN PRESSARTICLE IN PRESS","source_license":"CC0","license_restricted":false}