Additional single dose GnRH agonist during luteal phase support may improve live birth rate in GnRHa-HRT frozen–thawed embryo transfer cycle: a retrospective cohort study

Additional single dose GnRH agonist during luteal phase support may improve live birth rate in GnRHa-HRT frozen–thawed embryo transfer cycle: a retrospective cohort 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 Additional single dose GnRH agonist during luteal phase support may improve live birth rate in GnRHa-HRT frozen–thawed embryo transfer cycle: a retrospective cohort study Wei-Shan Chang, Pei-Hsuan Lin, Chia-Jung Li, Chyi-Uei Chern, Yu-Chen Chen, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2456935/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background GnRH agonist (GnRHa) has been reported to have direct effects and functional roles in the endometrium and embryos. Several meta-analyses have shown that GnRHa administration in the luteal phase improved the live birth rate or pregnancy rate in both fresh and frozen embryo transfer (FET) cycles. The aim of this study was to investigate whether luteal GnRHa administration could also improve in vitro fertilization (IVF) outcomes in patients undergoing hormone replacement therapy (HRT) cycles with GnRHa suppression. Methods The retrospective cohort study included a total of 414 patients undergoing GnRHa-HRT FET cycles. The study group included 216 patients receiving an additional single dose of GnRHa in the luteal phase following embryo transfer. A total of 198 patients in the control group did not receive luteal GnRHa. The baseline and cycle characteristics and reproductive outcomes were compared between the two groups. Results Baseline and cycle characteristics were similar between the two groups, except lower AMH levels were found in the luteal GnRHa group than in the control group. The luteal GnRHa group had a significantly higher ongoing pregnancy rate and live birth rate than the control group. The multivariate analysis revealed that luteal GnRHa administration was positively associated with ongoing pregnancy (OR 1.66, 95% CI 1.01–2.72, P = 0.048) and live birth (OR 1.67, 95% CI 1.01–2.75, P = 0.044). When the subgroup of patients with recurrent implantation failure (RIF) was analyzed, the multivariate analysis also showed that luteal GnRHa administration had beneficial effects on ongoing pregnancy (OR 2.79, 95% CI 1.14–6.82, P = 0.024) and live birth (OR 2.89, 95% CI 1.15–7.22, P = 0.023). Conclusions Our data suggest that the addition of one luteal dose of GnRHa may improve the live birth rate in patients undergoing the GnRHa-HRT protocol, especially in RIF patients. Luteal GnRH agonist in vitro fertilization frozen embryo transfer hormone replacement therapy cycles artificial cycles GnRH agonist pretreatment Figures Figure 1 Introduction Embryo transfer (ET) is a critical step in assisted reproductive technology (ART) treatment. Frozen–thawed embryo transfer (FET) has become an effective and popular approach in ART mainly because of the development of vitrification (1). FET cycles were associated with lower ovarian hyperstimulation syndrome risk and reduced risk of low birth weight, preterm birth, and small for gestational age infants (2, 3). Among the endometrial preparation methods for FET, the hormone replacement therapy (HRT) protocol is quite popular because of its flexibility and convenience. However, endometrial receptivity may be impaired in the HRT cycle because of medication use (4). Successful implantation requires good-quality embryos, receptive endometrium and synchronized embryo–endometrial crosstalk. The gonadotropin-releasing hormone (GnRH) pathway plays an important role in the hypothalamus-pituitary-gonadal axis of reproduction (5, 6). Both GnRH and GnRH receptors (GnRH-R) are expressed not only in the hypothalamic pituitary but also in the endometrium and embryos; their expression reaches the highest levels at the secretory-phase endometrium and at the stage of expanded blastocyst (7–10). Therefore, GnRH agonists (GnRHa) may have direct effects and functional roles in the endometrium and embryos. Indeed, GnRH has been reported to enhance endometrium receptivity and embryo development (11–14).Several systematic reviews and meta-analyses indicated that adding GnRHa to progesterone significantly improved the ongoing pregnancy rate and live birth rate compared with using progesterone alone for luteal phase support in fresh embryo transfer (fET) cycles (15–18). Furthermore, a systematic review and meta-analysis including 20 studies and 5497 patients demonstrated that GnRHa administration in the luteal phase boosted the clinical pregnancy rate in both fET and FET cycles, and the beneficial effect was similar between the fET and FET cycles (19). GnRHa downregulation combined with HRT cycles has been increasingly used in recent years. Although the efficacy of GnRHa pretreatment is controversial (20, 21), a recent systematic review and meta-analysis of 27 articles with 14152 patients reported that HRT cycles with GnRHa suppression were associated with an increased live birth rate and clinical pregnancy rate compared to those without GnRHa suppression (22). Additionally, some studies have demonstrated that GnRHa pretreatment in HRT cycles may have a beneficial effect on specific groups, such as adenomyosis (23, 24), recurrent implantation failure (RIF) (25, 26) and thin endometrium (27). We wondered whether additional administration of GnRHa during the luteal phase still takes effect in the GnRHa-HRT protocol. However, to date, no studies have investigated this issue. Thus, we designed this retrospective cohort study to assess the effects of the luteal-phase administration of single-dose GnRHa on reproductive outcomes in patients undergoing GnRHa-HRT FET cycles. Materials And Methods Study Design and Participants This retrospective cohort study was performed at the Reproductive Medical Center of Kaohsiung Veterans General Hospital from January 2020 to September 2021. The study was approved by the institutional review board at Kaohsiung Veterans General Hospital (reference number of institutional review board: KSVGH22-CT12-14). Because of its retrospective design, the requirement for consent was waived by the institutional review board. All patient data were collected from electronic medical records and in vitro fertilization (IVF) treatment sheets. Patients who received the first IVF-FET cycle in our reproductive medical center were included in this study. The exclusion criteria were as follows: (1) patients whose age was over 46 years old, (2) patients who did not undergo GnRHa-HRT cycles, (3) patients who had thin endometrium (< 8 mm) after estradiol priming, (4) patients who received preimplantation genetic testing for aneuploidy (PGT-A), (5) patients who were oocyte recipients, (6) patients whose husbands underwent testicular sperm extraction (TESE) and (7) patients who were lost to follow-up. Finally, 414 patients undergoing the GnRHa-HRT protocol were identified and divided into the luteal GnRHa group (n = 216) and the control group (n = 198). The addition of luteal GnRHa administration was determined according to the patients’ consideration and preference after full consultation provided by a doctor. In the luteal GnRHa group, a single dose of GnRHa (2 mg, Nang Kuang Pharmaceutical Co, Ltd., Tainan, Taiwan) was injected subcutaneously 2 hours after ET. The study flow chart is shown in Fig. 1 . IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection; FET, frozen–thawed embryo transfer; GnRHa, gonadotropin-releasing hormone agonist; HRT, hormonal replacement therapy; PGT-A, preimplantation genetic testing for aneuploidy; TESE, testicular sperm extraction Endometrial preparation and frozen – thawed embryo transfer All participants included in this study underwent FET cycles using the GnRHa-HRT protocol. A single injection of 3.75 mg long-acting GnRHa (Leuplin Depot, Takeda Pharmaceutical Company Limited, Yamaguchi, Japan) was given subcutaneously on menstruation cycle Day 2 or 3 after a thin endometrium (< 5 mm) was confirmed by transvaginal sonography. Twenty-eight to thirty days later, endometrial preparation was commenced with daily oral estradiol 6–8 mg (Ediol, Synmosa Biopharma Corporation, Hsinchu County, Taiwan) and estradiol gel (Oestrogel gel, Besins, Drogenbos, Belgium). After consecutive administration for 14 days, a transvaginal ultrasound scan was performed to evaluate the endometrial thickness. If endometrial thickness was less than 8 mm, the dosage of estrogen was increased, and the medication duration was extended. If the endometrial thickness was still not sufficient after 20 days of estrogen administration, the cycle was cancelled. When the endometrial thickness reached at least 8 mm, luteal phase support was initiated using daily intravaginal gel 90 mg (Crinone 8% gel, Merck Serono, Hertfordshire, UK), daily oral dydrogesterone 30 mg (Duphaston, Abbott, Olst, the Netherlands) and intramuscular injection of progesterone 125 mg (Progeston Depot, Tafong Pharmaceutical Co., Ltd., Changhua City, Taiwan) twice a week. All embryos were cryopreserved using the vitrification technique. The cleavage-stage embryos and blastocysts were thawed and transferred on the 4th or 6th day after administration of progesterone, respectively. ET was carried out under the guidance of transabdominal ultrasound. In the luteal GnRHa group, a single dose of GnRHa (2 mg, Nang Kuang Pharmaceutical Co, Ltd., Tainan, Taiwan) was injected subcutaneously 2 hours after ET. Once pregnancy was achieved, luteal support was continued until 10–12 gestational weeks. Outcome measures The primary outcome was live birth rate. The secondary outcomes included the clinical pregnancy rate and ongoing pregnancy rate. Biochemical pregnancy was confirmed by elevated serum β-human chorionic gonadotropin (hCG) levels (> 25 IU/L) at 14 days after ET. Clinical pregnancy was determined by visualization of fetal cardiac activity on transvaginal ultrasound at 6–7 weeks of gestation. A viable pregnancy beyond 12 weeks of gestation was considered ongoing pregnancy. Live birth was defined as the delivery of a viable fetus past 24 weeks of gestation. A loss of pregnancy before 24 weeks of gestation was regarded as miscarriage. Statistical analysis The Kolmogorov–Smirnov test was used to test the normal distribution of continuous variables. Quantitative variables and categorical variables were assessed using Student’s t test and the chi-square test, respectively. Multivariable logistic regression was used to identify the independent effects of additional luteal GnRHa on live birth and ongoing pregnancy in all populations and patients with RIF after adjusting for age, body mass index, infertility duration, types of infertility, basal follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), endometrial thickness, day of ET and number of transferred embryos. The results are shown as the odds ratio (OR) and 95% confidence interval (CI). A two-tailed value of P < 0.05 was considered statistically significant. Data processing and statistical analysis were carried out using IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA). Results As shown in Fig. 1 , a total of 1,376 IVF/ICSI cycles were conducted from January 2020 until September 2021 in our reproductive medical center. During the period, 572 patients with their first IVF-FET cycle in our reproductive medical center were identified. Among the 572 patients, there were 16 patients who were older than 46 years old, 98 patients who did not undergo GnRHa-HRT cycles, 9 patients who had thin endometrium (< 8 mm) after estradiol priming, 28 patients who received PGT-A, 2 patients who were oocyte recipients, 4 patients whose husbands underwent TESE, and 1 patient who was lost to follow-up. Those patients were excluded from the study. The remaining 414 patients with the GnRHa-HRT protocol were included and divided into the luteal GnRHa group (n = 216) and the control group (n = 198). The baseline characteristics of the study population are summarized in Table 1 . There were no significant differences between the two groups regarding age, body mass index, infertility duration, previous IVF attempts, infertility types and causes. Furthermore, basal FSH levels in the two groups were similar. However, lower AMH levels were found in the luteal GnRHa group than in the control group. Table 1 Baseline characteristics of patients undergoing the GnRHa-HRT protocol with or without luteal GnRHa administration Parameters Luteal GnRHa group (n = 216) Control group(n = 198) p value Age (years) 37.5 ± 4.4 37.3 ± 4.5 0.686 Body mass index (kg/m 2 ) 24.4 ± 4.5 24.1 ± 4.1 0.499 Infertility duration (years) 4.7 ± 3.2 4.7 ± 2.9 0.911 Previous IVF attempts (%) 0.816 0–1 34.3%(74/216) 31.3%(62/198) 2 23.6%(51/216) 24.7%(49/198) ≧ 3 42.1%(91/216) 43.9%(87/198) Types of infertility (%) 0.744 Primary infertility 45.4%(98/216) 47.0%(93/198) Secondary infertility 54.6%(118/216) 53.0%(105/198) Causes of infertility (%) 0.784 Tubal factor 7.9%(17/216) 6.1%(12/198) Male factor 8.3%(18/216) 6.6%(13/198) POR 9.7%(21/216) 10.1%(20/198) PCOS 14.8%(32/216) 15.7%(31/198) Endometriosis 14.4%(31/216) 11.1%(22/198) Uterine factor 9.7%(21/216) 7.6%(15/198) Unexplained 11.1%(24/216) 13.6%(27/198) Multiple 24.1%(52/216) 29.3%(58/198) Basal FSH (IU/l) 4.7 ± 2.1 5.0 ± 4.0 0.414 Anti-Müllerian hormone(ng/mL) 3.17 ± 3.00 3.98 ± 3.77 0.020 Data are presented as the mean ± standard deviation or %. GnRHa, gonadotropin-releasing hormone agonist; HRT, hormonal replacement therapy; IVF, in vitro fertilization; POR, poor ovarian responders; PCOS, polycystic ovarian syndrome; FSH, follicle-stimulating hormone As shown in Table 2 , there were no significant differences between the two groups in terms of endometrial thickness, ET day, number of transferred embryos, and percentage of ≥ one top-quality embryo transferred. A higher biochemical pregnancy rate (60.2% vs. 44.4%, P = 0.001), ongoing pregnancy rate (44.0% vs. 33.8%, P = 0.035) and live birth rate (42.6% vs. 31.8%, P = 0.024) were observed in the luteal GnRHa group than in the control group. However, no significant difference in miscarriage rate was observed between the two groups. Table 2 Cycle characteristics of patients undergoing the GnRHa-HRT protocol with or without luteal GnRHa administration Parameters Luteal GnRHa group (n = 216) Control group (n = 198) p value Endometrial thickness (mm) 11.0 ± 2.5 11.4 ± 2.5 0.111 Rate of ET day (%) 0.403 Day 3 ET 61.1% (132/216) 57.1% (113/198) Day 5 ET 38.9% (84/216) 42.9% (85/198) No. of transferred embryos 2.5 ± 0.9 2.5 ± 0.8 0.680 Rate of at least one top-quality embryo transferred (%) 84.7% (183/198) 83.8% (166/198) 0.805 Biochemical pregnancy rate (%) 60.2% (130/216) 44.4% (88/198) 0.001 Clinical pregnancy rate (%) 48.1% (104/216) 38.9% (77/198) 0.058 Ongoing pregnancy rate (%) 44.0% (95/216) 33.8% (67/198) 0.035 Live birth rate (%) 42.6% (92/216) 31.8% (63/198) 0.024 Miscarriage rate (%) 11.5% (12/104) 18.2% (14/77) 0.208 Data are presented as the mean ± standard deviation or %. GnRHa, gonadotropin-releasing hormone agonist; HRT, hormonal replacement therapy; ET, embryo transfer In Table 3 , a binary logistic regression analysis was performed to assess the effects of additional luteal GnRH agonist in GnRHa-HRT cycles on ongoing pregnancy and live birth. Confounding parameters such as age, body mass index, infertility duration, types of infertility, basal FSH, AMH, endometrial thickness, day of ET and number of transferred embryos were included in the analysis. The multivariate analysis showed that the addition of a luteal GnRH agonist in GnRHa-HRT cycles had beneficial effects on the ongoing pregnancy rate (OR 1.66, 95% CI 1.01–2.72, P = 0.048) and live birth rate (OR 1.67, 95% CI 1.01–2.75, P = 0.044). Moreover, age and day of ET were independent factors that could affect the ongoing pregnancy rate and live birth rate. Table 3 Analyses of factors affecting the ongoing pregnancy rate and live birth rate using logistic regression Ongoing pregnancy Live birth Adjusted OR (95% CI) p value Adjusted OR (95% CI) p value Luteal GnRHa vs. control 1.66(1.01–2.72) 0.048 1.67(1.01–2.75) 0.044 Age (years) 0.83(0.77–0.89) < 0.001 0.83(0.77–0.89) < 0.001 BMI (kg/m 2 ) 1.10(1.04–1.16) 0.001 1.10(1.04–1.16) 0.002 Infertility duration (years) 1.01(0.92–1.11) 0.834 0.99(0.90–1.09) 0.865 Types of infertility 0.77(0.46–1.30) 0.325 0.80(0.47–1.34) 0.393 Basal FSH (IU/l) 0.96(0.87–1.07) 0.469 0.94(0.84–1.06) 0.303 AMH (ng/mL) 0.98(0.90–1.07) 0.703 0.96(0.88–1.05) 0.340 Endometrial thickness (mm) 1.04(0.94–1.14) 0.469 1.01(0.91–1.11) 0.903 Day of embryo transfer 2.26(1.33–3.84) 0.003 2.14(1.26–3.65) 0.005 No. of transferred embryos 0.97(0.70–1.34) 0.860 0.98(0.71–1.35) 0.886 OR, odds ratio; CI, confidence interval; BMI, body mass index; FSH, follicle- stimulating hormone; AMH, anti-Müllerian hormone We then attempted to investigate the effects of additional luteal GnRHa in patients with RIF. RIF was defined as failure to achieve a clinical pregnancy after at least three IVF or ICSI treatments with transfer of at least one good-quality embryo per transfer or transfer of 10 good-quality embryos according to a previous study (28). As presented in Table 4 , basal characteristics, including age, body mass index, infertility duration, infertility types, basal FSH and AMH, as well as cycle characteristics, including endometrial thickness, ET day, number of transferred embryos, and percentage of ≥ one top-quality embryo transferred, were comparable between the two groups. Compared to the control group, the luteal GnRHa group had a significantly higher biochemical pregnancy rate (58.2% vs. 37.9%, P = 0.007), clinical pregnancy rate (45.1% vs. 29.9%, P = 0.037) and ongoing pregnancy rate (38.5% vs. 24.1%, P = 0.040). Although the luteal GnRHa group had a tendency toward a higher live birth rate, the difference did not reach statistical significance (36.3% vs. 23.0%, P = 0.053). Table 4 Subgroup analysis of RIF patients undergoing the GnRHa-HRT protocol with or without luteal GnRHa administration Parameters Luteal GnRHa group (n = 91) Control group (n = 87) p value Age (years) 39.2 ± 3.9 39.2 ± 4.0 0.966 Body mass index (kg/m2) 11.4 ± 2.5 11.4 ± 2.5 0.620 Infertility duration (years) 5.7 ± 3.1 5.3 ± 3.2 0.334 Types of infertility (%) 0.245 Primary infertility 31.9% (29/91) 40.2% (35/87) Secondary infertility 68.1% (62/91) 59.8% (52/87) Basal FSH (IU/l) 4.7 ± 2.1 5.2 ± 5.6 0.473 Anti-Müllerian hormone (ng/mL) 2.57 ± 2.54 2.81 ± 3.19 0.573 Endometrial thickness (mm) 10.8 ± 2.4 11.2 ± 2.1 0.334 Rate of ET day (%) 0.100 Day 3 ET 72.5% (66/91) 60.9% (53/87) Day 5 ET 27.5% (25/91) 39.1% (34/87) No. of transferred embryos 2.8 ± 0.8 2.8 ± 0.9 0.985 Rate of at least one top-quality embryo transferred (%) 79.1% (72/91) 80.5% (70/87) 0.824 Biochemical pregnancy rate (%) 58.2% (53/91) 37.9% (33/87) 0.007 Clinical pregnancy rate (%) 45.1% (41/91) 29.9% (26/87) 0.037 Ongoing pregnancy rate (%) 38.5% (35/91) 24.1% (21/87) 0.040 Live birth rate (%) 36.3% (33/91) 23.0% (20/87) 0.053 Miscarriage rate (%) 19.5% (8/41) 23.1% (6/26) 0.727 Data are presented as the mean ± standard deviation or %. RIF, recurrent implantation failure; GnRHa, gonadotropin-releasing hormone agonist; HRT, hormonal replacement therapy; FSH, follicle-stimulating hormone; ET, embryo transfer As shown in Table 5 , a binary logistic regression analysis was conducted to analyze the effects of additional luteal GnRHa in GnRHa-HRT cycles on ongoing pregnancy and live birth in the RIF subgroup. Age, body mass index, infertility duration, types of infertility, basal FSH, AMH, endometrial thickness, day of ET and number of transferred embryos were considered confounding factors in this analysis. The multivariate analysis revealed increased odds of ongoing pregnancy (OR 2.79, 95% CI 1.14–6.82, P = 0.024) and live birth (OR 2.89, 95% CI 1.15–7.22, P = 0.023) when luteal GnRHa was added in RIF patients undergoing the GnRHa-HRT protocol. In addition, age was negatively associated with ongoing pregnancy and live birth. The day of ET was an independent factor affecting the ongoing pregnancy rate but not the live birth rate. Table 5 Analyses of factors affecting the ongoing pregnancy rate and live birth rate in RIF patients using logistic regression Ongoing pregnancy Live birth Adjusted OR (95% CI) p value Adjusted OR (95% CI) p value Luteal GnRHa vs. control 2.79(1.14–6.82) 0.024 2.89(1.15–7.22) 0.023 Age (years) 0.85(0.74–0.96) 0.011 0.85(0.74–0.96) 0.012 BMI (kg/m 2 ) 1.12(1.01–1.24) 0.035 1.09(0.98–1.21) 0.103 Infertility duration (years) 1.00(0.86–1.16) 0.954 0.95(0.81–1.12) 0.551 Types of infertility 0.52(0.21–1.32) 0.167 0.56(0.22–1.44) 0.227 Basal FSH (IU/l) 0.88(0.70–1.10) 0.249 0.84(0.61–1.07) 0.155 AMH (ng/mL) 0.97(0.80–1.16) 0.703 0.93(0.77–1.13) 0.475 Endometrial thickness (mm) 0.94(0.77–1.13) 0.485 0.86(0.70–1.05) 0.137 Day of embryo transfer 3.06(1.15–8.13) 0.025 2.49(0.92–6.72) 0.072 No. of transferred embryos 0.62(0.36–1.08) 0.091 0.64(0.37–1.11) 0.109 RIF, recurrent implantation failure; OR, odds ratio; CI, confidence interval; BMI, body mass index; FSH, follicle- stimulating hormone; AMH, anti-Müllerian hormone. Discussion This retrospective cohort study is the first to explore the possible effects of administration of single-dose GnRHa in luteal phase support on IVF outcomes in patients who underwent GnRHa-HRT cycles, and the results showed that additional luteal GnRHa was associated with a higher ongoing pregnancy rate and live birth rate. Moreover, the multivariate analysis revealed a 1.66-fold increase in the possibility of ongoing pregnancy (95% CI 1.01–2.72, P = 0.048) and a 1.67-fold increase in the possibility of live birth (95% CI 1.01–2.75, P = 0.044) when single-dose GnRHa was added to luteal phase support in patients receiving HRT cycles with GnRHa suppression. GnRH analogs may have the potential to act on the endometrium and early stages of embryos. Both GnRH and GnRH-R have been reported to be expressed in both the epithelium and the stroma of the endometrium and reach the highest levels in the secretory phase of the menstrual cycle (7, 8, 29, 30), suggesting that the GnRH–GnRH-R pathway has functional roles in endometrium receptivity and implantation. GnRHa therapy may enhance the expression of endometrial integrin αvβ3, an adhesive molecule, and implantation-related factors, such as HOXA10 and LIF, in humans (11, 12) and mice (31, 32). Furthermore, in a study of human decidual stromal cells, GnRH has been found to be able to modulate matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue-specific inhibitor of matrix metalloproteinases (TIMPs) (33), both of which are associated with cyclic remodeling of the endometrium and decidualization (34). GnRHa has also been demonstrated to directly stimulate cell invasion and migration of human decidual endometrial stromal cells, a key process of embryo implantation and pregnancy programming (35). This support for GnRHa may facilitate endometrial receptivity and implantation. Moreover, both GnRH and GnRH-R have been shown to be present in human, mouse and porcine preimplantation embryos (9, 10, 13). The levels of GnRH and GnRH-R significantly increased at the early blastocyst stage and reached their highest levels at the expanded blastocyst stage (10, 14). In addition, the expression of GnRH and GnRH-R was detected in both the inner cell mass and trophectoderm cells of blastocysts (14). These results implied that the GnRH–GnRH-R pathway could be a potential modulator of early embryo development. In animal models, treatment with GnRHa in culture medium can promote embryo development and inhibit apoptosis. In contrast, treatment with a GnRH antagonist suppressed embryo development and induced apoptosis via the intrinsic mitochondrial pathway, but the adverse effects could be reversed by cotreatment with GnRHa (10, 13, 14). In addition, treatment with GnRH antagonist in mouse blastocysts significantly reduced the levels of EGF and IGF-II (14), which have been reported to be associated with embryo development and inhibition of apoptosis in blastocysts (36, 37). In a study of human extravillous cytotrophoblasts, GnRHa was suggested to have the capacity to promote trophoblast invasion by regulating the expression of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1) (38). Additionally, GnRHa could regulate the synthesis and secretion of hCG in the preimplantation embryo and placenta (39, 40). This suggests that GnRHa may be involved in early embryo development. Taken together, GnRH analogs play an important role in the establishment of receptive endometrium and the development of peri-implantation embryos, by which GnRHa could facilitate successful implantation and pregnancy. However, more human studies are required to confirm the effects of GnRHa on the endometrium and embryos. A Cochrane meta-analysis including 10 randomized controlled trials (RCTs) and 2861 women demonstrated that live birth or ongoing pregnancy rates were higher in the progesterone plus GnRHa group than in the progesterone-only group (15). Several other systematic reviews and meta-analyses reported similar results (16–18). Furthermore, a systematic review and network meta-analysis of 89 RCTs with 29,625 women was performed to compare the effectiveness and safety of various methods of luteal phase support and showed that the addition of GnRHa to progesterone significantly improved the live birth rate compared to progesterone alone (41). Another systematic review and network meta-analysis aimed to evaluate the effectiveness and safety of multiple-dose versus single-dose GnRHa protocols for luteal phase support in patients undergoing IVF/ICSI cycles. The results indicated that the multiple-dose GnRHa protocol might be the best strategy for improving the live birth rate and clinical pregnancy rate (42). Nevertheless, these meta-analyses only included patients undergoing fET cycles. In terms of FET cycles, a systematic review and meta-analysis demonstrated that GnRHa administration in the luteal phase improved the clinical pregnancy rate in FET cycles, and the beneficial effect was similar to fresh cycles (19). These studies supported our results in this article. However, a recent RCT including a total of 287 HRT–FET cycles showed no significant benefit in live birth rate and clinical pregnancy rate by administering two GnRHa boluses (43). Therefore, more large-scale RCTs are needed to verify the beneficial effects of luteal GnRHa administration on IVF outcomes, especially in FET cycles. The endometrium of the RIF patients showed decreased LIF expression and dysregulated LIF signaling (44, 45). GnRHa therapy may boost the expression of implantation-related factors, such as HOXA10 and LIF (11, 12, 31, 32). Thus, we speculated that additional GnRHa administration during the luteal phase may have a beneficial effect on reproductive outcomes in women with RIF. The multivariate analysis of our study supported this speculation, showing a 2.79-fold increase in the possibility of ongoing pregnancy (95% CI 1.14–6.82, P = 0.024) and a 2.89-fold increase in the possibility of live birth (95% CI 1.15–7.22, P = 0.023) when luteal GnRHa was added to progesterone in RIF patients undergoing GnRHa-HRT cycles. However, we must interpret the data from the subgroup analysis discreetly because of the small population. More large-scale studies are required to prove our results. This study has several limitations. First, the main limitation of this study was its retrospective design and limited sample size. Large-scale RCTs are needed to verify our results. Next, whether to administer luteal GnRHa was determined on the basis of patients’ consideration and preference after physician consultation, which may introduce bias. Moreover, embryo selection was based on morphological grading, not euploidy, because PGT-A has not been widely used in our center. Therefore, the confounding effects from embryo aneuploidy could not be excluded. Fourth, the data from the subgroup analysis should be interpreted cautiously on account of the potential bias from the small population. Finally, no sample size calculations were performed because this study included all patients who met the criteria during the study period. In conclusion, our data suggest that single-dose administration of GnRHa during the luteal phase may improve the live birth rate in patients undergoing the GnRHa-HRT protocol, especially in RIF patients. Abbreviations AMH, anti-Müllerian hormone ART, assisted reproductive technology CI, confidence interval ET, embryo transfer fET, fresh embryo transfer FET, frozen thawed embryo transfer FSH, follicle-stimulating hormone GnRH, gonadotropin-releasing hormone GnRHa, GnRH agonist GnRH-R, GnRH receptor HRT, hormone replacement therapy hCG, human chorionic gonadotropin ICSI, intracytoplasmic sperm injection IVF, in vitro fertilization MMPs, modulate matrix metalloproteinases OR, odds ratio PAI-1, plasminogen activator inhibitor PGT-A, preimplantation genetic testing for aneuploidy RCTs, randomized controlled trials RIF, recurrent implantation failure TESE, testicular sperm extraction TIMPs, tissue-specific inhibitor of matrix metalloproteinases uPA, urokinase-type plasminogen activator Declarations Ethics approval and consent to participate The study conformed to the Declaration of Helsinki for Medical Research about human subjects. In addition, approval was obtained from the institutional review board at Kaohsiung Veterans General Hospital, with the identifier KSVGH22-CT12-14 . The study was performed in accordance with approved guidelines. Consent for publication Not applicable Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding Not applicable Authors’ contributions Li-Te Lin, Kuan-Hao Tsui and Pei-Hsuan Lin contributed to the conception and design of the study; Yu-Chen Chen and Chyi-Uei Chern organized the database and prepared figure 1; Chia-Jung Li performed the statistical analysis and prepared tables; Wei-Shan Chang wrote the first draft of the manuscript; Li-Te Lin and Kuan-Hao Tsui wrote sections of the manuscript. All authors reviewed the manuscript. Acknowledgments Not applicable References Kushnir VA, Barad DH, Albertini DF, Darmon SK, Gleicher N. Systematic review of worldwide trends in assisted reproductive technology 2004-2013. Reprod Biol Endocrinol. 2017;15(1):6. Zaat T, Zagers M, Mol F, Goddijn M, van Wely M, Mastenbroek S. Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database Syst Rev. 2021;2(2):Cd011184. Sha T, Yin X, Cheng W, Massey IY. Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis. Fertil Steril. 2018;109(2):330-42.e9. 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. Journal of assisted reproduction and genetics. 2021;38(8):1913-26. Wu HM, Wang HS, Huang HY, Soong YK, MacCalman CD, Leung PC. GnRH signaling in intrauterine tissues. Reproduction (Cambridge, England). 2009;137(5):769-77. Cheng CK, Leung PC. Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans. Endocrine reviews. 2005;26(2):283-306. Raga F, Casañ EM, Kruessel JS, Wen Y, Huang HY, Nezhat C, et al. Quantitative gonadotropin-releasing hormone gene expression and immunohistochemical localization in human endometrium throughout the menstrual cycle. Biol Reprod. 1998;59(3):661-9. Casañ EM, Raga F, Kruessel JS, Wen Y, Nezhat C, Polan ML. Immunoreactive gonadotropin-releasing hormone expression in cycling human endometrium of fertile patients. Fertil Steril. 1998;70(1):102-6. Casañ EM, Raga F, Polan ML. GnRH mRNA and protein expression in human preimplantation embryos. Molecular human reproduction. 1999;5(3):234-9. Raga F, Casañ EM, Kruessel J, Wen Y, Bonilla-Musoles F, Polan ML. The role of gonadotropin-releasing hormone in murine preimplantation embryonic development. Endocrinology. 1999;140(8):3705-12. Li 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. Xu B, Geerts D, Hu S, Yue J, Li Z, Zhu G, et al. The depot GnRH agonist protocol improves the live birth rate per fresh embryo transfer cycle, but not the cumulative live birth rate in normal responders: a randomized controlled trial and molecular mechanism study. Hum Reprod. 2020;35(6):1306-18. Nam DH, Lee SH, Kim HS, Lee GS, Jeong YW, Kim S, et al. The role of gonadotropin-releasing hormone (GnRH) and its receptor in development of porcine preimplantation embryos derived from in vitro fertilization. Theriogenology. 2005;63(1):190-201. Kawamura K, Fukuda J, Kumagai J, Shimizu Y, Kodama H, Nakamura A, et al. Gonadotropin-releasing hormone I analog acts as an antiapoptotic factor in mouse blastocysts. Endocrinology. 2005;146(9):4105-16. van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev. 2015(7):CD009154. Oliveira JB, Baruffi R, Petersen CG, Mauri AL, Cavagna M, Franco JG, Jr. Administration of single-dose GnRH agonist in the luteal phase in ICSI cycles: a meta-analysis. Reprod Biol Endocrinol. 2010;8:107. Kyrou D, Kolibianakis EM, Fatemi HM, Tarlatzi TB, Devroey P, Tarlatzis BC. Increased live birth rates with GnRH agonist addition for luteal support in ICSI/IVF cycles: a systematic review and meta-analysis. Hum Reprod Update. 2011;17(6):734-40. Ma X, Du W, Hu J, Yang Y, Zhang X. Effect of Gonadotrophin-Releasing Hormone Agonist Addition for Luteal Support on Pregnancy Outcome in vitro Fertilization/Intracytoplasmic Sperm Injection Cycles: A Meta-Analysis Based on Randomized Controlled Trials. Gynecologic and obstetric investigation. 2020;85(1):13-25. Chau LTM, Tu DK, Lehert P, Dung DV, Thanh LQ, Tuan VM. Clinical pregnancy following GnRH agonist administration in the luteal phase of fresh or frozen assisted reproductive technology (ART) cycles: Systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol X. 2019;3:100046. Xu J, Li SZ, Yin MN, Liang PL, Li P, Sun L. Endometrial Preparation for Frozen-Thawed Embryo Transfer With or Without Pretreatment With GnRH Agonist: A Randomized Controlled Trial at Two Centers. Front Endocrinol (Lausanne). 2021;12:722253. Samsami A, Chitsazi Z, Namazi G. Frozen thawed embryo transfer cycles; A comparison of pregnancy outcomes with and without prior pituitary suppression by GnRH agonists: An RCT. International journal of reproductive biomedicine. 2018;16(9):587-94. Li 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. Archives of gynecology and obstetrics. 2022. Wu Y, Huang J, Zhong G, Lan J, Lin H, Zhang Q. Long-term GnRH agonist pretreatment before frozen embryo transfer improves pregnancy outcomes in women with adenomyosis. Reprod Biomed Online. 2022;44(2):380-8. Niu Z, Chen Q, Sun Y, Feng Y. Long-term pituitary downregulation before frozen embryo transfer could improve pregnancy outcomes in women with adenomyosis. Gynecol Endocrinol. 2013;29(12):1026-30. Xia 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 (Lausanne). 2022;13:803471. Pan D, Yang J, Zhang N, Wang L, Li N, Shi J, et al. 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. Reprod Biol Endocrinol. 2022;20(1):26. Liu Y, Ma L, Zhu M, Yin H, Yan H, Shi M. STROBE-GnRHa pretreatment in frozen-embryo transfer cycles improves clinical outcomes for patients with persistent thin endometrium: A case-control study. Medicine (Baltimore). 2022;101(31):e29928. Koot YEM, Hviid Saxtorph M, Goddijn M, de Bever S, Eijkemans MJC, Wely MV, et al. What is the prognosis for a live birth after unexplained recurrent implantation failure following IVF/ICSI? Hum Reprod. 2019;34(10):2044-52. Shemesh M. Actions of gonadotrophins on the uterus. Reproduction (Cambridge, England). 2001;121(6):835-42. Maggi R, Cariboni AM, Marelli MM, Moretti RM, Andrè V, Marzagalli M, et al. GnRH and GnRH receptors in the pathophysiology of the human female reproductive system. Hum Reprod Update. 2016;22(3):358-81. Guo S, Li Z, Yan L, Sun Y, Feng Y. GnRH agonist improves pregnancy outcome in mice with induced adenomyosis by restoring endometrial receptivity. Drug design, development and therapy. 2018;12:1621-31. Ruan HC, Zhu XM, Luo Q, Liu AX, Qian YL, Zhou CY, et al. Ovarian stimulation with GnRH agonist, but not GnRH antagonist, partially restores the expression of endometrial integrin beta3 and leukaemia-inhibitory factor and improves uterine receptivity in mice. Hum Reprod. 2006;21(10):2521-9. Chou CS, Tai CJ, MacCalman CD, Leung PC. Dose-dependent effects of gonadotropin releasing hormone on matrix metalloproteinase (MMP)-2, and MMP-9 and tissue specific inhibitor of metalloproteinases-1 messenger ribonucleic acid levels in human decidual Stromal cells in vitro. The Journal of clinical endocrinology and metabolism. 2003;88(2):680-8. Vu TH, Werb Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes & development. 2000;14(17):2123-33. Wu HM, Huang HY, Lee CL, Soong YK, Leung PC, Wang HS. Gonadotropin-releasing hormone type II (GnRH-II) agonist regulates the motility of human decidual endometrial stromal cells: possible effect on embryo implantation and pregnancy. Biol Reprod. 2015;92(4):98. Hardy K, Spanos S. Growth factor expression and function in the human and mouse preimplantation embryo. The Journal of endocrinology. 2002;172(2):221-36. Kane MT, Morgan PM, Coonan C. Peptide growth factors and preimplantation development. Hum Reprod Update. 1997;3(2):137-57. Chou CS, Zhu H, Shalev E, MacCalman CD, Leung PC. The effects of gonadotropin-releasing hormone (GnRH) I and GnRH II on the urokinase-type plasminogen activator/plasminogen activator inhibitor system in human extravillous cytotrophoblasts in vitro. The Journal of clinical endocrinology and metabolism. 2002;87(12):5594-603. Lin LS, Roberts VJ, Yen SS. Expression of human gonadotropin-releasing hormone receptor gene in the placenta and its functional relationship to human chorionic gonadotropin secretion. The Journal of clinical endocrinology and metabolism. 1995;80(2):580-5. Iwashita M, Kudo Y, Shinozaki Y, Takeda Y. Gonadotropin-releasing hormone increases serum human chorionic gonadotropin in pregnant women. Endocrine journal. 1993;40(5):539-44. Wu H, Zhang S, Lin X, Wang S, Zhou P. Luteal phase support for in vitro fertilization/intracytoplasmic sperm injection fresh cycles: a systematic review and network meta-analysis. Reprod Biol Endocrinol. 2021;19(1):103. Liu Y, Wu Y, Pan Z, Jiang F, Lu Y, Meng Y. Single-Dose Versus Multiple-Dose GnRH Agonist for Luteal-Phase Support in Women Undergoing IVF/ICSI Cycles: A Network Meta-Analysis of Randomized Controlled Trials. Front Endocrinol (Lausanne). 2022;13:802688. Alsbjerg B, Kesmodel US, Elbaek HO, Laursen R, Laursen SB, Andreasen D, et al. GnRH agonist supplementation in hormone replacement therapy-frozen embryo transfer cycles: a randomized controlled trial. Reprod Biomed Online. 2022;44(2):261-70. Huang C, Sun H, Wang Z, Liu Y, Cheng X, Liu J, et al. Increased Krüppel-like factor 12 impairs embryo attachment via downregulation of leukemia inhibitory factor in women with recurrent implantation failure. Cell death discovery. 2018;4:23. Choi Y, Kim HR, Lim EJ, Park M, Yoon JA, Kim YS, et al. Integrative Analyses of Uterine Transcriptome and MicroRNAome Reveal Compromised LIF-STAT3 Signaling and Progesterone Response in the Endometrium of Patients with Recurrent/Repeated Implantation Failure (RIF). PloS one. 2016;11(6):e0157696. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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-2456935","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":166188052,"identity":"251026fe-f003-4105-84a5-598c02fc6b1b","order_by":0,"name":"Wei-Shan Chang","email":"","orcid":"","institution":"Kaohsiung Veterans General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wei-Shan","middleName":"","lastName":"Chang","suffix":""},{"id":166188053,"identity":"878f4a89-d563-4c9a-909f-68e188bf3bf8","order_by":1,"name":"Pei-Hsuan Lin","email":"","orcid":"","institution":"Kaohsiung Veterans General 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1","display":"","copyAsset":false,"role":"figure","size":58641,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow chart\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2456935/v1/787be46e034c2377622d3961.png"},{"id":31442700,"identity":"e9fed0ab-7536-4f07-880b-53f8b248603d","added_by":"auto","created_at":"2023-01-11 19:19:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":416176,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2456935/v1/59b012c1-56a2-47f6-ab58-f023fc3e0797.pdf"},{"id":31442699,"identity":"bb048a80-0d51-4bed-bb87-3808b428360c","added_by":"auto","created_at":"2023-01-11 19:19:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":416176,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2456935/v1/1ba74da4-63da-4d8b-8cd9-7561f63ebe99.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Additional single dose GnRH agonist during luteal phase support may improve live birth rate in GnRHa-HRT frozen–thawed embryo transfer cycle: a retrospective cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEmbryo transfer (ET) is a critical step in assisted reproductive technology (ART) treatment.\u003c/p\u003e \u003cp\u003eFrozen\u0026ndash;thawed embryo transfer (FET) has become an effective and popular approach in ART mainly because of the development of vitrification (1). FET cycles were associated with lower ovarian hyperstimulation syndrome risk and reduced risk of low birth weight, preterm birth, and small for gestational age infants (2, 3). Among the endometrial preparation methods for FET, the hormone replacement therapy (HRT) protocol is quite popular because of its flexibility and convenience. However, endometrial receptivity may be impaired in the HRT cycle because of medication use (4).\u003c/p\u003e \u003cp\u003eSuccessful implantation requires good-quality embryos, receptive endometrium and synchronized embryo\u0026ndash;endometrial crosstalk. The gonadotropin-releasing hormone (GnRH) pathway plays an important role in the hypothalamus-pituitary-gonadal axis of reproduction (5, 6). Both GnRH and GnRH receptors (GnRH-R) are expressed not only in the hypothalamic pituitary but also in the endometrium and embryos; their expression reaches the highest levels at the secretory-phase endometrium and at the stage of expanded blastocyst (7\u0026ndash;10). Therefore, GnRH agonists (GnRHa) may have direct effects and functional roles in the endometrium and embryos. Indeed, GnRH has been reported to enhance endometrium receptivity and embryo development (11\u0026ndash;14).Several systematic reviews and meta-analyses indicated that adding GnRHa to progesterone significantly improved the ongoing pregnancy rate and live birth rate compared with using progesterone alone for luteal phase support in fresh embryo transfer (fET) cycles (15\u0026ndash;18). Furthermore, a systematic review and meta-analysis including 20 studies and 5497 patients demonstrated that GnRHa administration in the luteal phase boosted the clinical pregnancy rate in both fET and FET cycles, and the beneficial effect was similar between the fET and FET cycles (19).\u003c/p\u003e \u003cp\u003eGnRHa downregulation combined with HRT cycles has been increasingly used in recent years. Although the efficacy of GnRHa pretreatment is controversial (20, 21), a recent systematic review and meta-analysis of 27 articles with 14152 patients reported that HRT cycles with GnRHa suppression were associated with an increased live birth rate and clinical pregnancy rate compared to those without GnRHa suppression (22). Additionally, some studies have demonstrated that GnRHa pretreatment in HRT cycles may have a beneficial effect on specific groups, such as adenomyosis (23, 24), recurrent implantation failure (RIF) (25, 26) and thin endometrium (27). We wondered whether additional administration of GnRHa during the luteal phase still takes effect in the GnRHa-HRT protocol. However, to date, no studies have investigated this issue. Thus, we designed this retrospective cohort study to assess the effects of the luteal-phase administration of single-dose GnRHa on reproductive outcomes in patients undergoing GnRHa-HRT FET cycles.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Participants\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study was performed at the Reproductive Medical Center of Kaohsiung Veterans General Hospital from January 2020 to September 2021. The study was approved by the institutional review board at Kaohsiung Veterans General Hospital (reference number of institutional review board: KSVGH22-CT12-14). Because of its retrospective design, the requirement for consent was waived by the institutional review board. All patient data were collected from electronic medical records and in vitro fertilization (IVF) treatment sheets. Patients who received the first IVF-FET cycle in our reproductive medical center were included in this study. The exclusion criteria were as follows: (1) patients whose age was over 46 years old, (2) patients who did not undergo GnRHa-HRT cycles, (3) patients who had thin endometrium (\u0026lt;\u0026thinsp;8 mm) after estradiol priming, (4) patients who received preimplantation genetic testing for aneuploidy (PGT-A), (5) patients who were oocyte recipients, (6) patients whose husbands underwent testicular sperm extraction (TESE) and (7) patients who were lost to follow-up. Finally, 414 patients undergoing the GnRHa-HRT protocol were identified and divided into the luteal GnRHa group (n\u0026thinsp;=\u0026thinsp;216) and the control group (n\u0026thinsp;=\u0026thinsp;198). The addition of luteal GnRHa administration was determined according to the patients\u0026rsquo; consideration and preference after full consultation provided by a doctor. In the luteal GnRHa group, a single dose of GnRHa (2 mg, Nang Kuang Pharmaceutical Co, Ltd., Tainan, Taiwan) was injected subcutaneously 2 hours after ET. The study flow chart is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection; FET, frozen\u0026ndash;thawed embryo transfer; GnRHa, gonadotropin-releasing hormone agonist; HRT, hormonal replacement therapy; PGT-A, preimplantation genetic testing for aneuploidy; TESE, testicular sperm extraction\u003c/p\u003e \u003cp\u003e \u003cb\u003eEndometrial preparation and frozen\u003c/b\u003e\u0026ndash;\u003cb\u003ethawed embryo transfer\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAll participants included in this study underwent FET cycles using the GnRHa-HRT protocol. A single injection of 3.75 mg long-acting GnRHa (Leuplin Depot, Takeda Pharmaceutical Company Limited, Yamaguchi, Japan) was given subcutaneously on menstruation cycle Day 2 or 3 after a thin endometrium (\u0026lt;\u0026thinsp;5 mm) was confirmed by transvaginal sonography. Twenty-eight to thirty days later, endometrial preparation was commenced with daily oral estradiol 6\u0026ndash;8 mg (Ediol, Synmosa Biopharma Corporation, Hsinchu County, Taiwan) and estradiol gel (Oestrogel gel, Besins, Drogenbos, Belgium). After consecutive administration for 14 days, a transvaginal ultrasound scan was performed to evaluate the endometrial thickness. If endometrial thickness was less than 8 mm, the dosage of estrogen was increased, and the medication duration was extended. If the endometrial thickness was still not sufficient after 20 days of estrogen administration, the cycle was cancelled. When the endometrial thickness reached at least 8 mm, luteal phase support was initiated using daily intravaginal gel 90 mg (Crinone 8% gel, Merck Serono, Hertfordshire, UK), daily oral dydrogesterone 30 mg (Duphaston, Abbott, Olst, the Netherlands) and intramuscular injection of progesterone 125 mg (Progeston Depot, Tafong Pharmaceutical Co., Ltd., Changhua City, Taiwan) twice a week.\u003c/p\u003e \u003cp\u003eAll embryos were cryopreserved using the vitrification technique. The cleavage-stage embryos and blastocysts were thawed and transferred on the 4th or 6th day after administration of progesterone, respectively. ET was carried out under the guidance of transabdominal ultrasound. In the luteal GnRHa group, a single dose of GnRHa (2 mg, Nang Kuang Pharmaceutical Co, Ltd., Tainan, Taiwan) was injected subcutaneously 2 hours after ET. Once pregnancy was achieved, luteal support was continued until 10\u0026ndash;12 gestational weeks.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eOutcome measures\u003c/h2\u003e \u003cp\u003eThe primary outcome was live birth rate. The secondary outcomes included the clinical pregnancy rate and ongoing pregnancy rate. Biochemical pregnancy was confirmed by elevated serum β-human chorionic gonadotropin (hCG) levels (\u0026gt;\u0026thinsp;25 IU/L) at 14 days after ET. Clinical pregnancy was determined by visualization of fetal cardiac activity on transvaginal ultrasound at 6\u0026ndash;7 weeks of gestation. A viable pregnancy beyond 12 weeks of gestation was considered ongoing pregnancy. Live birth was defined as the delivery of a viable fetus past 24 weeks of gestation. A loss of pregnancy before 24 weeks of gestation was regarded as miscarriage.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe Kolmogorov\u0026ndash;Smirnov test was used to test the normal distribution of continuous variables. Quantitative variables and categorical variables were assessed using Student\u0026rsquo;s t test and the chi-square test, respectively. Multivariable logistic regression was used to identify the independent effects of additional luteal GnRHa on live birth and ongoing pregnancy in all populations and patients with RIF after adjusting for age, body mass index, infertility duration, types of infertility, basal follicle-stimulating hormone (FSH), anti-M\u0026uuml;llerian hormone (AMH), endometrial thickness, day of ET and number of transferred embryos. The results are shown as the odds ratio (OR) and 95% confidence interval (CI). A two-tailed value of P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Data processing and statistical analysis were carried out using IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, a total of 1,376 IVF/ICSI cycles were conducted from January 2020 until September 2021 in our reproductive medical center. During the period, 572 patients with their first IVF-FET cycle in our reproductive medical center were identified. Among the 572 patients, there were 16 patients who were older than 46 years old, 98 patients who did not undergo GnRHa-HRT cycles, 9 patients who had thin endometrium (\u0026lt;\u0026thinsp;8 mm) after estradiol priming, 28 patients who received PGT-A, 2 patients who were oocyte recipients, 4 patients whose husbands underwent TESE, and 1 patient who was lost to follow-up. Those patients were excluded from the study. The remaining 414 patients with the GnRHa-HRT protocol were included and divided into the luteal GnRHa group (n\u0026thinsp;=\u0026thinsp;216) and the control group (n\u0026thinsp;=\u0026thinsp;198).\u003c/p\u003e \u003cp\u003eThe baseline characteristics of the study population are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. There were no significant differences between the two groups regarding age, body mass index, infertility duration, previous IVF attempts, infertility types and causes. Furthermore, basal FSH levels in the two groups were similar. However, lower AMH levels were found in the luteal GnRHa group than in the control group.\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\u003eBaseline characteristics of patients undergoing the GnRHa-HRT protocol with or without luteal GnRHa administration\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\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLuteal GnRHa group (n\u0026thinsp;=\u0026thinsp;216)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group(n\u0026thinsp;=\u0026thinsp;198)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.686\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.499\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfertility duration (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.911\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious IVF attempts (%)\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\u003e0.816\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.3%(74/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.3%(62/198)\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\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.6%(51/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.7%(49/198)\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≧\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42.1%(91/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43.9%(87/198)\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\u003eTypes of infertility (%)\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\u003e0.744\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary infertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45.4%(98/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47.0%(93/198)\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\u003eSecondary infertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54.6%(118/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.0%(105/198)\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\u003eCauses of infertility (%)\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\u003e0.784\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTubal factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.9%(17/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.1%(12/198)\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\u003eMale factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.3%(18/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.6%(13/198)\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\u003ePOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.7%(21/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.1%(20/198)\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\u003ePCOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.8%(32/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.7%(31/198)\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\u003eEndometriosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.4%(31/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.1%(22/198)\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\u003eUterine factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.7%(21/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.6%(15/198)\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\u003eUnexplained\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.1%(24/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.6%(27/198)\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\u003eMultiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.1%(52/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.3%(58/198)\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\u003eBasal FSH (IU/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.414\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-M\u0026uuml;llerian hormone(ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.17\u0026thinsp;\u0026plusmn;\u0026thinsp;3.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.98\u0026thinsp;\u0026plusmn;\u0026thinsp;3.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.020\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\u003eData are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or %.\u003c/p\u003e \u003cp\u003eGnRHa, gonadotropin-releasing hormone agonist; HRT, hormonal replacement therapy; IVF, in vitro fertilization; POR, poor ovarian responders; PCOS, polycystic ovarian syndrome; FSH, follicle-stimulating hormone\u003c/p\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, there were no significant differences between the two groups in terms of endometrial thickness, ET day, number of transferred embryos, and percentage of \u0026ge;\u0026thinsp;one top-quality embryo transferred. A higher biochemical pregnancy rate (60.2% vs. 44.4%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), ongoing pregnancy rate (44.0% vs. 33.8%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.035) and live birth rate (42.6% vs. 31.8%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024) were observed in the luteal GnRHa group than in the control group. However, no significant difference in miscarriage rate was observed between the two groups.\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\u003eCycle characteristics of patients undergoing the GnRHa-HRT protocol with or without luteal GnRHa administration\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\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLuteal GnRHa group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;216)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;198)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrial thickness (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.111\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRate of ET day (%)\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\u003e0.403\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay 3 ET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61.1% (132/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57.1% (113/198)\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\u003eDay 5 ET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38.9% (84/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42.9% (85/198)\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\u003eNo. of transferred embryos\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.680\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRate of at least one top-quality embryo transferred (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84.7% (183/198)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83.8% (166/198)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.805\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiochemical pregnancy rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.2% (130/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44.4% (88/198)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical pregnancy rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48.1% (104/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38.9% (77/198)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOngoing pregnancy rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44.0% (95/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.8% (67/198)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLive birth rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42.6% (92/216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.8% (63/198)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMiscarriage rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.5% (12/104)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.2% (14/77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.208\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\u003eData are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or %.\u003c/p\u003e \u003cp\u003eGnRHa, gonadotropin-releasing hormone agonist; HRT, hormonal replacement therapy; ET, embryo transfer\u003c/p\u003e \u003cp\u003eIn Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, a binary logistic regression analysis was performed to assess the effects of additional luteal GnRH agonist in GnRHa-HRT cycles on ongoing pregnancy and live birth. Confounding parameters such as age, body mass index, infertility duration, types of infertility, basal FSH, AMH, endometrial thickness, day of ET and number of transferred embryos were included in the analysis. The multivariate analysis showed that the addition of a luteal GnRH agonist in GnRHa-HRT cycles had beneficial effects on the ongoing pregnancy rate (OR 1.66, 95% CI 1.01\u0026ndash;2.72, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048) and live birth rate (OR 1.67, 95% CI 1.01\u0026ndash;2.75, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.044). Moreover, age and day of ET were independent factors that could affect the ongoing pregnancy rate and live birth rate.\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\u003eAnalyses of factors affecting the ongoing pregnancy rate and live birth rate using logistic regression\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eOngoing pregnancy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eLive birth\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdjusted OR\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAdjusted OR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLuteal GnRHa vs. control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.66(1.01\u0026ndash;2.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1.67(1.01\u0026ndash;2.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.044\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.83(0.77\u0026ndash;0.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.83(0.77\u0026ndash;0.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\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\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.10(1.04\u0026ndash;1.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1.10(1.04\u0026ndash;1.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfertility duration (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.01(0.92\u0026ndash;1.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.834\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.99(0.90\u0026ndash;1.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.865\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTypes of infertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.77(0.46\u0026ndash;1.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.325\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.80(0.47\u0026ndash;1.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.393\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasal FSH (IU/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.96(0.87\u0026ndash;1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.469\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.94(0.84\u0026ndash;1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.303\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAMH (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.98(0.90\u0026ndash;1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.703\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.96(0.88\u0026ndash;1.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.340\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrial thickness (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.04(0.94\u0026ndash;1.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.469\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1.01(0.91\u0026ndash;1.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.903\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay of embryo transfer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.26(1.33\u0026ndash;3.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e2.14(1.26\u0026ndash;3.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo. of transferred embryos\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.97(0.70\u0026ndash;1.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.860\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.98(0.71\u0026ndash;1.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.886\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\u003eOR, odds ratio; CI, confidence interval; BMI, body mass index; FSH, follicle- stimulating hormone; AMH, anti-M\u0026uuml;llerian hormone\u003c/p\u003e \u003cp\u003eWe then attempted to investigate the effects of additional luteal GnRHa in patients with RIF. RIF was defined as failure to achieve a clinical pregnancy after at least three IVF or ICSI treatments with transfer of at least one good-quality embryo per transfer or transfer of 10 good-quality embryos according to a previous study (28). As presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, basal characteristics, including age, body mass index, infertility duration, infertility types, basal FSH and AMH, as well as cycle characteristics, including endometrial thickness, ET day, number of transferred embryos, and percentage of \u0026ge;\u0026thinsp;one top-quality embryo transferred, were comparable between the two groups. Compared to the control group, the luteal GnRHa group had a significantly higher biochemical pregnancy rate (58.2% vs. 37.9%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007), clinical pregnancy rate (45.1% vs. 29.9%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037) and ongoing pregnancy rate (38.5% vs. 24.1%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.040). Although the luteal GnRHa group had a tendency toward a higher live birth rate, the difference did not reach statistical significance (36.3% vs. 23.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.053).\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\u003eSubgroup analysis of RIF patients undergoing the GnRHa-HRT protocol with or without luteal GnRHa administration\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLuteal GnRHa group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;91)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;87)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.966\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (kg/m2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.620\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfertility duration (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.334\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTypes of infertility (%)\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 \u003cp\u003e0.245\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary infertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.9% (29/91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.2% (35/87)\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\u003eSecondary infertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68.1% (62/91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59.8% (52/87)\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\u003eBasal FSH (IU/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.473\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-M\u0026uuml;llerian hormone (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.57\u0026thinsp;\u0026plusmn;\u0026thinsp;2.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.81\u0026thinsp;\u0026plusmn;\u0026thinsp;3.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.573\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrial thickness (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.334\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRate of ET day (%)\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 \u003cp\u003e0.100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay 3 ET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72.5% (66/91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.9% (53/87)\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\u003eDay 5 ET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.5% (25/91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39.1% (34/87)\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\u003eNo. of transferred embryos\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.985\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRate of at least one top-quality embryo transferred (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79.1% (72/91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80.5% (70/87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.824\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiochemical pregnancy rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58.2% (53/91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.9% (33/87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical pregnancy rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45.1% (41/91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.9% (26/87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.037\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOngoing pregnancy rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38.5% (35/91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.1% (21/87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLive birth rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36.3% (33/91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.0% (20/87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMiscarriage rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19.5% (8/41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.1% (6/26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.727\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\u003eData are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or %.\u003c/p\u003e \u003cp\u003eRIF, recurrent implantation failure; GnRHa, gonadotropin-releasing hormone agonist; HRT, hormonal replacement therapy; FSH, follicle-stimulating hormone; ET, embryo transfer\u003c/p\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, a binary logistic regression analysis was conducted to analyze the effects of additional luteal GnRHa in GnRHa-HRT cycles on ongoing pregnancy and live birth in the RIF subgroup. Age, body mass index, infertility duration, types of infertility, basal FSH, AMH, endometrial thickness, day of ET and number of transferred embryos were considered confounding factors in this analysis. The multivariate analysis revealed increased odds of ongoing pregnancy (OR 2.79, 95% CI 1.14\u0026ndash;6.82, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024) and live birth (OR 2.89, 95% CI 1.15\u0026ndash;7.22, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023) when luteal GnRHa was added in RIF patients undergoing the GnRHa-HRT protocol. In addition, age was negatively associated with ongoing pregnancy and live birth. The day of ET was an independent factor affecting the ongoing pregnancy rate but not the live birth rate.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAnalyses of factors affecting the ongoing pregnancy rate and live birth rate in RIF patients using logistic regression\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eOngoing pregnancy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eLive birth\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdjusted OR\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAdjusted OR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLuteal GnRHa vs. control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.79(1.14\u0026ndash;6.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e2.89(1.15\u0026ndash;7.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.85(0.74\u0026ndash;0.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.85(0.74\u0026ndash;0.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.12(1.01\u0026ndash;1.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1.09(0.98\u0026ndash;1.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.103\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfertility duration (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.00(0.86\u0026ndash;1.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.954\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.95(0.81\u0026ndash;1.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.551\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTypes of infertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.52(0.21\u0026ndash;1.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.56(0.22\u0026ndash;1.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.227\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasal FSH (IU/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.88(0.70\u0026ndash;1.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.249\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.84(0.61\u0026ndash;1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.155\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAMH (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.97(0.80\u0026ndash;1.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.703\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.93(0.77\u0026ndash;1.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.475\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrial thickness (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.94(0.77\u0026ndash;1.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.485\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.86(0.70\u0026ndash;1.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.137\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay of embryo transfer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.06(1.15\u0026ndash;8.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e2.49(0.92\u0026ndash;6.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo. of transferred embryos\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.62(0.36\u0026ndash;1.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.64(0.37\u0026ndash;1.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.109\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\u003eRIF, recurrent implantation failure; OR, odds ratio; CI, confidence interval; BMI, body mass index; FSH, follicle- stimulating hormone; AMH, anti-M\u0026uuml;llerian hormone.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis retrospective cohort study is the first to explore the possible effects of administration of single-dose GnRHa in luteal phase support on IVF outcomes in patients who underwent GnRHa-HRT cycles, and the results showed that additional luteal GnRHa was associated with a higher ongoing pregnancy rate and live birth rate. Moreover, the multivariate analysis revealed a 1.66-fold increase in the possibility of ongoing pregnancy (95% CI 1.01\u0026ndash;2.72, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048) and a 1.67-fold increase in the possibility of live birth (95% CI 1.01\u0026ndash;2.75, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.044) when single-dose GnRHa was added to luteal phase support in patients receiving HRT cycles with GnRHa suppression.\u003c/p\u003e \u003cp\u003eGnRH analogs may have the potential to act on the endometrium and early stages of embryos. Both GnRH and GnRH-R have been reported to be expressed in both the epithelium and the stroma of the endometrium and reach the highest levels in the secretory phase of the menstrual cycle (7, 8, 29, 30), suggesting that the GnRH\u0026ndash;GnRH-R pathway has functional roles in endometrium receptivity and implantation. GnRHa therapy may enhance the expression of endometrial integrin αvβ3, an adhesive molecule, and implantation-related factors, such as HOXA10 and LIF, in humans (11, 12) and mice (31, 32). Furthermore, in a study of human decidual stromal cells, GnRH has been found to be able to modulate matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue-specific inhibitor of matrix metalloproteinases (TIMPs) (33), both of which are associated with cyclic remodeling of the endometrium and decidualization (34). GnRHa has also been demonstrated to directly stimulate cell invasion and migration of human decidual endometrial stromal cells, a key process of embryo implantation and pregnancy programming (35). This support for GnRHa may facilitate endometrial receptivity and implantation. Moreover, both GnRH and GnRH-R have been shown to be present in human, mouse and porcine preimplantation embryos (9, 10, 13). The levels of GnRH and GnRH-R significantly increased at the early blastocyst stage and reached their highest levels at the expanded blastocyst stage (10, 14). In addition, the expression of GnRH and GnRH-R was detected in both the inner cell mass and trophectoderm cells of blastocysts (14). These results implied that the GnRH\u0026ndash;GnRH-R pathway could be a potential modulator of early embryo development. In animal models, treatment with GnRHa in culture medium can promote embryo development and inhibit apoptosis. In contrast, treatment with a GnRH antagonist suppressed embryo development and induced apoptosis via the intrinsic mitochondrial pathway, but the adverse effects could be reversed by cotreatment with GnRHa (10, 13, 14). In addition, treatment with GnRH antagonist in mouse blastocysts significantly reduced the levels of EGF and IGF-II (14), which have been reported to be associated with embryo development and inhibition of apoptosis in blastocysts (36, 37). In a study of human extravillous cytotrophoblasts, GnRHa was suggested to have the capacity to promote trophoblast invasion by regulating the expression of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1) (38). Additionally, GnRHa could regulate the synthesis and secretion of hCG in the preimplantation embryo and placenta (39, 40). This suggests that GnRHa may be involved in early embryo development.\u003c/p\u003e \u003cp\u003eTaken together, GnRH analogs play an important role in the establishment of receptive endometrium and the development of peri-implantation embryos, by which GnRHa could facilitate successful implantation and pregnancy. However, more human studies are required to confirm the effects of GnRHa on the endometrium and embryos. A Cochrane meta-analysis including 10 randomized controlled trials (RCTs) and 2861 women demonstrated that live birth or ongoing pregnancy rates were higher in the progesterone plus GnRHa group than in the progesterone-only group (15). Several other systematic reviews and meta-analyses reported similar results (16\u0026ndash;18). Furthermore, a systematic review and network meta-analysis of 89 RCTs with 29,625 women was performed to compare the effectiveness and safety of various methods of luteal phase support and showed that the addition of GnRHa to progesterone significantly improved the live birth rate compared to progesterone alone (41). Another systematic review and network meta-analysis aimed to evaluate the effectiveness and safety of multiple-dose versus single-dose GnRHa protocols for luteal phase support in patients undergoing IVF/ICSI cycles. The results indicated that the multiple-dose GnRHa protocol might be the best strategy for improving the live birth rate and clinical pregnancy rate (42). Nevertheless, these meta-analyses only included patients undergoing fET cycles. In terms of FET cycles, a systematic review and meta-analysis demonstrated that GnRHa administration in the luteal phase improved the clinical pregnancy rate in FET cycles, and the beneficial effect was similar to fresh cycles (19). These studies supported our results in this article. However, a recent RCT including a total of 287 HRT\u0026ndash;FET cycles showed no significant benefit in live birth rate and clinical pregnancy rate by administering two GnRHa boluses (43). Therefore, more large-scale RCTs are needed to verify the beneficial effects of luteal GnRHa administration on IVF outcomes, especially in FET cycles.\u003c/p\u003e \u003cp\u003eThe endometrium of the RIF patients showed decreased LIF expression and dysregulated LIF signaling (44, 45). GnRHa therapy may boost the expression of implantation-related factors, such as HOXA10 and LIF (11, 12, 31, 32). Thus, we speculated that additional GnRHa administration during the luteal phase may have a beneficial effect on reproductive outcomes in women with RIF. The multivariate analysis of our study supported this speculation, showing a 2.79-fold increase in the possibility of ongoing pregnancy (95% CI 1.14\u0026ndash;6.82, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024) and a 2.89-fold increase in the possibility of live birth (95% CI 1.15\u0026ndash;7.22, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023) when luteal GnRHa was added to progesterone in RIF patients undergoing GnRHa-HRT cycles. However, we must interpret the data from the subgroup analysis discreetly because of the small population. More large-scale studies are required to prove our results.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, the main limitation of this study was its retrospective design and limited sample size. Large-scale RCTs are needed to verify our results. Next, whether to administer luteal GnRHa was determined on the basis of patients\u0026rsquo; consideration and preference after physician consultation, which may introduce bias. Moreover, embryo selection was based on morphological grading, not euploidy, because PGT-A has not been widely used in our center. Therefore, the confounding effects from embryo aneuploidy could not be excluded. Fourth, the data from the subgroup analysis should be interpreted cautiously on account of the potential bias from the small population. Finally, no sample size calculations were performed because this study included all patients who met the criteria during the study period.\u003c/p\u003e \u003cp\u003eIn conclusion, our data suggest that single-dose administration of GnRHa during the luteal phase may improve the live birth rate in patients undergoing the GnRHa-HRT protocol, especially in RIF patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAMH, anti-M\u0026uuml;llerian hormone\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eART, assisted reproductive technology\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI, confidence interval\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eET, embryo transfer\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003efET, fresh embryo transfer\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFET, frozen\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethawed embryo transfer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFSH, follicle-stimulating hormone\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGnRH, gonadotropin-releasing hormone\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGnRHa, GnRH agonist\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGnRH-R, GnRH receptor\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHRT, hormone replacement therapy\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ehCG, human chorionic gonadotropin\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICSI, intracytoplasmic sperm injection\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIVF, in vitro fertilization\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMMPs, modulate matrix metalloproteinases\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOR, odds ratio\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePAI-1, plasminogen activator inhibitor\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePGT-A, preimplantation genetic testing for aneuploidy\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRCTs, randomized controlled trials\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRIF, recurrent implantation failure\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTESE, testicular sperm extraction\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTIMPs, tissue-specific inhibitor of matrix metalloproteinases\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003euPA, urokinase-type plasminogen activator\u003c/div\u003e \u003cdiv class=\"Description\"\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\u003eThe study conformed to the Declaration of Helsinki for Medical\u0026nbsp;Research about human subjects. In addition,\u0026nbsp;approval was obtained from the institutional review board\u0026nbsp;at Kaohsiung Veterans General Hospital, with the identifier\u0026nbsp;KSVGH22-CT12-14\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003eThe study was performed\u0026nbsp;in accordance with approved guidelines.\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 used and/or analyzed during the current study 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\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLi-Te Lin, Kuan-Hao Tsui and Pei-Hsuan Lin contributed to the conception and design of the study; Yu-Chen Chen and Chyi-Uei Chern organized the database and prepared figure 1; Chia-Jung Li performed the statistical analysis and prepared tables; Wei-Shan Chang wrote the first draft of the manuscript; Li-Te Lin and Kuan-Hao Tsui wrote sections of the manuscript. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eKushnir VA, Barad DH, Albertini DF, Darmon SK, Gleicher N. Systematic review of worldwide trends in assisted reproductive technology 2004-2013. Reprod Biol Endocrinol. 2017;15(1):6.\u003c/li\u003e\n \u003cli\u003eZaat T, Zagers M, Mol F, Goddijn M, van Wely M, Mastenbroek S. Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database Syst Rev. 2021;2(2):Cd011184.\u003c/li\u003e\n \u003cli\u003eSha T, Yin X, Cheng W, Massey IY. Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in\u0026nbsp;vitro fertilization: a meta-analysis. Fertil Steril. 2018;109(2):330-42.e9.\u003c/li\u003e\n \u003cli\u003eWu H, Zhou P, Lin X, Wang S, Zhang S. 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Clinical pregnancy following GnRH agonist administration in the luteal phase of fresh or frozen assisted reproductive technology (ART) cycles: Systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol X. 2019;3:100046.\u003c/li\u003e\n \u003cli\u003eXu J, Li SZ, Yin MN, Liang PL, Li P, Sun L. Endometrial Preparation for Frozen-Thawed Embryo Transfer With or Without Pretreatment With GnRH Agonist: A Randomized Controlled Trial at Two Centers. Front Endocrinol (Lausanne). 2021;12:722253.\u003c/li\u003e\n \u003cli\u003eSamsami A, Chitsazi Z, Namazi G. Frozen thawed embryo transfer cycles; A comparison of pregnancy outcomes with and without prior pituitary suppression by GnRH agonists: An RCT. International journal of reproductive biomedicine. 2018;16(9):587-94.\u003c/li\u003e\n \u003cli\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. Archives of gynecology and obstetrics. 2022.\u003c/li\u003e\n \u003cli\u003eWu Y, Huang J, Zhong G, Lan J, Lin H, Zhang Q. Long-term GnRH agonist pretreatment before frozen embryo transfer improves pregnancy outcomes in women with adenomyosis. Reprod Biomed Online. 2022;44(2):380-8.\u003c/li\u003e\n \u003cli\u003eNiu Z, Chen Q, Sun Y, Feng Y. Long-term pituitary downregulation before frozen embryo transfer could improve pregnancy outcomes in women with adenomyosis. Gynecol Endocrinol. 2013;29(12):1026-30.\u003c/li\u003e\n \u003cli\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 (Lausanne). 2022;13:803471.\u003c/li\u003e\n \u003cli\u003ePan D, Yang J, Zhang N, Wang L, Li N, Shi J, et al. 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. Reprod Biol Endocrinol. 2022;20(1):26.\u003c/li\u003e\n \u003cli\u003eLiu Y, Ma L, Zhu M, Yin H, Yan H, Shi M. STROBE-GnRHa pretreatment in frozen-embryo transfer cycles improves clinical outcomes for patients with persistent thin endometrium: A case-control study. Medicine (Baltimore). 2022;101(31):e29928.\u003c/li\u003e\n \u003cli\u003eKoot YEM, Hviid Saxtorph M, Goddijn M, de Bever S, Eijkemans MJC, Wely MV, et al. What is the prognosis for a live birth after unexplained recurrent implantation failure following IVF/ICSI? Hum Reprod. 2019;34(10):2044-52.\u003c/li\u003e\n \u003cli\u003eShemesh M. Actions of gonadotrophins on the uterus. Reproduction (Cambridge, England). 2001;121(6):835-42.\u003c/li\u003e\n \u003cli\u003eMaggi R, Cariboni AM, Marelli MM, Moretti RM, Andr\u0026egrave; V, Marzagalli M, et al. GnRH and GnRH receptors in the pathophysiology of the human female reproductive system. Hum Reprod Update. 2016;22(3):358-81.\u003c/li\u003e\n \u003cli\u003eGuo S, Li Z, Yan L, Sun Y, Feng Y. GnRH agonist improves pregnancy outcome in mice with induced adenomyosis by restoring endometrial receptivity. Drug design, development and therapy. 2018;12:1621-31.\u003c/li\u003e\n \u003cli\u003eRuan HC, Zhu XM, Luo Q, Liu AX, Qian YL, Zhou CY, et al. Ovarian stimulation with GnRH agonist, but not GnRH antagonist, partially restores the expression of endometrial integrin beta3 and leukaemia-inhibitory factor and improves uterine receptivity in mice. Hum Reprod. 2006;21(10):2521-9.\u003c/li\u003e\n \u003cli\u003eChou CS, Tai CJ, MacCalman CD, Leung PC. Dose-dependent effects of gonadotropin releasing hormone on matrix metalloproteinase (MMP)-2, and MMP-9 and tissue specific inhibitor of metalloproteinases-1 messenger ribonucleic acid levels in human decidual Stromal cells in vitro. The Journal of clinical endocrinology and metabolism. 2003;88(2):680-8.\u003c/li\u003e\n \u003cli\u003eVu TH, Werb Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes \u0026amp; development. 2000;14(17):2123-33.\u003c/li\u003e\n \u003cli\u003eWu HM, Huang HY, Lee CL, Soong YK, Leung PC, Wang HS. Gonadotropin-releasing hormone type II (GnRH-II) agonist regulates the motility of human decidual endometrial stromal cells: possible effect on embryo implantation and pregnancy. Biol Reprod. 2015;92(4):98.\u003c/li\u003e\n \u003cli\u003eHardy K, Spanos S. Growth factor expression and function in the human and mouse preimplantation embryo. The Journal of endocrinology. 2002;172(2):221-36.\u003c/li\u003e\n \u003cli\u003eKane MT, Morgan PM, Coonan C. Peptide growth factors and preimplantation development. Hum Reprod Update. 1997;3(2):137-57.\u003c/li\u003e\n \u003cli\u003eChou CS, Zhu H, Shalev E, MacCalman CD, Leung PC. The effects of gonadotropin-releasing hormone (GnRH) I and GnRH II on the urokinase-type plasminogen activator/plasminogen activator inhibitor system in human extravillous cytotrophoblasts in vitro. The Journal of clinical endocrinology and metabolism. 2002;87(12):5594-603.\u003c/li\u003e\n \u003cli\u003eLin LS, Roberts VJ, Yen SS. Expression of human gonadotropin-releasing hormone receptor gene in the placenta and its functional relationship to human chorionic gonadotropin secretion. The Journal of clinical endocrinology and metabolism. 1995;80(2):580-5.\u003c/li\u003e\n \u003cli\u003eIwashita M, Kudo Y, Shinozaki Y, Takeda Y. Gonadotropin-releasing hormone increases serum human chorionic gonadotropin in pregnant women. Endocrine journal. 1993;40(5):539-44.\u003c/li\u003e\n \u003cli\u003eWu H, Zhang S, Lin X, Wang S, Zhou P. Luteal phase support for in vitro fertilization/intracytoplasmic sperm injection fresh cycles: a systematic review and network meta-analysis. Reprod Biol Endocrinol. 2021;19(1):103.\u003c/li\u003e\n \u003cli\u003eLiu Y, Wu Y, Pan Z, Jiang F, Lu Y, Meng Y. Single-Dose Versus Multiple-Dose GnRH Agonist for Luteal-Phase Support in Women Undergoing IVF/ICSI Cycles: A Network Meta-Analysis of Randomized Controlled Trials. Front Endocrinol (Lausanne). 2022;13:802688.\u003c/li\u003e\n \u003cli\u003eAlsbjerg B, Kesmodel US, Elbaek HO, Laursen R, Laursen SB, Andreasen D, et al. GnRH agonist supplementation in hormone replacement therapy-frozen embryo transfer cycles: a randomized controlled trial. Reprod Biomed Online. 2022;44(2):261-70.\u003c/li\u003e\n \u003cli\u003eHuang C, Sun H, Wang Z, Liu Y, Cheng X, Liu J, et al. Increased Kr\u0026uuml;ppel-like factor 12 impairs embryo attachment via downregulation of leukemia inhibitory factor in women with recurrent implantation failure. Cell death discovery. 2018;4:23.\u003c/li\u003e\n \u003cli\u003eChoi Y, Kim HR, Lim EJ, Park M, Yoon JA, Kim YS, et al. Integrative Analyses of Uterine Transcriptome and MicroRNAome Reveal Compromised LIF-STAT3 Signaling and Progesterone Response in the Endometrium of Patients with Recurrent/Repeated Implantation Failure (RIF). PloS one. 2016;11(6):e0157696.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Luteal GnRH agonist, in vitro fertilization, frozen embryo transfer, hormone replacement therapy cycles, artificial cycles, GnRH agonist pretreatment","lastPublishedDoi":"10.21203/rs.3.rs-2456935/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2456935/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eGnRH agonist (GnRHa) has been reported to have direct effects and functional roles in the endometrium and embryos. Several meta-analyses have shown that GnRHa administration in the luteal phase improved the live birth rate or pregnancy rate in both fresh and frozen embryo transfer (FET) cycles. The aim of this study was to investigate whether luteal GnRHa administration could also improve in vitro fertilization (IVF) outcomes in patients undergoing hormone replacement therapy (HRT) cycles with GnRHa suppression.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe retrospective cohort study included a total of 414 patients undergoing GnRHa-HRT FET cycles. The study group included 216 patients receiving an additional single dose of GnRHa in the luteal phase following embryo transfer. A total of 198 patients in the control group did not receive luteal GnRHa. The baseline and cycle characteristics and reproductive outcomes were compared between the two groups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBaseline and cycle characteristics were similar between the two groups, except lower AMH levels were found in the luteal GnRHa group than in the control group. The luteal GnRHa group had a significantly higher ongoing pregnancy rate and live birth rate than the control group. The multivariate analysis revealed that luteal GnRHa administration was positively associated with ongoing pregnancy (OR 1.66, 95% CI 1.01\u0026ndash;2.72, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048) and live birth (OR 1.67, 95% CI 1.01\u0026ndash;2.75, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.044). When the subgroup of patients with recurrent implantation failure (RIF) was analyzed, the multivariate analysis also showed that luteal GnRHa administration had beneficial effects on ongoing pregnancy (OR 2.79, 95% CI 1.14\u0026ndash;6.82, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024) and live birth (OR 2.89, 95% CI 1.15\u0026ndash;7.22, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur data suggest that the addition of one luteal dose of GnRHa may improve the live birth rate in patients undergoing the GnRHa-HRT protocol, especially in RIF patients.\u003c/p\u003e","manuscriptTitle":"Additional single dose GnRH agonist during luteal phase support may improve live birth rate in GnRHa-HRT frozen–thawed embryo transfer cycle: a retrospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-01-11 19:19:37","doi":"10.21203/rs.3.rs-2456935/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e04796ef-5718-4241-bc5c-c1e87e1b7050","owner":[],"postedDate":"January 11th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-01-20T13:44:34+00:00","versionOfRecord":[],"versionCreatedAt":"2023-01-11 19:19:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2456935","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2456935","identity":"rs-2456935","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}