The impact of long-acting GnRHa pretreatment on the clinical pregnancy outcomes of hormone replacement therapy-frozen embryo transfer in RIF patients with PCOS: a retrospective clinical study

The impact of long-acting GnRHa pretreatment on the clinical pregnancy outcomes of hormone replacement therapy-frozen embryo transfer in RIF patients with PCOS: a retrospective clinical study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The impact of long-acting GnRHa pretreatment on the clinical pregnancy outcomes of hormone replacement therapy-frozen embryo transfer in RIF patients with PCOS: a retrospective clinical study Chenyang Huang, Yuan Yan, Jie Mei, Yue Jiang, Haixiang Sun, Jun Xing This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4869543/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Feb, 2025 Read the published version in BMC Pregnancy and Childbirth → Version 1 posted 10 You are reading this latest preprint version Abstract Background Several studies have demonstrated that pre-treatment with long-acting Gonadotropin-Releasing Hormone agonists (GnRHa) can significantly enhance the clinical pregnancy rate among recurrent implantation failure (RIF) patients. Investigations have also suggested that GnRHa pre-treatment could ameliorate the clinical pregnancy and live birth rates in polycystic ovary syndrome (PCOS) patients. But there is a dearth of research on whether long-acting GnRHa pre-treatment yields superior clinical outcomes for RIF patients with PCOS. Methods The retrospective study enrolled 1602 patients under the age of 40 meeting the criteria for RIF at the Reproductive Medicine Center of Nanjing Drum Tower Hospital, who underwent frozen-thawed embryo transfer (FET) between January 2017 and December 2021. Univariate analysis and a multivariate logistic regression model were employed to assess the impact of GnRHa pretreatment on the clinical pregnancy rate in RIF patients. The influence of long-acting GnRHa pretreatment on clinical pregnancy outcomes was re-examined in PCOS and non-PCOS subgroups. Additionally, an interaction analysis was performed to evaluate the effect of PCOS on the relationship between long-acting GnRHa pretreatment and the clinical pregnancy rate. Results Multiple regression analysis showed that long-acting GnRHa pretreatment had a positive impact on the clinical pregnancy rate. We divided the RIF population into two subgroups, for PCOS patients, although the clinical pregnancy rate was higher in women who received GnRHa pretreatment compared to those who did not, it was not statistically significant. Interaction analysis suggested that for PCOS patients, there was no significant difference in the clinical pregnancy rate between women who received GnRHa pretreatment and those who did not, indicating that the effect of GnRHa pretreatment on the clinical pregnancy rate was not influenced by PCOS. Conclusions Our study demonstrates that long-acting GnRHa pretreatment can enhance clinical pregnancy outcomes in patients with RIF. Among RIF patients without PCOS, the clinical pregnancy rate exhibited a significant increase following GnRHa pretreatment compared to the control group. However, in RIF patients with concurrent PCOS, although there was no significant elevation in the clinical pregnancy rate post-GnRHa pretreatment. Additionally, the influence of GnRHa pretreatment on the clinical pregnancy rate was found not to be affected by the presence of PCOS. Long-acting GnRHa RIF PCOS clinical pregnancy rate interaction analysis Figures Figure 1 Background Recurrent Implantation Failure (RIF) is a prominent challenge within Assisted Reproductive Technology (ART), significantly impacting the fertility success rates in women. Despite the absence of a universally accepted definition within the academic sphere, RIF is typically characterized by the failure to achieve a clinical pregnancy following a minimum of two transfers involving high-quality embryos (inclusive of at least four high-quality cleavage embryos or two high-quality blastocysts)[ 1 – 3 ]. The prevalence of RIF ranges between 10% and 20%, and for patients within this category, the success rate per embryo transfer may fall below 10%[ 4 ]. The etiology of RIF is multifactorial, encompassing embryo-associated factors, uterine cavity environmental factors, maternal factors, and immune factors, amongst others[ 5 ]. Presently, there are no efficacious interventions available to enhance the clinical pregnancy outcomes in patients diagnosed with RIF[ 4 ]. In addressing RIF, the utilization of pretreatment with long-acting gonadotropin-releasing hormone agonists (GnRHa) is gaining traction. Certain studies have indicated that this pretreatment with long-acting GnRHa can notably enhance the clinical pregnancy rate amongst RIF patients[ 6 – 8 ]. This enhancement may be attributed to GnRHa's ability to augment the receptivity of the endometrium, thereby elevating the success rate of embryo implantation[ 9 ]. GnRHa accomplishes this by curbing the excessive secretion of gonadotropins, preventing premature endometrial thickening, ameliorating the uterine environment, and boosting the success rate of frozen embryo transfer (FET)[ 9 – 11 ]. Consequently, pretreatment with long-acting GnRHa could potentially serve as an efficacious strategy to improve the clinical outcomes in patients diagnosed with RIF. Several studies have identified an elevated risk of RIF in patients diagnosed with Polycystic Ovary Syndrome (PCOS), which might be associated with the endocrine and metabolic dysfunctions, aberrant endometrium, and chronic inflammatory state observed in these patients[ 12 , 13 ]. The pretreatment with long-acting GnRHa is postulated to enhance the clinical pregnancy outcomes in patients diagnosed with PCOS. Several investigations have reported an increase in the clinical pregnancy rate and live birth rate in PCOS patients following GnRHa pretreatment[ 14 , 15 ]. Nonetheless, a study has found no significant improvement in the clinical pregnancy rate in PCOS patients post-GnRHa pretreatment[ 16 ]. Consequently, the findings of various studies regarding the efficacy of GnRHa pretreatment in improving clinical pregnancy outcomes in PCOS patients are incongruous. Moreover, research investigating whether long-acting GnRHa exhibits superior clinical efficacy in RIF patients with a history of PCOS is limited. Therefore, we conducted a retrospective study on RIF patients at our reproductive medicine center from 2017 to 2021 to investigate the impact of long-acting GnRHa pretreatment on the clinical pregnancy outcomes of RIF patients. Additionally, we aimed to explore the differential effects of long-acting GnRHa on both PCOS and non-PCOS populations. Methods Patients In this retrospective study, the inclusion criteria encompassed 1602 patients who experienced RIF and underwent FET at the Reproductive Medicine Center of Nanjing Drum Tower Hospital from January 2017 to December 2021 (Fig. 1 ). The diagnostic criteria for RIF comprised of the following: individuals under 40 years of age, a minimum of two prior embryo transfers, and the inability to conceive post the transfer of at least four high-quality cleavage embryos, two high-quality blastocysts, or a combination of two high-quality cleavage embryos and one high-quality blastocyst[ 17 ]. The patients were subjected to either hormone replacement therapy (HRT, Femoston, 2 mg estradiol; 2 mg estradiol plus 10 mg dydrogesterone, Abbott, USA) or a long-acting GnRHa pretreated-HRT protocol. Given the retrospective design of the study, written informed consent was exempted for all patients, which had received approval from the Ethics Committee of Nanjing Drum Tower Hospital. Prior to the embryo transfer cycles, all patients underwent extensive preconception examinations to rule out any contraindications to medication or pregnancy. The overall health status of the patients involved in this study was deemed normal. The study's exclusion criteria included: (1) usage of other hormone replacement medications; (2) existence of tubal hydrosalpinx, uterine cavity or endometrial abnormalities; (3) moderate to severe endometriosis or adenomyosis; (4) chromosomal abnormalities or patients who underwent preimplantation genetic testing (PGT). Endometrial preparation and thawed embryo transfer Control group (HRT): During the initial phase of menstruation (on day two or three of the menstrual cycle), hormonal serum tests and transvaginal ultrasound examinations are conducted. In the absence of abnormalities, patients commence an oral fixed dose of exogenous estradiol (Femoston, 2 mg estradiol, 2 mg t.i.d.) and continue for 12–14 days. Serum oestrogen (E 2 ) and progesterone (P) levels, along with endometrial thickness, are monitored. Patients with decreased endometrial thickness receive additional medication (Femoston, 2 mg estradiol, 4 mg b.i.d.). Upon reaching a specific endometrial thickness standard (≥ 8 mm), patients begin oral administration of estradiol combined with dydrogesterone compound tablets (Femoston, 2 mg estradiol and 10 mg dydrogesterone, t.i.d. for 5 or 6 days), and progesterone injections (progesterone injection solution, Zhejiang Xianju Pharmaceutical, China, 60 mg q.d.) to induce endometrial transformation. On the fifth day of endometrial transformation, cleavage-stage embryos are thawed and transferred, or on the sixth day, blastocysts are thawed and transferred. Patients typically consume Femoston (2 mg estradiol and 10 mg dydrogesterone, t.i.d.) and receive luteal support with progesterone sustained-release vaginal gel (Crinone, Merck Pharmaceuticals, Switzerland, 90 mg q.d.). For the following patients, we may preferentially choose GnRHa pretreatment in clinical treatment: 1. thin endometrium in the previous transfer cycle; 2. history of endometritis suggested by previous examinations; 3. potential endometriosis; 4. empirical decision by the clinician. Research group (GnRHa-HRT): In the long-acting GnRHa pre-treated HRT cycle, a long-acting GnRHa (Decapeptyl, 3.75 mg) is administered on day two or three of menstruation, followed by the HRT cycle after 4 weeks. Serum β-human chorionic gonadotropin (β-hCG) is tested two weeks post-embryo transfer to ascertain biochemical pregnancy. Four weeks post-embryo transfer, transvaginal ultrasound examination is performed on patients with elevated β-hCG levels to confirm clinical pregnancy and the number of implanted embryos. Clinical pregnancy is characterized by the presence of a gestational sac observed on ultrasound. Luteal support for pregnant patients persists for two months post-embryo transfer. Patients are followed up to detect any pregnancy abnormalities. Early miscarriage is defined as spontaneous miscarriage occurring before 12 weeks of gestation. Live birth is defined as the delivery of a viable infant post 28 weeks of gestation, and the live birth rate is calculated as the ratio of the number of live births to the number of embryo transfer cycles. Statistical analysis Most of our data is directly extracted from the patients' medical record systems, while a small portion is registered by dedicated data entry personnel and verified by the responsible clinical doctors. The method of data collection is standardized, and the data source is genuine and reliable. Primary outcomes investigated in this study was clinical pregnancy rate, while live birth rate and early miscarriage rate were deemed as secondary outcomes. All cycles were categorized into HRT Group and GnRHa-HRT Group, contingent on the usage of long-acting GnRHa pretreatment. The association between GnRHa pretreatment and clinical pregnancy rate in RIF patients during FET cycles was evaluated. Univariate analysis was employed to initially assess potential confounding factors that may influence the clinical pregnancy rate, and these were included as adjusting variables in subsequent analyses. Moreover, a multivariate logistic regression model was utilized to examine the impact of GnRHa pretreatment on the clinical pregnancy rate in RIF patients. The diagnosis of PCOS was according to the Rotterdam criteria[ 18 ], and the population was bifurcated into non-PCOS and PCOS groups. The effect of long-acting GnRHa pretreatment on clinical pregnancy outcomes was reevaluated in both subgroups. Furthermore, an interaction analysis was conducted to assess the influence of PCOS on the relationship between long-acting GnRHa pretreatment and clinical pregnancy rate. The study variables were expressed as mean ± standard deviation (SD). All analyses were performed using R software ( http://www.R-project.org ) and EmpowerStats software ( www.empowerstats.com , X&Y Solutions, Inc. Boston MA). A p-value < 0.05 was considered to indicate statistical significance. Results The baseline and clinical outcome variables of the HRT group (n = 1283) and the GnRHa-HRT group (n = 319) are presented in Table 1 . No significant differences were observed in female age, male age, body mass index (BMI), duration of infertility, type of infertility, baseline follicle-stimulating hormone (FSH), baseline luteinizing hormone (LH), fertilization method in the retrieval cycle, number and quality of transferred embryos, and type of transferred embryos between the two groups. A notable difference was found in anti-müllerian hormone (AMH) levels, with the GnRHa-HRT group showing significantly lower levels compared to the HRT group (3.00 ± 2.11 ng/mL vs 3.74 ± 2.51 ng/mL, P = 0.023). However, there were no significant differences in baseline FSH levels and AFC between the two groups, indicating that there is no significant deviation in ovarian reserve function between the two groups. In addition, the endometrial thickness in the GnRHa-HRT group () was significantly greater than that in the HRT group (9.98 ± 1.73 mm vs 9.42 ± 1.37 mm, P < 0.001). The number of embryos implanted, and the clinical pregnancy rate differed significantly between the two groups. The clinical pregnancy rate was significantly higher in the GnRHa-HRT group compared to the HRT group (59.25% vs 47.70%, P < 0.001), while no significant difference was observed in the early miscarriage rate. Table 1 Characteristics of FET cycles according to different endometrial preparation protocols. Group HRT GnRHa-HRT P-value Number 1283 319 0.907 Female age (years) 31.90 ± 4.17 31.87 ± 4.02 0.907 Male age (years) 33.53 ± 5.15 33.33 ± 4.75 0.528 BMI (kg/m 2 ) 22.62 ± 3.16 22.56 ± 3.14 0.751 Duration of infertility (years) 3.99 ± 2.89 3.98 ± 3.03 0.954 AMH (ng/mL) 3.74 ± 2.51 3.00 ± 2.11 0.023 Basic FSH (IU/L) 7.34 ± 2.54 7.46 ± 2.43 0.448 Basic LH (IU/L) 5.02 ± 3.50 4.99 ± 3.05 0.903 AFC (n) 16.7 ± 7.9 17.1 ± 7.5 0.864 Endometrium thickness (mm) 9.42 ± 1.37 9.98 ± 1.73 < 0.001 Implanted embryo number (n) 0.59 ± 0.69 0.74 ± 0.70 < 0.001 Fertilization mode 0.814 IVF 924 (72.07%) 223 (69.91%) ICSI 262 (20.44%) 73 (22.88%) RICSI 35 (2.73%) 8 (2.51%) TESA/PESA-ICSI 61 (4.76%) 15 (4.70%) Infertility type 0.454 Primary infertility 690 (53.78%) 179 (56.11%) Secondary infertility 593 (46.22%) 140 (43.89%) Number of transferred embryos 0.093 1 475 (37.02%) 102 (31.97%) 2 808 (62.98%) 217 (68.03%) Embryo quality 0.077 0 646 (50.35%) 143 (44.83%) 1 637 (49.65%) 176 (55.17%) Type of transferred embryos 0.233 Cleavage-stage embryo 804 (62.67%) 184 (57.68%) Blastocyst 465 (36.24%) 130 (40.75%) Sequential transfer 14 (1.09%) 5 (1.57%) Clinical pregnancy rate 612 (47.70%) 189 (59.25%) < 0.001 Early miscarriage rate 78 (12.75%) 27 (14.29%) 0.583 Notes : Embryo quality: 1 for at least one high-quality cleavage-stage embryo or blastocyst. We conducted preliminary univariate analysis (Table S1 ), which showed that both female age and male age were significantly negatively correlated with clinical pregnancy rate. GnRHa pretreatment, AMH level, endometrial thickness, number and quality of transferred embryos, as well as embryo type, were all significantly positively correlated with clinical pregnancy rate. These potential confounding factors were included as adjustment variables in subsequent regression analysis to eliminate their influence. Multiple regression analysis (Table 2 ) revealed that after considering the above confounding factors, GnRHa pretreatment still had a positive impact on clinical pregnancy rate. The clinical pregnancy rate in the GnRHa pretreatment group was 1.51 times higher than that in the control group. Table 2 Multivariate analysis for GnRHa pretreatment in FET cycles involved in the clinical pregnancy rate. GnRHa pretreatment Adjusted OR 95% CI p value No 1.00 1.00 Yes 1.51 (1.15, 1.99) 0.003 We conducted further stratified analysis by dividing the RIF population into two groups: non-PCOS patients and PCOS patients. A comparison of baseline and clinical outcome variables between the two groups revealed that the clinical pregnancy rates in the GnRHa-HRT group were higher than those in the HRT group for both groups of patients (Table S2 and S3). To further elucidate the correlation, multivariate regression analysis was performed on the two groups of patients, considering confounding factors such as female age, male age, AMH, endometrial thickness, number of transferred embryos, embryo quality, and type of transferred embryos. For non-PCOS patients, the clinical pregnancy rate after GnRHa pretreatment was 1.59 times higher than that in the control group (P = 0.004, Table 3 ). However, for PCOS patients, although the clinical pregnancy rate was higher in those who received GnRHa pretreatment compared to those who did not (aOR = 1.51), it was not statistically significant. This suggests that GnRHa pretreatment can significantly enhance the clinical pregnancy rate in non-PCOS patients, but its impact on PCOS patients is not significant. Table 3 Multivariate analysis for GnRHa pretreatment in FET cycles of patients with PCOS or not involved in the clinical pregnancy rate. Non-PCOS PCOS GnRHa pretreatment Adjusted OR 95% CI p-value Adjusted OR 95% CI p-value No 1 1 Yes 1.59 (1.16, 2.18) 0.004 1.51 (0.81, 2.82) 0.195 To further investigate whether PCOS modifies the impact of GnRHa pretreatment on the clinical pregnancy rate of RIF patients, we conducted an interaction analysis (Table 4 ). After adjusting for confounding factors, we found that for non-PCOS patients, the clinical pregnancy rate of females who underwent GnRHa pretreatment was 1.60 times higher than that of untreated females (P = 0.003). However, for PCOS patients, there was no significant difference in the clinical pregnancy rate between females who received GnRHa pretreatment and those who did not (aOR = 0.89, P = 0.936). Moreover, the influence of GnRHa pretreatment on the clinical pregnancy rate was not affected by PCOS (interaction P-value = 0.818). Table 4 Effect modification of GnRHa pretreatment on clinical pregnancy rate according to whether PCOS or not. GnRHa pretreatment PCOS N Clinical pregnancy rate Adjusted OR (95%CI) P-value No No 874 874 (45.88%) 1.00 Yes No 256 256 (57.81%) 1.60 (1.17, 2.19) 0.003 No Yes 409 409 (51.59%) 0.61 (0.04, 9.37) 0.719 Yes Yes 63 63 (65.08%) 0.89 (0.05, 14.54) 0.936 P interaction 0.818 Discussion Prior research has indicated that pre-treatment with long-acting GnRHa may enhance clinical pregnancy outcomes in patients with RIF[ 6 , 19 , 20 ]. Our study corroborated these findings: through multiple regression analysis, it was observed that, when accounting for pertinent confounding variables, the clinical pregnancy rate in the GnRHa pre-treatment cohort was 1.51 times higher compared to the control group. Subsequent stratified analysis revealed that, among non-PCOS patients, the clinical pregnancy rate post-GnRHa pre-treatment was 1.59 times greater than that in the control group. Conversely, for PCOS patients, while the clinical pregnancy rate was elevated in those who underwent GnRHa pre-treatment in contrast to those who did not, the disparity lacked statistical significance. Furthermore, the impact of GnRHa pre-treatment on clinical pregnancy rate remained unaffected by PCOS status. The artificial cycle is a commonly utilized method for endometrial preparation in FET, yet research findings regarding the addition of GnRHa pre-treatment are inconclusive. GnRHa may enhance embryo implantation rates and clinical pregnancy outcomes by influencing endometrial status and early embryos[ 21 ]. Previous studies have indicated that GnRHa can enhance clinical outcomes in fresh embryo transfer, although findings in FET cycles are inconsistent[ 22 , 23 ]. A meta-analysis encompassing a total sample size exceeding 10,000 cases assessed the impact of GnRHa pre-treatment on outcomes in HRT-FET cycle: the embryo implantation rate (OR = 1.31), clinical pregnancy rate (OR = 1.27), and live birth rate (OR = 1.16) in the GnRHa pre-treatment group surpassed those in the non-pretreatment group. Subgroup analysis focused on patients with recurrent implantation failure, revealing that GnRHa pre-treatment significantly enhanced embryo implantation and clinical pregnancy rates in such individuals[ 20 ]. Furthermore, a study explored the effects of long-acting GnRHa pre-treatment on the clinical outcomes of women with varying numbers of prior transplant failures: while reproductive outcomes were comparable for women with no or one prior failure, those with multiple failures exhibited higher pregnancy rates in the GnRHa pre-treatment group, particularly among younger patients aged 35–37 years[ 6 ]. Our study produced similar findings, underscoring the potential of long-acting GnRHa pre-treatment to enhance clinical pregnancy outcomes in patients with Recurrent Implantation Failure. Prior research has indicated that GnRHa may enhance endometrial receptivity and facilitate embryo implantation, potentially serving as a mechanism to enhance clinical outcomes in patients with RIF. The expression of GnRH and its receptors in various peripheral tissues, including the uterus, suggests that GnRH may exert autocrine and paracrine effects, with the uterus serving as a target for GnRHa activity. GnRHa therapy has been shown to modulate the growth and apoptosis processes of diverse cells, as well as the expression of growth factors and cytokines. Moreover, GnRHa treatment influences the expression of lipid receptors in the uterine endometrium and exhibits a notable anti-proliferative impact[ 11 , 24 – 29 ]. RIF may be linked to immune dysregulation, such as an imbalance in Th17/Treg cells. GnRHa can directly modulate immune cell receptors in the uterus and impact Th17/Treg levels, thereby enhancing the uterine environment[ 10 ]. Research findings have indicated that patients with PCOS exhibit reduced fertility rates and elevated miscarriage rates even following in vitro fertilization (IVF) treatment[ 13 ]. These observations imply potential impairments in endometrial development and receptivity among PCOS patients[ 13 ]. Studies have revealed notable decreases in crucial molecules involved in embryo adhesion within the endometrium, such as HOXA10 and LIF, in individuals with PCOS, potentially attributed to the inhibitory effects of elevated androgen levels. Furthermore, factors like insufficient energy supply, heightened oxidative stress, diminished angiogenesis, and abnormal pro-inflammatory conditions within the endometrium of PCOS patients can also impact the process of embryo implantation[ 12 ]. Clinical investigations have demonstrated that the utilization of a combination therapy of GnRHa and human menopausal gonadotropin (hMG) can lead to reduced miscarriage rates and increased live birth rates in anovulatory PCOS women compared to gonadotropin monotherapy[ 30 ]. Specifically, in PCOS women undergoing GnRHa pretreatment, there is a significant enhancement in ongoing pregnancy rates during frozen embryo transfer cycles[ 15 ]. Conversely, conflicting study results have been reported regarding the impact of GnRHa pretreatment on live birth rates in PCOS women[ 16 ]. Subgroup analysis was performed to evaluate the potential differential effects of GnRHa pretreatment on treatment outcomes in RIF patients with PCOS. The analysis revealed a notable rise in clinical pregnancy rates among the PCOS subgroup of RIF patients following GnRHa pretreatment. However, correlation and interaction analyses indicated no statistically significant association between GnRHa pretreatment and improvements in clinical pregnancy rates. Notably, the clinical pregnancy rate among RIF patients with concurrent PCOS in our institution was higher than that in non-PCOS patients. This suggests the importance of defining individualized RIF patients. Perhaps PCOS patients need a more specific definition of RIF. The definition of RIF cannot be generalized, which provides new ideas for our future research. Therefore, despite observing an increase in clinical pregnancy rates post-GnRHa pretreatment, statistical significance was not achieved. There are several limitations to our study. Our investigation is constrained to HRT cycles primarily due to the limited number of PCOS patients undergoing controlled ovarian stimulation to prime the endometrium, aiming to prevent excessive follicle development that could result in ovarian hyperstimulation syndrome (OHSS). Moreover, we did not categorize PCOS patients into specific subtypes, raising the possibility that GnRHa may exert a more pronounced therapeutic effect on certain PCOS subtypes. While the number, type, and quality of embryo transfers were considered as adjusted variables for statistical analyses, detailed embryo grading was not incorporated. Additionally, due to constraints in our data system, accessing comprehensive data on patient follicle retrieval cycles during the pre-transfer preparation phase was challenging, preventing further analysis of potential confounding variables associated with these cycles. Due to our inability to identify potential patients with endometriosis and obtain corresponding data, we are unable to exclude the potential benefits of using GnRHa treatment in such patients. The primary limitation of our study lies in its retrospective nature, underscoring the need for caution when extrapolating these findings to real-world scenarios. To gain deeper insights into the impact of GnRHa pretreatment on patients with RIF and concurrent PCOS, high-quality, large-scale prospective studies are essential. Such studies would facilitate more precise selection of cycle preparation strategies for RIF patients, minimize unnecessary GnRHa pretreatment, reduce time and costs, and uphold superior clinical pregnancy rates. Conclusions Our study demonstrates that long-acting GnRHa pretreatment can enhance clinical pregnancy outcomes in patients with RIF. Among RIF patients without PCOS, the clinical pregnancy rate exhibited a significant increase following GnRHa pretreatment compared to the control group. However, in RIF patients with concurrent PCOS, although there was an elevation in the clinical pregnancy rate post-GnRHa pretreatment, the difference did not reach statistical significance. Moreover, the influence of GnRHa pretreatment on the clinical pregnancy rate was found to be consistent regardless of the presence of PCOS. Abbreviations GnRHa Gonadotropin-Releasing Hormone agonist RIF recurrent implantation failure PCOS polycystic ovary syndrome FET frozen-thawed embryo transfer ART Assisted Reproductive Technology HRT hormone replacement therapy PGT preimplantation genetic testing β-hCG β-human chorionic gonadotropin SD Standard Deviation BMI body mass index FSH follicle-stimulating hormone LH luteinizing hormone AMH anti-müllerian hormone AFC antral follicle count hMG human menopausal gonadotropin IVF in vitro fertilization OHSS ovarian hyperstimulation syndrome. Declarations Ethics approval and consent to participate This retrospective study received ethical approval from the ethics committee of Nanjing Drum Tower Hospital. All methods were carried out in accordance with relevant guidelines and regulations. Consent for publication Not applicable. Availability of data and materials The datasets generated and analyzed during the current study are not publicly available due to the special requirements of our hospital and our reproductive medicine center for the disclosure of patients’ clinical data but are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This work was supported by Fertility Research Program of Young and Middle-aged Physicians-Clinical Research In 2022 and 2023 (Beijing Health Promotion Association, BJHPA-2022-SHZHYXZHQNYJ-LCH-002, BJHPA-2023-SZHYXZHQN-006), fundings for Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University (2022-LCYJ-MS-35, 2021-LCYJ-MS-20), National Natural Science Foundation of China (82071646), Scientific research project of Jiangsu Province Association of Maternal and Child Health (No. FYX202203), Open project of the Affiliated Jiangning Hospital of Nanjing Medical University Immune Cell Transformation Research Center (JNYYZXKY202213) and Nanjing Drum Tower Hospital Medical Center Project (2022-YXZX-FC-03). There are no conflicts of interest. Authors’ contributions C.Y.H., H.X.S. and J.X. contributed to study design, execution, acquisition, analysis, and interpretation of data, manuscript drafting, and critical discussion. 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Changes in tissue inflammation, angiogenesis and apoptosis in endometriosis, adenomyosis and uterine myoma after GnRH agonist therapy. Hum Reprod. 2010;25(3):642–53. Wu H, Zhou P, Lin X, Wang S, Zhang S. Endometrial preparation for frozen-thawed embryo transfer cycles: a systematic review and network meta-analysis. J Assist Reprod Genet. 2021;38(8):1913–26. Glujovsky D, Pesce R, Sueldo C, Quinteiro Retamar AM, Hart RJ, Ciapponi A. Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes. Cochrane Database Syst Rev. 2020;10(10):CD006359. Dong KW, Marcelin K, Hsu MI, Chiang CM, Hoffman G, Roberts JL. Expression of gonadotropin-releasing hormone (GnRH) gene in human uterine endometrial tissue. Mol Hum Reprod. 1998;4(9):893–8. Cheon KW, Lee HS, Parhar IS, Kang IS. Expression of the second isoform of gonadotrophin-releasing hormone (GnRH-II) in human endometrium throughout the menstrual cycle. Mol Hum Reprod. 2001;7(5):447–52. Dou Q, Zhao Y, Tarnuzzer RW, Rong H, Williams RS, Schultz GS, Chegini N. Suppression of transforming growth factor-beta (TGF beta) and TGF beta receptor messenger ribonucleic acid and protein expression in leiomyomata in women receiving gonadotropin-releasing hormone agonist therapy. J Clin Endocrinol Metab. 1996;81(9):3222–30. Vignali M. Molecular action of GnRH analogues on ectopic endometrial cells. Gynecol Obstet Invest. 1998;45(Suppl 1):2–5. discussion 35. Imai A, Takagi A, Tamaya T. Gonadotropin-releasing hormone analog repairs reduced endometrial cell apoptosis in endometriosis in vitro. Am J Obstet Gynecol. 2000;182(5):1142–6. Chegini N, Ma C, Tang XM, Williams RS. Effects of GnRH analogues, 'add-back' steroid therapy, antiestrogen and antiprogestins on leiomyoma and myometrial smooth muscle cell growth and transforming growth factor-beta expression. Mol Hum Reprod. 2002;8(12):1071–8. Homburg R, Levy T, Berkovitz D, Farchi J, Feldberg D, Ashkenazi J, Ben-Rafael Z. Gonadotropin-releasing hormone agonist reduces the miscarriage rate for pregnancies achieved in women with polycystic ovarian syndrome. Fertil Steril. 1993;59(3):527–31. Additional Declarations No competing interests reported. Supplementary Files TableS1.docx TableS2.docx TableS3.docx Cite Share Download PDF Status: Published Journal Publication published 11 Feb, 2025 Read the published version in BMC Pregnancy and Childbirth → Version 1 posted Editorial decision: Revision requested 03 Nov, 2024 Reviews received at journal 19 Sep, 2024 Reviewers agreed at journal 19 Sep, 2024 Reviews received at journal 16 Sep, 2024 Reviewers agreed at journal 11 Sep, 2024 Reviewers invited by journal 04 Sep, 2024 Editor invited by journal 12 Aug, 2024 Editor assigned by journal 06 Aug, 2024 Submission checks completed at journal 06 Aug, 2024 First submitted to journal 06 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4869543","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":347913476,"identity":"e0941306-dada-4bd1-be02-5b8e0b89f615","order_by":0,"name":"Chenyang Huang","email":"","orcid":"","institution":"Drum Tower Clinic Medical College of Nanjing Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chenyang","middleName":"","lastName":"Huang","suffix":""},{"id":347913477,"identity":"9bce998e-7da1-456b-80c3-4a13fe1a311a","order_by":1,"name":"Yuan Yan","email":"","orcid":"","institution":"Drum Tower Clinic Medical College of Nanjing Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Yan","suffix":""},{"id":347913478,"identity":"8f9b26e1-65b9-4b29-96f7-a2a06a3b80fd","order_by":2,"name":"Jie Mei","email":"","orcid":"","institution":"Drum Tower Clinic Medical College of Nanjing Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Mei","suffix":""},{"id":347913479,"identity":"99d01b7f-5bec-400e-8ad1-24c3a549a866","order_by":3,"name":"Yue Jiang","email":"","orcid":"","institution":"Drum Tower Clinic Medical College of Nanjing Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Jiang","suffix":""},{"id":347913480,"identity":"ac084c48-e253-43f8-9f81-b76d832ba012","order_by":4,"name":"Haixiang Sun","email":"","orcid":"","institution":"Drum Tower Clinic Medical College of Nanjing Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Haixiang","middleName":"","lastName":"Sun","suffix":""},{"id":347913481,"identity":"dfbc214b-ded3-4e23-9784-56189db8cd98","order_by":5,"name":"Jun Xing","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAs0lEQVRIiWNgGAWjYDACZhDBw8DAT7oWyQaSbTM4QLTK47yHXzDIHM4zvnb82QOGGptoglokm/nSLBh4Dheb3c4xN2A4lpZL0IH8zDxmBkAtidtu57BJMDYcJqyFDaZl8+z0Z8RpAdpi/ACkZYN0ghlxWiSbecwYEnjSE2fczjGTSCDGLwbnzxh/+NhjndgPctiHGhvCWkDekUjsgTITiFAOAswfGH4QqXQUjIJRMApGJgAAGzk3tsLQyKUAAAAASUVORK5CYII=","orcid":"","institution":"Drum Tower Clinic Medical College of Nanjing Medical University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Xing","suffix":""}],"badges":[],"createdAt":"2024-08-06 15:21:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4869543/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4869543/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12884-025-07264-1","type":"published","date":"2025-02-11T15:58:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":64570818,"identity":"224e5907-e5d3-43ae-b8ed-ff238fbb762f","added_by":"auto","created_at":"2024-09-16 01:08:33","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":191801,"visible":true,"origin":"","legend":"\u003cp\u003eA flow chart of the inclusion and exclusion of patients.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4869543/v1/c32f32d5825115e558e94ef4.jpg"},{"id":76487637,"identity":"3a02e77e-23f2-4dae-a55d-ed6214107c8d","added_by":"auto","created_at":"2025-02-17 16:10:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1128048,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4869543/v1/7e825aab-fc35-4852-b36a-425f6f51fc4d.pdf"},{"id":64570218,"identity":"5e11fc79-edb8-46e0-ab32-a45c052e4bea","added_by":"auto","created_at":"2024-09-16 01:00:33","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":16022,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4869543/v1/6a64f83966a81c99edcf5321.docx"},{"id":64570215,"identity":"e1965cbc-eaca-4158-996c-65bd50f68abe","added_by":"auto","created_at":"2024-09-16 01:00:33","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":19057,"visible":true,"origin":"","legend":"","description":"","filename":"TableS2.docx","url":"https://assets-eu.researchsquare.com/files/rs-4869543/v1/d69398a408b62e473a7e914e.docx"},{"id":64570819,"identity":"00056686-3a49-46ab-a116-bb1c22396cd9","added_by":"auto","created_at":"2024-09-16 01:08:33","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":19061,"visible":true,"origin":"","legend":"","description":"","filename":"TableS3.docx","url":"https://assets-eu.researchsquare.com/files/rs-4869543/v1/cb213674d9d094f4824ce294.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The impact of long-acting GnRHa pretreatment on the clinical pregnancy outcomes of hormone replacement therapy-frozen embryo transfer in RIF patients with PCOS: a retrospective clinical study","fulltext":[{"header":"Background","content":"\u003cp\u003eRecurrent Implantation Failure (RIF) is a prominent challenge within Assisted Reproductive Technology (ART), significantly impacting the fertility success rates in women. Despite the absence of a universally accepted definition within the academic sphere, RIF is typically characterized by the failure to achieve a clinical pregnancy following a minimum of two transfers involving high-quality embryos (inclusive of at least four high-quality cleavage embryos or two high-quality blastocysts)[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The prevalence of RIF ranges between 10% and 20%, and for patients within this category, the success rate per embryo transfer may fall below 10%[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The etiology of RIF is multifactorial, encompassing embryo-associated factors, uterine cavity environmental factors, maternal factors, and immune factors, amongst others[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Presently, there are no efficacious interventions available to enhance the clinical pregnancy outcomes in patients diagnosed with RIF[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In addressing RIF, the utilization of pretreatment with long-acting gonadotropin-releasing hormone agonists (GnRHa) is gaining traction. Certain studies have indicated that this pretreatment with long-acting GnRHa can notably enhance the clinical pregnancy rate amongst RIF patients[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This enhancement may be attributed to GnRHa's ability to augment the receptivity of the endometrium, thereby elevating the success rate of embryo implantation[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. GnRHa accomplishes this by curbing the excessive secretion of gonadotropins, preventing premature endometrial thickening, ameliorating the uterine environment, and boosting the success rate of frozen embryo transfer (FET)[\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Consequently, pretreatment with long-acting GnRHa could potentially serve as an efficacious strategy to improve the clinical outcomes in patients diagnosed with RIF.\u003c/p\u003e \u003cp\u003eSeveral studies have identified an elevated risk of RIF in patients diagnosed with Polycystic Ovary Syndrome (PCOS), which might be associated with the endocrine and metabolic dysfunctions, aberrant endometrium, and chronic inflammatory state observed in these patients[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The pretreatment with long-acting GnRHa is postulated to enhance the clinical pregnancy outcomes in patients diagnosed with PCOS. Several investigations have reported an increase in the clinical pregnancy rate and live birth rate in PCOS patients following GnRHa pretreatment[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Nonetheless, a study has found no significant improvement in the clinical pregnancy rate in PCOS patients post-GnRHa pretreatment[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Consequently, the findings of various studies regarding the efficacy of GnRHa pretreatment in improving clinical pregnancy outcomes in PCOS patients are incongruous. Moreover, research investigating whether long-acting GnRHa exhibits superior clinical efficacy in RIF patients with a history of PCOS is limited. Therefore, we conducted a retrospective study on RIF patients at our reproductive medicine center from 2017 to 2021 to investigate the impact of long-acting GnRHa pretreatment on the clinical pregnancy outcomes of RIF patients. Additionally, we aimed to explore the differential effects of long-acting GnRHa on both PCOS and non-PCOS populations.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003e In this retrospective study, the inclusion criteria encompassed 1602 patients who experienced RIF and underwent FET at the Reproductive Medicine Center of Nanjing Drum Tower Hospital from January 2017 to December 2021 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The diagnostic criteria for RIF comprised of the following: individuals under 40 years of age, a minimum of two prior embryo transfers, and the inability to conceive post the transfer of at least four high-quality cleavage embryos, two high-quality blastocysts, or a combination of two high-quality cleavage embryos and one high-quality blastocyst[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The patients were subjected to either hormone replacement therapy (HRT, Femoston, 2 mg estradiol; 2 mg estradiol plus 10 mg dydrogesterone, Abbott, USA) or a long-acting GnRHa pretreated-HRT protocol. Given the retrospective design of the study, written informed consent was exempted for all patients, which had received approval from the Ethics Committee of Nanjing Drum Tower Hospital. Prior to the embryo transfer cycles, all patients underwent extensive preconception examinations to rule out any contraindications to medication or pregnancy. The overall health status of the patients involved in this study was deemed normal. The study's exclusion criteria included: (1) usage of other hormone replacement medications; (2) existence of tubal hydrosalpinx, uterine cavity or endometrial abnormalities; (3) moderate to severe endometriosis or adenomyosis; (4) chromosomal abnormalities or patients who underwent preimplantation genetic testing (PGT).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEndometrial preparation and thawed embryo transfer\u003c/h2\u003e \u003cp\u003eControl group (HRT): During the initial phase of menstruation (on day two or three of the menstrual cycle), hormonal serum tests and transvaginal ultrasound examinations are conducted. In the absence of abnormalities, patients commence an oral fixed dose of exogenous estradiol (Femoston, 2 mg estradiol, 2 mg t.i.d.) and continue for 12\u0026ndash;14 days. Serum oestrogen (E\u003csub\u003e2\u003c/sub\u003e) and progesterone (P) levels, along with endometrial thickness, are monitored. Patients with decreased endometrial thickness receive additional medication (Femoston, 2 mg estradiol, 4 mg b.i.d.). Upon reaching a specific endometrial thickness standard (\u0026ge;\u0026thinsp;8 mm), patients begin oral administration of estradiol combined with dydrogesterone compound tablets (Femoston, 2 mg estradiol and 10 mg dydrogesterone, t.i.d. for 5 or 6 days), and progesterone injections (progesterone injection solution, Zhejiang Xianju Pharmaceutical, China, 60 mg q.d.) to induce endometrial transformation. On the fifth day of endometrial transformation, cleavage-stage embryos are thawed and transferred, or on the sixth day, blastocysts are thawed and transferred. Patients typically consume Femoston (2 mg estradiol and 10 mg dydrogesterone, t.i.d.) and receive luteal support with progesterone sustained-release vaginal gel (Crinone, Merck Pharmaceuticals, Switzerland, 90 mg q.d.). For the following patients, we may preferentially choose GnRHa pretreatment in clinical treatment: 1. thin endometrium in the previous transfer cycle; 2. history of endometritis suggested by previous examinations; 3. potential endometriosis; 4. empirical decision by the clinician. Research group (GnRHa-HRT): In the long-acting GnRHa pre-treated HRT cycle, a long-acting GnRHa (Decapeptyl, 3.75 mg) is administered on day two or three of menstruation, followed by the HRT cycle after 4 weeks. Serum β-human chorionic gonadotropin (β-hCG) is tested two weeks post-embryo transfer to ascertain biochemical pregnancy. Four weeks post-embryo transfer, transvaginal ultrasound examination is performed on patients with elevated β-hCG levels to confirm clinical pregnancy and the number of implanted embryos. Clinical pregnancy is characterized by the presence of a gestational sac observed on ultrasound. Luteal support for pregnant patients persists for two months post-embryo transfer. Patients are followed up to detect any pregnancy abnormalities. Early miscarriage is defined as spontaneous miscarriage occurring before 12 weeks of gestation. Live birth is defined as the delivery of a viable infant post 28 weeks of gestation, and the live birth rate is calculated as the ratio of the number of live births to the number of embryo transfer cycles.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eMost of our data is directly extracted from the patients' medical record systems, while a small portion is registered by dedicated data entry personnel and verified by the responsible clinical doctors. The method of data collection is standardized, and the data source is genuine and reliable. Primary outcomes investigated in this study was clinical pregnancy rate, while live birth rate and early miscarriage rate were deemed as secondary outcomes. All cycles were categorized into HRT Group and GnRHa-HRT Group, contingent on the usage of long-acting GnRHa pretreatment. The association between GnRHa pretreatment and clinical pregnancy rate in RIF patients during FET cycles was evaluated. Univariate analysis was employed to initially assess potential confounding factors that may influence the clinical pregnancy rate, and these were included as adjusting variables in subsequent analyses. Moreover, a multivariate logistic regression model was utilized to examine the impact of GnRHa pretreatment on the clinical pregnancy rate in RIF patients. The diagnosis of PCOS was according to the Rotterdam criteria[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], and the population was bifurcated into non-PCOS and PCOS groups. The effect of long-acting GnRHa pretreatment on clinical pregnancy outcomes was reevaluated in both subgroups. Furthermore, an interaction analysis was conducted to assess the influence of PCOS on the relationship between long-acting GnRHa pretreatment and clinical pregnancy rate. The study variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). All analyses were performed using R software (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.R-project.org\u003c/span\u003e\u003cspan address=\"http://www.R-project.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and EmpowerStats software (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.R-project.org\" target=\"_blank\"\u003ewww.empowerstats.com\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.empowerstats.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, X\u0026amp;Y Solutions, Inc. Boston MA). A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to indicate statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe baseline and clinical outcome variables of the HRT group (n\u0026thinsp;=\u0026thinsp;1283) and the GnRHa-HRT group (n\u0026thinsp;=\u0026thinsp;319) are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. No significant differences were observed in female age, male age, body mass index (BMI), duration of infertility, type of infertility, baseline follicle-stimulating hormone (FSH), baseline luteinizing hormone (LH), fertilization method in the retrieval cycle, number and quality of transferred embryos, and type of transferred embryos between the two groups. A notable difference was found in anti-m\u0026uuml;llerian hormone (AMH) levels, with the GnRHa-HRT group showing significantly lower levels compared to the HRT group (3.00\u0026thinsp;\u0026plusmn;\u0026thinsp;2.11 ng/mL vs 3.74\u0026thinsp;\u0026plusmn;\u0026thinsp;2.51 ng/mL, P\u0026thinsp;=\u0026thinsp;0.023). However, there were no significant differences in baseline FSH levels and AFC between the two groups, indicating that there is no significant deviation in ovarian reserve function between the two groups. In addition, the endometrial thickness in the GnRHa-HRT group () was significantly greater than that in the HRT group (9.98\u0026thinsp;\u0026plusmn;\u0026thinsp;1.73 mm vs 9.42\u0026thinsp;\u0026plusmn;\u0026thinsp;1.37 mm, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The number of embryos implanted, and the clinical pregnancy rate differed significantly between the two groups. The clinical pregnancy rate was significantly higher in the GnRHa-HRT group compared to the HRT group (59.25% vs 47.70%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), while no significant difference was observed in the early miscarriage rate.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of FET cycles according to different endometrial preparation protocols.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHRT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGnRHa-HRT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1283\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e319\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.907\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale age (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.90\u0026thinsp;\u0026plusmn;\u0026thinsp;4.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.87\u0026thinsp;\u0026plusmn;\u0026thinsp;4.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.907\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale age (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33.53\u0026thinsp;\u0026plusmn;\u0026thinsp;5.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.33\u0026thinsp;\u0026plusmn;\u0026thinsp;4.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.528\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI (kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.62\u0026thinsp;\u0026plusmn;\u0026thinsp;3.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.56\u0026thinsp;\u0026plusmn;\u0026thinsp;3.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.751\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDuration of infertility (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.99\u0026thinsp;\u0026plusmn;\u0026thinsp;2.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.98\u0026thinsp;\u0026plusmn;\u0026thinsp;3.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.954\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAMH (ng/mL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.74\u0026thinsp;\u0026plusmn;\u0026thinsp;2.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.00\u0026thinsp;\u0026plusmn;\u0026thinsp;2.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBasic FSH (IU/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.34\u0026thinsp;\u0026plusmn;\u0026thinsp;2.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.46\u0026thinsp;\u0026plusmn;\u0026thinsp;2.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.448\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBasic LH (IU/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.02\u0026thinsp;\u0026plusmn;\u0026thinsp;3.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.99\u0026thinsp;\u0026plusmn;\u0026thinsp;3.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.903\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAFC (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.7\u0026thinsp;\u0026plusmn;\u0026thinsp;7.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.864\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEndometrium thickness (mm)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.42\u0026thinsp;\u0026plusmn;\u0026thinsp;1.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.98\u0026thinsp;\u0026plusmn;\u0026thinsp;1.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eImplanted embryo number (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.59\u0026thinsp;\u0026plusmn;\u0026thinsp;0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFertilization mode\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.814\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIVF\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e924 (72.07%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e223 (69.91%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eICSI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e262 (20.44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73 (22.88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRICSI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (2.73%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (2.51%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTESA/PESA-ICSI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61 (4.76%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (4.70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInfertility type\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.454\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrimary infertility\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e690 (53.78%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e179 (56.11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSecondary infertility\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e593 (46.22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e140 (43.89%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of transferred embryos\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.093\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e475 (37.02%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e102 (31.97%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e808 (62.98%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e217 (68.03%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEmbryo quality\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.077\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e646 (50.35%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e143 (44.83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e637 (49.65%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e176 (55.17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eType of transferred embryos\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.233\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCleavage-stage embryo\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e804 (62.67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e184 (57.68%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBlastocyst\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e465 (36.24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e130 (40.75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSequential transfer\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (1.09%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (1.57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical pregnancy rate\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e612 (47.70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e189 (59.25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEarly miscarriage rate\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78 (12.75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (14.29%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.583\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cb\u003eNotes\u003c/b\u003e: Embryo quality: 1 for at least one high-quality cleavage-stage embryo or blastocyst.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe conducted preliminary univariate analysis (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e), which showed that both female age and male age were significantly negatively correlated with clinical pregnancy rate. GnRHa pretreatment, AMH level, endometrial thickness, number and quality of transferred embryos, as well as embryo type, were all significantly positively correlated with clinical pregnancy rate. These potential confounding factors were included as adjustment variables in subsequent regression analysis to eliminate their influence. Multiple regression analysis (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) revealed that after considering the above confounding factors, GnRHa pretreatment still had a positive impact on clinical pregnancy rate. The clinical pregnancy rate in the GnRHa pretreatment group was 1.51 times higher than that in the control group.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate analysis for GnRHa pretreatment in FET cycles involved in the clinical pregnancy rate.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGnRHa pretreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdjusted OR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e(1.15, 1.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe conducted further stratified analysis by dividing the RIF population into two groups: non-PCOS patients and PCOS patients. A comparison of baseline and clinical outcome variables between the two groups revealed that the clinical pregnancy rates in the GnRHa-HRT group were higher than those in the HRT group for both groups of patients (Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e and S3). To further elucidate the correlation, multivariate regression analysis was performed on the two groups of patients, considering confounding factors such as female age, male age, AMH, endometrial thickness, number of transferred embryos, embryo quality, and type of transferred embryos. For non-PCOS patients, the clinical pregnancy rate after GnRHa pretreatment was 1.59 times higher than that in the control group (P\u0026thinsp;=\u0026thinsp;0.004, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). However, for PCOS patients, although the clinical pregnancy rate was higher in those who received GnRHa pretreatment compared to those who did not (aOR\u0026thinsp;=\u0026thinsp;1.51), it was not statistically significant. This suggests that GnRHa pretreatment can significantly enhance the clinical pregnancy rate in non-PCOS patients, but its impact on PCOS patients is not significant.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate analysis for GnRHa pretreatment in FET cycles of patients with PCOS or not involved in the clinical pregnancy rate.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-PCOS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePCOS\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGnRHa pretreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdjusted OR 95% CI p-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdjusted OR 95% CI p-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.59 (1.16, 2.18) 0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.51 (0.81, 2.82) 0.195\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTo further investigate whether PCOS modifies the impact of GnRHa pretreatment on the clinical pregnancy rate of RIF patients, we conducted an interaction analysis (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). After adjusting for confounding factors, we found that for non-PCOS patients, the clinical pregnancy rate of females who underwent GnRHa pretreatment was 1.60 times higher than that of untreated females (P\u0026thinsp;=\u0026thinsp;0.003). However, for PCOS patients, there was no significant difference in the clinical pregnancy rate between females who received GnRHa pretreatment and those who did not (aOR\u0026thinsp;=\u0026thinsp;0.89, P\u0026thinsp;=\u0026thinsp;0.936). Moreover, the influence of GnRHa pretreatment on the clinical pregnancy rate was not affected by PCOS (interaction P-value\u0026thinsp;=\u0026thinsp;0.818).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEffect modification of GnRHa pretreatment on clinical pregnancy rate according to whether PCOS or not.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGnRHa pretreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePCOS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClinical pregnancy rate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAdjusted OR (95%CI) P-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e874\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e874 (45.88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256 (57.81%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.60 (1.17, 2.19) 0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e409\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e409 (51.59%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.61 (0.04, 9.37) 0.719\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e63 (65.08%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.89 (0.05, 14.54) 0.936\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP interaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.818\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePrior research has indicated that pre-treatment with long-acting GnRHa may enhance clinical pregnancy outcomes in patients with RIF[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Our study corroborated these findings: through multiple regression analysis, it was observed that, when accounting for pertinent confounding variables, the clinical pregnancy rate in the GnRHa pre-treatment cohort was 1.51 times higher compared to the control group. Subsequent stratified analysis revealed that, among non-PCOS patients, the clinical pregnancy rate post-GnRHa pre-treatment was 1.59 times greater than that in the control group. Conversely, for PCOS patients, while the clinical pregnancy rate was elevated in those who underwent GnRHa pre-treatment in contrast to those who did not, the disparity lacked statistical significance. Furthermore, the impact of GnRHa pre-treatment on clinical pregnancy rate remained unaffected by PCOS status.\u003c/p\u003e \u003cp\u003eThe artificial cycle is a commonly utilized method for endometrial preparation in FET, yet research findings regarding the addition of GnRHa pre-treatment are inconclusive. GnRHa may enhance embryo implantation rates and clinical pregnancy outcomes by influencing endometrial status and early embryos[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Previous studies have indicated that GnRHa can enhance clinical outcomes in fresh embryo transfer, although findings in FET cycles are inconsistent[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. A meta-analysis encompassing a total sample size exceeding 10,000 cases assessed the impact of GnRHa pre-treatment on outcomes in HRT-FET cycle: the embryo implantation rate (OR\u0026thinsp;=\u0026thinsp;1.31), clinical pregnancy rate (OR\u0026thinsp;=\u0026thinsp;1.27), and live birth rate (OR\u0026thinsp;=\u0026thinsp;1.16) in the GnRHa pre-treatment group surpassed those in the non-pretreatment group. Subgroup analysis focused on patients with recurrent implantation failure, revealing that GnRHa pre-treatment significantly enhanced embryo implantation and clinical pregnancy rates in such individuals[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Furthermore, a study explored the effects of long-acting GnRHa pre-treatment on the clinical outcomes of women with varying numbers of prior transplant failures: while reproductive outcomes were comparable for women with no or one prior failure, those with multiple failures exhibited higher pregnancy rates in the GnRHa pre-treatment group, particularly among younger patients aged 35\u0026ndash;37 years[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Our study produced similar findings, underscoring the potential of long-acting GnRHa pre-treatment to enhance clinical pregnancy outcomes in patients with Recurrent Implantation Failure. Prior research has indicated that GnRHa may enhance endometrial receptivity and facilitate embryo implantation, potentially serving as a mechanism to enhance clinical outcomes in patients with RIF. The expression of GnRH and its receptors in various peripheral tissues, including the uterus, suggests that GnRH may exert autocrine and paracrine effects, with the uterus serving as a target for GnRHa activity. GnRHa therapy has been shown to modulate the growth and apoptosis processes of diverse cells, as well as the expression of growth factors and cytokines. Moreover, GnRHa treatment influences the expression of lipid receptors in the uterine endometrium and exhibits a notable anti-proliferative impact[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25 CR26 CR27 CR28\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. RIF may be linked to immune dysregulation, such as an imbalance in Th17/Treg cells. GnRHa can directly modulate immune cell receptors in the uterus and impact Th17/Treg levels, thereby enhancing the uterine environment[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eResearch findings have indicated that patients with PCOS exhibit reduced fertility rates and elevated miscarriage rates even following in vitro fertilization (IVF) treatment[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. These observations imply potential impairments in endometrial development and receptivity among PCOS patients[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Studies have revealed notable decreases in crucial molecules involved in embryo adhesion within the endometrium, such as HOXA10 and LIF, in individuals with PCOS, potentially attributed to the inhibitory effects of elevated androgen levels. Furthermore, factors like insufficient energy supply, heightened oxidative stress, diminished angiogenesis, and abnormal pro-inflammatory conditions within the endometrium of PCOS patients can also impact the process of embryo implantation[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Clinical investigations have demonstrated that the utilization of a combination therapy of GnRHa and human menopausal gonadotropin (hMG) can lead to reduced miscarriage rates and increased live birth rates in anovulatory PCOS women compared to gonadotropin monotherapy[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Specifically, in PCOS women undergoing GnRHa pretreatment, there is a significant enhancement in ongoing pregnancy rates during frozen embryo transfer cycles[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Conversely, conflicting study results have been reported regarding the impact of GnRHa pretreatment on live birth rates in PCOS women[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Subgroup analysis was performed to evaluate the potential differential effects of GnRHa pretreatment on treatment outcomes in RIF patients with PCOS. The analysis revealed a notable rise in clinical pregnancy rates among the PCOS subgroup of RIF patients following GnRHa pretreatment. However, correlation and interaction analyses indicated no statistically significant association between GnRHa pretreatment and improvements in clinical pregnancy rates. Notably, the clinical pregnancy rate among RIF patients with concurrent PCOS in our institution was higher than that in non-PCOS patients. This suggests the importance of defining individualized RIF patients. Perhaps PCOS patients need a more specific definition of RIF. The definition of RIF cannot be generalized, which provides new ideas for our future research. Therefore, despite observing an increase in clinical pregnancy rates post-GnRHa pretreatment, statistical significance was not achieved.\u003c/p\u003e \u003cp\u003eThere are several limitations to our study. Our investigation is constrained to HRT cycles primarily due to the limited number of PCOS patients undergoing controlled ovarian stimulation to prime the endometrium, aiming to prevent excessive follicle development that could result in ovarian hyperstimulation syndrome (OHSS). Moreover, we did not categorize PCOS patients into specific subtypes, raising the possibility that GnRHa may exert a more pronounced therapeutic effect on certain PCOS subtypes. While the number, type, and quality of embryo transfers were considered as adjusted variables for statistical analyses, detailed embryo grading was not incorporated. Additionally, due to constraints in our data system, accessing comprehensive data on patient follicle retrieval cycles during the pre-transfer preparation phase was challenging, preventing further analysis of potential confounding variables associated with these cycles. Due to our inability to identify potential patients with endometriosis and obtain corresponding data, we are unable to exclude the potential benefits of using GnRHa treatment in such patients. The primary limitation of our study lies in its retrospective nature, underscoring the need for caution when extrapolating these findings to real-world scenarios. To gain deeper insights into the impact of GnRHa pretreatment on patients with RIF and concurrent PCOS, high-quality, large-scale prospective studies are essential. Such studies would facilitate more precise selection of cycle preparation strategies for RIF patients, minimize unnecessary GnRHa pretreatment, reduce time and costs, and uphold superior clinical pregnancy rates.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur study demonstrates that long-acting GnRHa pretreatment can enhance clinical pregnancy outcomes in patients with RIF. Among RIF patients without PCOS, the clinical pregnancy rate exhibited a significant increase following GnRHa pretreatment compared to the control group. However, in RIF patients with concurrent PCOS, although there was an elevation in the clinical pregnancy rate post-GnRHa pretreatment, the difference did not reach statistical significance. Moreover, the influence of GnRHa pretreatment on the clinical pregnancy rate was found to be consistent regardless of the presence of PCOS.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGnRHa\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGonadotropin-Releasing Hormone agonist\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRIF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erecurrent implantation failure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePCOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epolycystic ovary syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFET\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efrozen-thawed embryo transfer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eART\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAssisted Reproductive Technology\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehormone replacement therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePGT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epreimplantation genetic testing\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eβ-hCG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eβ-human chorionic gonadotropin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStandard Deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebody mass index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFSH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efollicle-stimulating hormone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eluteinizing hormone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAMH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eanti-m\u0026uuml;llerian hormone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAFC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eantral follicle count\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ehMG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehuman menopausal gonadotropin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIVF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ein vitro fertilization\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOHSS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eovarian hyperstimulation syndrome.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study received ethical approval from the ethics committee of Nanjing Drum Tower Hospital. All methods were carried out in accordance with relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are not publicly available due to the special requirements of our hospital and our reproductive medicine center for the disclosure of patients\u0026rsquo; clinical data but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Fertility Research Program of Young and Middle-aged Physicians-Clinical Research In 2022 and 2023 (Beijing Health Promotion Association, BJHPA-2022-SHZHYXZHQNYJ-LCH-002, BJHPA-2023-SZHYXZHQN-006), fundings for Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University (2022-LCYJ-MS-35, 2021-LCYJ-MS-20), National Natural Science Foundation of China (82071646), Scientific research project of Jiangsu Province Association of Maternal and Child Health (No. FYX202203), Open project of the Affiliated Jiangning Hospital of Nanjing Medical University Immune Cell Transformation Research Center (JNYYZXKY202213) and Nanjing Drum Tower Hospital Medical Center Project (2022-YXZX-FC-03). There are no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eC.Y.H., H.X.S. and J.X. contributed to study design, execution, acquisition, analysis, and interpretation of data, manuscript drafting, and critical discussion. Y.Y., J.M. and Y.J. contributed to acquisition and interpretation of data, manuscript drafting, and critical discussion. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTimeva T, Shterev A, Kyurkchiev S. Recurrent implantation failure: the role of the endometrium. J Reprod infertility. 2014;15(4):173\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSomigliana E, Busnelli A, Kalafat E, Vigano P, Ata B. Recurrent implantation failure: a plea for a widely adopted rational definition. Reprod Biomed Online. 2022;45(2):183\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoughlan C, Walters S, Ledger W, Li TC. A comparison of psychological stress among women with and without reproductive failure. Int J Gynaecol Obstet. 2014;124(2):143\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFailure EWGRI, Cimadomo D, de Los Santos MJ, Griesinger G, Lainas G, Le Clef N, McLernon DJ, Montjean D, Toth B, Vermeulen N, et al. ESHRE good practice recommendations on recurrent implantation failure. Hum Reprod open. 2023;2023(3):hoad023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMa J, Gao W, Li D. Recurrent implantation failure: A comprehensive summary from etiology to treatment. Front Endocrinol. 2022;13:1061766.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXia L, Tian L, Zhang S, Huang J, Wu Q. Hormonal Replacement Treatment for Frozen-Thawed Embryo Transfer With or Without GnRH Agonist Pretreatment: A Retrospective Cohort Study Stratified by Times of Embryo Implantation Failures. Front Endocrinol. 2022;13:803471.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen X, Zhang W, Xu Y, Li W, Wang X, Shi S, Liu X. Efficacy of the long-acting gonadotropin-releasing hormone agonist long protocol on IVF/ICSI outcomes of patients with repeated implantation failure. Int J Gynaecol Obstet. 2024;164(2):563\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang X, Huang R, Wang YF, Liang XY. Pituitary suppression before frozen embryo transfer is beneficial for patients suffering from idiopathic repeated implantation failure. \u003cem\u003eJournal of Huazhong University of Science and Technology Medical sciences\u0026thinsp;=\u0026thinsp;Hua zhong ke ji da xue xue bao Yi xue Ying De wen ban\u0026thinsp;=\u0026thinsp;Huazhong keji daxue xuebao Yixue Yingdewen ban\u003c/em\u003e 2016, 36(1):127\u0026ndash;131.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi L, Liu L, Kou Z, Huo M, An J, Zhang X. GnRH agonist treatment regulates IL-6 and IL-11 expression in endometrial stromal cells for patients with HRT regiment in frozen embryo transfer cycles. Reprod Biol. 2022;22(2):100608.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo Z, Shi P, Hao C. Effect of GnRHa on Th17/Treg cells in peripheral blood of patients with unexplained repeated implantation failure. Arch Gynecol Obstet. 2018;298(6):1211\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuo X, Xu J, Chegini N. Gonadotropin releasing hormone analogue (GnRHa) alters the expression and activation of Smad in human endometrial epithelial and stromal cells. \u003cem\u003eReproductive biology and endocrinology: RB\u0026amp;E\u003c/em\u003e 2003, 1:125.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo F, Huang Y, Fernando T, Shi Y. Altered Molecular Pathways and Biomarkers of Endometrial Receptivity in Infertile Women with Polycystic Ovary Syndrome. Reproductive Sci. 2022;29(12):3335\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao J, Chen Q, Xue X. An Update on the Progress of Endometrial Receptivity in Women with Polycystic Ovary Syndrome. Reproductive Sci. 2022;29(8):2136\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAghahoseini M, Alyasin A, Rashidi S, Samaei-Nouroozi A, Saeidi H, Shabani-Nashtaei M. The efficacy of gonadotropin-releasing hormone (GNRH) agonist before frozen embryo transfer in improving pregnancy outcome and decreasing miscarriage rate in hyperandrogenic polycystic ovary syndrome women: a randomized clinical trial. Minerva Ginecol. 2020;72(4):212\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsai HW, Wang PH, Lin LT, Chen SN, Tsui KH. Using gonadotropin-releasing hormone agonist before frozen embryo transfer may improve ongoing pregnancy rates in hyperandrogenic polycystic ovary syndrome women. Gynecol endocrinology: official J Int Soc Gynecol Endocrinol. 2017;33(9):686\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu X, Shi J, Bai H, Wen W. Pretreatment with a GnRH agonist and hormone replacement treatment protocol could not improve live birth rate for PCOS women undergoing frozen-thawed embryo transfer cycles. BMC Pregnancy Childbirth. 2021;21(1):835.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoughlan C, Ledger W, Wang Q, Liu F, Demirol A, Gurgan T, Cutting R, Ong K, Sallam H, Li TC. Recurrent implantation failure: definition and management. Reprod Biomed Online. 2014;28(1):14\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRotterdam EA-SP. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan D, Yang J, Zhang N, Wang L, Li N, Shi J, Zhou H. Gonadotropin-releasing hormone agonist downregulation combined with hormone replacement therapy improves the reproductive outcome in frozen-thawed embryo transfer cycles for patients of advanced reproductive age with idiopathic recurrent implantation failure. \u003cem\u003eReproductive biology and endocrinology: RB\u0026amp;E\u003c/em\u003e 2022, 20(1):26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi X, Lin J, Zhang L, Liu Y. Effects of gonadotropin-releasing hormone agonist pretreatment on frozen embryo transfer outcomes in artificial cycles: a meta-analysis. Arch Gynecol Obstet. 2023;308(3):675\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhan KN, Kitajima M, Hiraki K, Fujishita A, Sekine I, Ishimaru T, Masuzaki H. Changes in tissue inflammation, angiogenesis and apoptosis in endometriosis, adenomyosis and uterine myoma after GnRH agonist therapy. Hum Reprod. 2010;25(3):642\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu H, Zhou P, Lin X, Wang S, Zhang S. Endometrial preparation for frozen-thawed embryo transfer cycles: a systematic review and network meta-analysis. J Assist Reprod Genet. 2021;38(8):1913\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlujovsky D, Pesce R, Sueldo C, Quinteiro Retamar AM, Hart RJ, Ciapponi A. Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes. Cochrane Database Syst Rev. 2020;10(10):CD006359.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDong KW, Marcelin K, Hsu MI, Chiang CM, Hoffman G, Roberts JL. Expression of gonadotropin-releasing hormone (GnRH) gene in human uterine endometrial tissue. Mol Hum Reprod. 1998;4(9):893\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheon KW, Lee HS, Parhar IS, Kang IS. Expression of the second isoform of gonadotrophin-releasing hormone (GnRH-II) in human endometrium throughout the menstrual cycle. Mol Hum Reprod. 2001;7(5):447\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDou Q, Zhao Y, Tarnuzzer RW, Rong H, Williams RS, Schultz GS, Chegini N. Suppression of transforming growth factor-beta (TGF beta) and TGF beta receptor messenger ribonucleic acid and protein expression in leiomyomata in women receiving gonadotropin-releasing hormone agonist therapy. J Clin Endocrinol Metab. 1996;81(9):3222\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVignali M. Molecular action of GnRH analogues on ectopic endometrial cells. Gynecol Obstet Invest. 1998;45(Suppl 1):2\u0026ndash;5. discussion 35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eImai A, Takagi A, Tamaya T. Gonadotropin-releasing hormone analog repairs reduced endometrial cell apoptosis in endometriosis in vitro. Am J Obstet Gynecol. 2000;182(5):1142\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChegini N, Ma C, Tang XM, Williams RS. Effects of GnRH analogues, 'add-back' steroid therapy, antiestrogen and antiprogestins on leiomyoma and myometrial smooth muscle cell growth and transforming growth factor-beta expression. Mol Hum Reprod. 2002;8(12):1071\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHomburg R, Levy T, Berkovitz D, Farchi J, Feldberg D, Ashkenazi J, Ben-Rafael Z. Gonadotropin-releasing hormone agonist reduces the miscarriage rate for pregnancies achieved in women with polycystic ovarian syndrome. Fertil Steril. 1993;59(3):527\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Long-acting GnRHa, RIF, PCOS, clinical pregnancy rate, interaction analysis","lastPublishedDoi":"10.21203/rs.3.rs-4869543/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4869543/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSeveral studies have demonstrated that pre-treatment with long-acting Gonadotropin-Releasing Hormone agonists (GnRHa) can significantly enhance the clinical pregnancy rate among recurrent implantation failure (RIF) patients. Investigations have also suggested that GnRHa pre-treatment could ameliorate the clinical pregnancy and live birth rates in polycystic ovary syndrome (PCOS) patients. But there is a dearth of research on whether long-acting GnRHa pre-treatment yields superior clinical outcomes for RIF patients with PCOS.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe retrospective study enrolled 1602 patients under the age of 40 meeting the criteria for RIF at the Reproductive Medicine Center of Nanjing Drum Tower Hospital, who underwent frozen-thawed embryo transfer (FET) between January 2017 and December 2021. Univariate analysis and a multivariate logistic regression model were employed to assess the impact of GnRHa pretreatment on the clinical pregnancy rate in RIF patients. The influence of long-acting GnRHa pretreatment on clinical pregnancy outcomes was re-examined in PCOS and non-PCOS subgroups. Additionally, an interaction analysis was performed to evaluate the effect of PCOS on the relationship between long-acting GnRHa pretreatment and the clinical pregnancy rate.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMultiple regression analysis showed that long-acting GnRHa pretreatment had a positive impact on the clinical pregnancy rate. We divided the RIF population into two subgroups, for PCOS patients, although the clinical pregnancy rate was higher in women who received GnRHa pretreatment compared to those who did not, it was not statistically significant. Interaction analysis suggested that for PCOS patients, there was no significant difference in the clinical pregnancy rate between women who received GnRHa pretreatment and those who did not, indicating that the effect of GnRHa pretreatment on the clinical pregnancy rate was not influenced by PCOS.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur study demonstrates that long-acting GnRHa pretreatment can enhance clinical pregnancy outcomes in patients with RIF. Among RIF patients without PCOS, the clinical pregnancy rate exhibited a significant increase following GnRHa pretreatment compared to the control group. However, in RIF patients with concurrent PCOS, although there was no significant elevation in the clinical pregnancy rate post-GnRHa pretreatment. Additionally, the influence of GnRHa pretreatment on the clinical pregnancy rate was found not to be affected by the presence of PCOS.\u003c/p\u003e","manuscriptTitle":"The impact of long-acting GnRHa pretreatment on the clinical pregnancy outcomes of hormone replacement therapy-frozen embryo transfer in RIF patients with PCOS: a retrospective clinical study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-16 01:00:28","doi":"10.21203/rs.3.rs-4869543/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-04T04:45:30+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-19T06:40:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"121205940694860184057029973753495512062","date":"2024-09-19T05:44:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-16T16:21:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"311418978246750896109504096162138035297","date":"2024-09-11T09:05:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-04T11:32:32+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-08-12T12:04:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-06T23:22:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-06T23:21:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pregnancy and Childbirth","date":"2024-08-06T15:18:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1d02a628-5055-4766-ab39-9dc66dad68fe","owner":[],"postedDate":"September 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-02-17T16:04:20+00:00","versionOfRecord":{"articleIdentity":"rs-4869543","link":"https://doi.org/10.1186/s12884-025-07264-1","journal":{"identity":"bmc-pregnancy-and-childbirth","isVorOnly":false,"title":"BMC Pregnancy and Childbirth"},"publishedOn":"2025-02-11 15:58:00","publishedOnDateReadable":"February 11th, 2025"},"versionCreatedAt":"2024-09-16 01:00:28","video":"","vorDoi":"10.1186/s12884-025-07264-1","vorDoiUrl":"https://doi.org/10.1186/s12884-025-07264-1","workflowStages":[]},"version":"v1","identity":"rs-4869543","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4869543","identity":"rs-4869543","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}