{"paper_id":"b6049e8c-14f9-4d21-bf70-467fcd442174","body_text":"Original Research Articles \nEvaluating the Impact of Long-Term GnRH Agonist Therapy on          \nPregnancy Outcomes in Endometriosis-Associated Implantation      \nFailure and Pregnancy Loss     \nMasato Kobanawa1 a \n1 Kobanawa Clinic, 169-3 Tagiya, Omitama-shi, Ibaraki, Japan \nKeywords: Endometriosis, recurrent implantation failure, recurrent pregnancy loss, GnRH agonist, embryo transfer \nhttps://doi.org/10.46989/001c.115593 \nJournal of IVF-Worldwide \nVol. 2, Issue 1, 2024 \nPurpose  \nThis study aimed to investigate the efficacy of long-term gonadotropin-releasing \nhormone (GnRH) agonist therapy in preventing endometriosis progression and relieving \nsymptoms, particularly on pregnancy outcomes during thawed embryo transfer in \npatients experiencing endometriosis and recurrent implantation failure or recurrent \npregnancy loss. \nMethods  \nIn individuals with clinical endometriosis and a history of recurrent implantation failure \nor recurrent pregnancy loss, we conducted a comparative analysis of clinical outcomes \nbetween those undergoing long-term GnRH agonist treatment for symptom relief, such \nas menstrual pain, followed by embryo transfer using Hormone Replacement Therapy \n(HRT) cycle, and those undergoing embryo transfer using an HRT cycle without GnRH \nagonist treatment. The study examined various clinical outcomes between the two \ngroups. \nResults  \nThe primary outcomes included live birth rate (LBR), miscarriage rate, biochemical \npregnancy rate, and perinatal complications. The GnRH agonist group showed \nsignificantly higher LBR than the control group (37.50% vs. 13.04%; p=0.02). \nMultivariable logistic regression analysis, adjusted for age and gravidity, showed \nsignificantly higher LBR in the GnRH agonist group compared to the control group (odds \nratio: 15.3; 95% confidence interval: 2.30, 102.00; p=0.005). \nConclusions  \nThe findings of this study suggested that employing a GnRH agonist in the embryo \ntransfer protocol is effective for patients with endometriosis experiencing recurrent \nimplantation failure or recurrent pregnancy loss. \nINTRODUCTION \nEndometriosis, affecting approximately 10% of women in \ntheir reproductive years,1 is a condition characterized by \npain, notably menstrual cramps and infertility. Nearly half \nof patients with endometriosis experience infertility, with \nthe disease diagnosed in 20-25% of individuals facing fer-\ntility challenges. The fertility rate in women with en-\ndometriosis decreases from 0.15-0.2 women/month to \n0.02-0.10 women/month.2 \nAdditionally, the likelihood of endometriosis is six to \neight times higher in infertile women compared to their fer-\ntile counterparts.3 Reported causes of infertility in women \nwith endometriosis encompass luteinized unruptured folli-\ncle syndrome, impaired oocyte and embryo formation, en-\ndocrine disorders involving luteinizing hormone (LH) surge \nabnormalities, and ovulation disorders.4 Moreover, inflam-\nmation in the pelvic region is identified as a potential con-\ntributor to these conditions. \nCorresponding author, Email: masato.kobanawa@gmail.com a \nKobanawa M. Evaluating the Impact of Long-Term GnRH Agonist Therapy on Pregnancy\nOutcomes in Endometriosis-Associated Implantation Failure and Pregnancy Loss.\nJournal of IVF-Worldwide. 2024;2(1):29-36. doi:10.46989/001c.115593\n\nStudies have reported elevated levels of inflammatory \ncytokines in the pelvic region of individuals with en-\ndometriosis.5,6 Moreover, studies indicate an increased \nnumber of macrophages and cytokines in the peritoneal \nfluid of women with endometriosis, with this fluid demon-\nstrated to inhibit sperm and oviduct cilia function in vitro.7 \nIn individuals with endometriosis, elevated concentra-\ntions of IL-6 are observed in intraperitoneal reservoir fluid, \nblood, and follicular fluid. Studies have reported that high \nIL-6 levels in intraperitoneal fluid can suppress early em-\nbryonic development in mice, reduce human sperm motil-\nity, and inhibit estrogen production by granulosa cells. \nThese findings imply the involvement of increased cy-\ntokines in ascites and blood from individuals with en-\ndometriosis in reducing fertility.8 \nFurthermore, the reduced expression of decidualization \nmarkers in endometrial tissue from patients with en-\ndometriosis, compared to endometriosis-free en-\ndometrium, suggests the potential influence of cytokines, \nincreased in ascites fluid, on these markers.9 These suggest \na potential association between endometriosis and implan-\ntation failure. \nIncreased miscarriage rates have also been reported \namong patients with endometriosis.10,11 Moreover, it has \nbeen indicated that a higher miscarriage rate exists among \npatients with endometriosis compared to those without en-\ndometriosis, particularly in cases involving assisted repro-\nductive technology (ART).12 These findings suggest that \npatients with endometriosis may exhibit abnormal en-\ndometrial conditions due to inflammatory cytokines and \nother factors, leading to recurrent implantation failure and \nrepeated miscarriages. Furthermore, several studies have \nreported that GnRH agonist ameliorates pelvic inflamma-\ntion in endometriosis.13,14 \nIn this study, we retrospectively examined whether the \nuse of GnRH agonists in HRT cycles, with or without em-\nbryo transfer, influences the clinical outcomes for patients \nundergoing ART due to recurrent implantation failure (RIF) \n(defined as failure to conceive after three or more successful \nembryo transfers)15 or recurrent pregnancy loss (RPL) (de-\nfined as two or more miscarriages).16 The primary focus of \nthe retrospective examination was to assess if the use of \nGnRH agonists during embryo transfers in HRT cycles could \nbring about changes in the clinical outcome. \nMETHODS \nSeventy patients, all with a history of endometriosis and \ndiagnosed with recurrent implantation failure or recurrent \npregnancy loss, were included in this study based on their \nprevious medical history. The clinical outcomes of eligible \npatients who underwent thawed embryo transfer of frozen \nblastocysts by HRT cycle in assisted reproductive medicine \nbetween April 2022 and December 2022 were retrospec-\ntively analyzed. The diagnosis of endometriosis was based \non subjective symptoms such as dysmenorrhea, deep dys-\npareunia, and dysuria, with Beecham Classification stage II \nor higher considered indicative of clinical endometriosis, \nrelying on internal examination findings and transvaginal \nultrasound.17 \nFor the purposes of this study, RIF was defined as the \ninability to achieve pregnancy after three or more embryo \ntransfers involving good blastocysts (Gardner’s classifica-\ntion 3BB or higher). RPL was categorized for patients who \nhad encountered two or more previous miscarriages. Ethi-\ncal approval was obtained from the Ethical Review Commit-\ntee, and the study was performed on cases where informed \nconsent was obtained from the patients. \nFor controlled ovarian stimulation, beginning on the \nfirst three days of menstruation, either Follitropin alfa (Go-\nnal F; Merck Biopharma, Tokyo, Japan) or Follitropin delta \n(REKOVELLE; Ferring Pharma, Tokyo, Japan) was used in \nperforming the antagonist or progestin-primed ovarian \nstimulation (PPOS) method. \nUpon reaching approximately 14 mm, the primary folli-\ncle triggers the initiation of a GnRH antagonist (Ganirest; \nMSD, Tokyo, Japan) at a dose of 0.25 m/day, which was \nmaintained until the primary follicle attained a size of \n18-20 mm. The gonadotropin and GnRH antagonist 0.25 \nm/day were discontinued upon reaching this size. Simul-\ntaneously, on the same day, 250 μg of recombinant hCG \n(Ovidrel; Merck biopharma) or 600 μg of a GnRH agonist \n(Suprecur; CLINIGEN, Tokyo, Japan) was administered to \ntrigger oocyte maturation. Oocytes retrieval was performed \n34 to 36 hours after the triggering. Oocytes were insemi-\nnated with 1 to 5 pre-cultured oocytes at a sperm concen-\ntration of 10 × 104/ml. The following morning (approxi-\nmately 19 hours post-insemination), oocytes were denuded \nusing an inverted microscope (OLYMPUS IX73, Tokyo, \nJapan), and a clean bench in the intracytoplasmic sperm \ninjection (ICSI). Sperm collected after swim-up were used \nin 10% polyvinylpyrrolidone (Irvine Scientific, Santa Ana, \nU.S.A.) to achieve the optimal concentration. The retrieved \noocytes underwent pre-culture and denudation using Cu-\nmulus Remover (KITAZATO, Shizuoka, Japan). After ICSI, \nfertilization was confirmed the next morning (approxi-\nmately 18 hours post-ICSI). Embryos were cultured individ-\nually in ART CULTURE DISH 12 or 24 (nipro, Tokyo, Japan), \nwith 50 μL CSCM-NX per well. Blastocysts were cultured \nuntil Day 5/Day 6 and classified as good blastocysts accord-\ning to Gardner’s classification 3BB or higher before under-\ngoing freezing. Vitrification media (KITAZATO) served as \nthe embryo freezing medium, and CRYO-TOP (KITAZATO) \nas the device. \nThe GnRH agonist group received depot leuprolide ac-\netate (Leuprorelin Acetate; ASKA Pharmacy, Tokyo, Japan) \nfor 1 to 2 months from the 1st to 3rd day of any menstrual \nperiod to relieve symptoms such as menstrual cramps as-\nsociated with endometriosis, then administration of the \nestrogen preparation (ESTRANA Tapes; Hisamitsu Phar-\nmaceutical, Saga, Japan) 0.72 mg x 4/every other day was \nstarted without waiting for the onset of menstruation. \nUpon confirming endometrial thickness exceeding 7 mm, \nprogesterone drugs (LUTINUS Vaginal Tablets: Ferring \nPharma) at 100 mg thrice a day was initiated (P＋0). At \nsix days initiating progesterone drug(P+5), after thawing, \nthe embryos were cultured for 4-6 hours and then trans-\nEvaluating the Impact of Long-Term GnRH Agonist Therapy on Pregnancy Outcomes in Endometriosis-Ass…\nJournal of IVF-Worldwide 2\n\nTable 1. Patient Characteristics   \nCharacteristics GnRH agonist group \n(n=24) \nControl group \n(n=46) \np-value \nAge at oocytes pick up, age 38.04±5.61 35.22±4.38 0.02 \nAge at embryo transfer, age 38.71±5.92 37.39±4.76 0.31 \nboy weight, kg 58.05 [44.00, 75.00］ 57.00 [41.80, 95.00］ 0.90 \nBMI, kg/m2 23［18.00, 33.00］ 22.5［17.00, 34.00］ 0.50 \nAMH, ng/ml 2.57［0.20, 10.99］ 3.29［0.02, 17.64］ 0.07 \nGravidity, times 1.00［0.00, 3.00］ 1.00［0.00, 4.00］ 0.39 \nParity, times 0.00［0.00, 1.00］ 0.00［0.00, 2.00］ 0.009 \nNumber of past embryo transfers, times 4.00 [2.00, 29.00] 4.00 [2.00, 16.00] 0.24 \nDuration of estrogen supplementation until embryo transfer, \ndays \n19.00±2.04 17.93±1.73 0.02 \nThickness of the endometrium, mm 9.88±1.36 10.27±1.52 0.29 \nSerum estradiol level on day of progesterone start, pg/ml 275.12±178.64 299.35±158.23 0.56 \nSerum progesterone levels on the day of embryo transfer, ng/\nml \n10.89±2.71 11.64±5.09 0.50 \nIn vitro fertilization (%) 16 (66.70) 20 (43.50) 0.08 \nIntracytoplasmic sperm injection (%) 8 (33.30) 26 (56.50) 0.08 \nBlastocyst Quality Score, points 28.83±10.08 31.11±8.53 0.32 \nData are presented as mean ± standard deviation or median [Max, min] or n, n (%). The t-test or Mann-Whitney’s U test was used for patient characteristics. \nferred under transvaginal ultrasound guidance. In the con-\ntrol group, embryos were transferred without depot leupro-\nlide acetate in HRT cycles initiated on days 1-3 of any \nmenstrual period. \nIn order to evaluate the effects of GnRH agonist, only \npatients who underwent embryo transfer during HRT cycles \nwere included in the control group, regardless of menstrual \ncycle abnormalities or ovulation disorders. Clinical out-\ncomes, including live birth rate, miscarriage rate, biochem-\nical pregnancy rate and perinatal complications, were com-\npared following thawed embryo transfer. In this study, \nbiochemical pregnancies were defined with a cut-off as in-\ncreasing values of β-hCG > 5 IU/L not confirming fetal sac \nby transvaginal ultrasonography.18 \nStatistical analysis employed a t-test or Mann-Whitney’s \nU test for patient characteristics, with a significance set at \na p < 0.05. The χ2 test was used for clinical outcomes, with \na significance set at p < 0.05. \nAdditionally, a logistic regression model, adjusted for \nconfounding factors, was used to evaluate the effect of em-\nbryo transfer with GnRH agonist on the live birth rate \n(LBR). \nAll statistical analyses were performed using EZR \n(Saitama Medical Center, Saitama, Japan), a software that \nextends R’s capabilities (The R Foundation for Statistical \nComputing, Vienna, Austria). \nRESULTS \nA total of 70 patients (GnRH agonist group, n=24; control \ngroup, n=46) diagnosed with endometriosis-associated with \nRIF or RPL were included in the analysis. The demographic \ncharacteristics of the women are presented in Table 1. To \nfacilitate the comparison, the grades of transferred em-\nbryos were converted to continuous variables using the \nBlastocyst Quality Score.19 \nPatient characteristics were generally similar between \nthe groups. However, differences were observed in age at \noocyte pick-up (p = 0.02), parity (p = 0.009), and duration of \nestrogen supplementation until embryo transfer (p = 0.02) \n(Table 1 ). \nThe clinical results indicated that LBR was significantly \nhigher in the GnRH agonist group compared to the control \ngroup (p = 0.02), and the biochemical pregnancy rate was \nsignificantly lower in the GnRH agonist group (Table 2 ). \nThe univariate logistic analysis showed a significant as-\nsociation between LBR and age at oocyte pick-up and gra-\nvidity (Table 3 ). \nIn the multiple logistic regression analysis, adjusted for \nage at oocytes pick up and gravidity, the LBR was signifi-\ncantly higher in the GnRH agonist group than in the con-\ntrol group (odds ratio: 15.3; 95% confidence interval: 2.30, \n102.00; p = 0.005) (Table 4 ). \nDISCUSSION \nThis study suggests that utilizing a GnRH agonist in embryo \ntransfer with HRT cycle may be effective for patients with \nendometriosis experiencing RIF or RPL. Similar findings \nhave been reported in several previous studies. \nStudies have indicated that the long-term use of GnRH \nagonists prior to in vitro fertilization and embryo transfer \n(IVF-ET) in patients with endometriosis results in signifi-\ncantly higher rates of ongoing pregnancy compared to stan-\ndard controlled ovarian stimulation regimens.20 Similarly, \nthe long-term use of GnRH agonists before IVF/ICSI in in-\nEvaluating the Impact of Long-Term GnRH Agonist Therapy on Pregnancy Outcomes in Endometriosis-Ass…\nJournal of IVF-Worldwide 3\n\nTable 2. Comparison of clinical outcomes.     \nGnRH agonist group (n=24) Control group (n=46) p-value \nLive birth rate (%) 9 (37.50) 6 (13.04) 0.02 \nMiscarriage rate (%) 0 (0.00) 1 (14.20) 0.47 \nBiochemical pregnancy rate (%) 0 (0.00) 10 (21.74) 0.01 \nPerinatal complications (%) 1 (4.20) 0 (0.00) 0.34 \nThe data are presented as n, n (%). The chi-squared test was used to analyze the group difference. \nTable 3. Univariate logistic regression analysis for live birth rate.         \nVariables Adjusted OR(95%CI) p-value \nAge at oocytes pick up 0.84 (0.74, 0.96) 0.01 \nAge at embryo transfer 1.02 (0.91, 1.15) 0.68 \nboy weight 1.03 (0.98, 1.09) 0.26 \nBMI 1.13 (0.99, 1.29) 0.06 \nAMH 0.98 (0.79, 1.21) 0.82 \nGravidity 0.30(0.12, 0.77) 0.01 \nParity 0.25 (0.05, 1.21) 0.09 \nNumber of past embryo transfers 1.07 (0.95, 1.20) 0.27 \nDuration of estrogen supplementation until embryo transfer 1.17 (0.85, 1.60) 0.32 \nThickness of the endometrium 1.17 (0.81, 1.70) 0.41 \nSerum estradiol level on day of progesterone start 1.00 (0.99, 1.00) 0.70 \nSerum progesterone levels on the day of embryo transfer 0.97 (0.85, 1.11) 0.67 \nIn vitro fertilization 1.27 (0.41, 4.00) 0.68 \nIntracytoplasmic sperm injection 1.27 (0.41, 4.00) 0.68 \nBlastocyst Quality Score 0.98 (0.92, 1.05) 0.61 \nCI, confidence interval \nOR, Odds ratio \nTable 4. Multivariable logistic regression analysis results of the two groups and clinical outcomes.             \nVariables OR(95%CI) p-value \nGnRH agonist group vs Control group 15.3 (2.3, 102.00) 0.005 \nAge at oocytes pick up 0.72 (0.58, 0.88) 0.002 \nGravidity 0.18 (0.04, 0.70) 0.01 \nfertile women with endometriosis or adenomyosis has been \nassociated with increased ongoing pregnancy rates in both \nfresh and frozen cycles.21,22 \nPossible causes of implantation failure and miscarriage \nin patients with endometriosis include progesterone (P4) \nresistance, abnormal expression of integrin (a cell adhesion \nfactor), and overexpression of B-cell lymphoma 6 (BCL6), \na biomarker associated with endometriosis.23 Estrogen re-\nceptors (ER-α) in the endometrium, responding to estrogen \nduring the proliferative phase and decreasing during the se-\ncretory phase in response to P4, play a crucial role in im-\nplantation.24 Suppression of ER-α is important for implan-\ntation,25 and P4 is known to promote downregulation of \nestrogen receptors in the endometrium and promote decid-\nualization.26‑28 In endometriosis, abnormal expression of \naromatase leads to a local increase in estrogen in the en-\ndometrium,29 causing resistance to P4.30 Such abnormal-\nities in estrogen metabolism may affect endometrial re-\nceptivity, leading to downregulation of P4 receptors and \nupregulation of estrogen receptors, resulting in decidual-\nization.31 The absence of progesterone receptor B (PR-B), \none of the P4 receptor isoforms in endometriosis, has been \nsuggested as a potential cause of these abnormalities in es-\ntrogen metabolism.32 \nProgesterone receptor (PGR) has isoforms PR-A and PR-\nB, with PR-A acting as a major repressor of PR-B, whereas \nPR-B tends to be a more potent activator of P4 target \ngenes.33,34 P4 resistance in endometriosis tissue may be ex-\nplained by the presence of the inhibitory PR isoform PR-A \nand the absence of the active isoform PR-B.35,36 GnRH ag-\nEvaluating the Impact of Long-Term GnRH Agonist Therapy on Pregnancy Outcomes in Endometriosis-Ass…\nJournal of IVF-Worldwide 4\n\nonists inhibit aromatase activity in the endometrium, pre-\nventing local estrogen increase.37 This effect helps prevents \nupregulation of estrogen receptors and the active P4 re-\nceptor, PR-B, potentially improving decidualization and ad-\ndressing implantation failure. \nAnother biomarker indicative of the embryonic receptive \nstate during the implantation phase of the endometrium \nis the cell adhesion factor integrin, particularly ανβ3 inte-\ngrin. Expression of ανβ3 integrin has been linked to im-\nplantation failure.38‑42 Moreover, endometriosis has been \nassociated with significantly higher levels of ER-α expres-\nsion in the mid-secretory endometrium, leading to reduced \nαvβ3 integrin expression.25 \nThe administration of long-acting GnRH agonists prior \nto treatment has been shown to enhance αvβ3 integrin ex-\npression in patients with endometriosis, potentially con-\ntributing to improved implantation and pregnancy contin-\nuation rates.22,43 \nPatients with endometriosis often exhibit a high levels \nof BCL6 protein, with a positive predictive value of 96%. \nBCL6 is a protein encoded by a proto-oncogene located on \nchromosome 3 (3q27.3) that stimulates inflammatory cy-\ntokines, such as IL-6. Inflammation can lead to P4 resis-\ntance and abnormal decidualization.44 Similarly, overex-\npression of BCL6 protein is associated with P4 resistance \nby interfering with P4 signaling, a crucial factor for decidu-\nalization.45 Studies have reported a significantly lower live \nbirth rate in ART for patients with elevated BCL6 (11.5%) \ncompared to those without elevated BCL6 (58%).46 \nWomen suspected of having endometriosis with abnor-\nmal endometrial BCL6 expression have demonstrated sig-\nnificantly improved fertility following two months of GnRH \nagonist or surgical treatment.47 These findings suggest that \nin patients with endometriosis, RIF and RPL may result \nfrom P4 resistance due to abnormal estrogen metabolism, \ndecreased integrin expression, and excessive expression of \nBCL6 protein. The use of GnRH agonist as a premedication \nfor 1-2 months may improve the clinical outcomes for these \npatients. \nConsidering that the ESHRE RPL guidelines encompass \nbiochemical pregnancies in the definition of RPL,16 all pa-\ntients with implantation failure in this study had experi-\nenced at least two biochemical pregnancies, this study sug-\ngests that embryo transfer during HRT cycles with GnRH \nagonist can improve LBR and decrease biochemical preg-\nnancy rate for RPL patients in a broad sense. \nLIMITATIONS \nThe study was conducted with a limited number of patients \nwith uterine infertility, and a notable limitation is that the \ndiagnosis of endometriosis included patients clinically di-\nagnosed according to the Beecham classification,17 which \nencompasses a group where a definitive histological diag-\nnosis of endometriosis has not been established. However, \nin recent years, it is not always necessary to perform la-\nparoscopy and histological examination, as a therapeutic \nintervention is recommended when clinically suspicious \nfindings of endometriosis are identified during an internal \nexamination or transvaginal ultrasound.48‑50 Given the ret-\nrospective nature of this study, future prospective studies, \nwith or without prior administration of GnRH agonists in \npatients with endometriosis, are warranted. \nACKNOWLEDGMENTS \nWe want to thank Editage (www.editage.com) for editing \nthe English language. \nSTATEMENTS AND DECLARATIONS} \nThe authors have no conflicts of interest to declare. All \nprocedures were conducted in accordance with the ethical \nstandards of the responsible committee on human experi-\nmentation (facility and national levels) and adhered to the \nHelsinki Declaration of 1964 and its subsequent amend-\nments. Informed consent was obtained from all patients in-\ncluded in the study. This article does not involve any stud-\nies conducted by authors on animal subjects. The protocol \nfor the research project, which includes human subjects, \nhas been approved by the Medical Corporation Kobanawa \nClinic Ethic Screening Committee. \nCOMPETING INTERESTS \nThe authors have no competing interests to disclose. \nSubmitted: January 15, 2024 CDT, Accepted: March 22, 2024 \nCDT \nThis is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License \n(CCBY-NC-SA-4.0). View this license’s legal deed at https://creativecommons.org/licenses/by-nc-sa/4.0 and legal code at \nhttps://creativecommons.org/licenses/by-nc-sa/4.0/legalcode for more information. \nEvaluating the Impact of Long-Term GnRH Agonist Therapy on Pregnancy Outcomes in Endometriosis-Ass…\nJournal of IVF-Worldwide 5\n\nREFERENCES \n1. Eskenazi B, Warner ML. Epidemiology of \nendometriosis. Obstet Gynecol Clin North Am. \n1997;24(2):235-258. doi:10.1016/s0889-8545(05)7030\n2-8 \n2. Hughes EG, Fedorkow DM, Collins JA. A \nquantitative overview of controlled trials in \nendometriosis-associated infertility. Fertil Steril. \n1993;59(5):963-970. doi:10.1016/s0015-0282(16)5591\n1-1 \n3. Verkauf BS. Incidence, symptoms, and signs of \nendometriosis in fertile and infertile women. J Fla \nMed Assoc. 1987;74(9):671-675. \n4. Practice Committee of the American Society for \nReproductive Medicine (ASRM). Endometriosis and \ninfertility. Fertil Steril. 2006;86(5):S156-S160. doi:10.1\n016/j.fertnstert.2006.08.014 \n5. Agic A, Xu H, Finas D, Banz C, Diedrich K, Hornung \nD. Is endometriosis associated with systemic \nsubclinical inflammation? Gynecol Obstet Invest. \n2006;62(3):139-147. doi:10.1159/000093121 \n6. Weiss G, Goldsmith LT, Taylor RN, Bellet D, Taylor \nHS. Inflammation in reproductive disorders. Reprod \nSci. 2009;16(2):216-229. doi:10.1177/1933719108330\n087 \n7. Lyons RA, Djahanbakhch O, Saridogan E, et al. \nPeritoneal fluid, endometriosis, and ciliary beat \nfrequency in the human fallopian tube. Lancet. \n2002;360(9341):1221-1222. doi:10.1016/s0140-6736(0\n2)11247-5 \n8. Harada T, Iwabe T, Terakawa N. Role of cytokines \nin endometriosis. Fertil Steril. 2001;76(1):1-10. doi:1\n0.1016/s0015-0282(01)01816-7 \n9. Minici F, Tiberi F, Tropea A, et al. Endometriosis \nand human infertility: a new investigation into the \nrole of eutopic endometrium. Hum Reprod. \n2008;23(3):530-537. doi:10.1093/humrep/dem399 \n10. Santulli P, Marcellin L, Menard S, et al. Increased \nrate of spontaneous miscarriages in endometriosis-\naffected women. Hum Reprod. 2016;31(5):1014-1023. \ndoi:10.1093/humrep/dew035 \n11. Boje AD, Egerup P, Westergaard D, et al. \nEndometriosis is associated with pregnancy loss: a \nnationwide historical cohort study. Fertil Steril. \n2023;119(5):826-835. doi:10.1016/j.fertnstert.2022.1\n2.042 \n12. Zullo F, Spagnolo E, Saccone G, et al. \nEndometriosis and obstetrics complications: a \nsystematic review and meta-analysis. Fertil Steril. \n2017;108(4):667-672.e5. doi:10.1016/j.fertnstert.201\n7.07.019 \n13. Iwabe T, Harada T, Sakamoto Y, et al. \nGonadotropin-releasing hormone agonist treatment \nreduced serum interleukin-6 concentrations in \npatients with ovarian endometriomas. Fertil Steril. \n2003;80(2):300-304. doi:10.1016/s0015-0282(03)0060\n9-5 \n14. Khan KN, Kitajima M, Hiraki K, et al. Changes in \ntissue inflammation, angiogenesis and apoptosis in \nendometriosis, adenomyosis and uterine myoma after \nGnRH agonist therapy. Hum Reprod. \n2010;25(3):642-653. doi:10.1093/humrep/dep437 \n15. ESHRE Working Group on Recurrent Implantation \nFailure, Cimadomo D, de los Santos MJ, et al. ESHRE \ngood practice recommendations on recurrent \nimplantation failure. Hum Reprod Open. \n2023;2023(3):hoad023. doi:10.1093/hropen/hoad023 \n16. ESHRE Guideline Group on RPL, Bender Atik R, \nChristiansen OB, et al. ESHRE guideline: recurrent \npregnancy loss: an update in 2022. Hum Reprod Open. \n2022;2023(1). doi:10.1093/hropen/hoad002 \n17. Beecham CT. Classification of endometriosis. \nObstet Gynecol. 1966;28(3):437. \n18. De Neubourg D, Gerris J, Mangelschots K, Van \nRoyen E, Vercruyssen M, Elseviers M. Single top \nquality embryo transfer as a model for prediction of \nearly pregnancy outcome. Hum Reprod. \n2004;19(6):1476-1479. doi:10.1093/humrep/deh283 \n19. Rehman KS, Bukulmez O, Langley M, et al. Late \nstages of embryo progression are a much better \npredictor of clinical pregnancy than early cleavage in \nintracytoplasmic sperm injection and in vitro \nfertilization cycles with blastocyst-stage transfer. \nFertil Steril. 2007;87(5):1041-1052. doi:10.1016/j.fertn\nstert.2006.11.014 \n20. Surrey ES, Silverberg KM, Surrey MW, Schoolcraft \nWB. Effect of prolonged gonadotropin-releasing \nhormone agonist therapy on the outcome of in vitro \nfertilization-embryo transfer in patients with \nendometriosis. Fertil Steril. 2002;78(4):699-704. doi:1\n0.1016/s0015-0282(02)03373-3 \nEvaluating the Impact of Long-Term GnRH Agonist Therapy on Pregnancy Outcomes in Endometriosis-Ass…\nJournal of IVF-Worldwide 6\n\n21. Niu Z, Chen Q, Sun Y, Feng Y. Long-term pituitary \ndownregulation before frozen embryo transfer could \nimprove pregnancy outcomes in women with \nadenomyosis. Gynecological Endocrinology. \n2013;29(12):1026-1030. doi:10.3109/09513590.2013.8\n24960 \n22. Surrey ES, Katz-Jaffe M, Kondapalli LV, Gustofson \nRL, Schoolcraft WB. GnRH agonist administration \nprior to embryo transfer in freeze-all cycles of \npatients with endometriosis or aberrant endometrial \nintegrin expression. Reprod Biomed Online. \n2017;35(2):145-151. doi:10.1016/j.rbmo.2017.05.004 \n23. Evans-Hoeker E, Lessey BA, Jeong JW, et al. \nEndometrial BCL6 Overexpression in Eutopic \nEndometrium of Women With Endometriosis. Reprod \nSci. 2016;23(9):1234-1241. doi:10.1177/19337191166\n49711 \n24. Brenner RM, West NB. Hormonal regulation of \nthe reproductive tract in female mammals. Annu Rev \nPhysiol. 1975;37(1):273-302. doi:10.1146/annurev.p\nh.37.030175.001421 \n25. Lessey BA, Palomino WA, Apparao KB, Young SL, \nLininger RA. Estrogen receptor-alpha (ER-alpha) and \ndefects in uterine receptivity in women. Reprod Biol \nEndocrinol. 2006;4(Suppl 1):S9. doi:10.1186/1477-782\n7-4-s1-s9 \n26. Franco HL, Rubel CA, Large MJ, et al. Epithelial \nprogesterone receptor exhibits pleiotropic roles in \nuterine development and function. FASEB J. \n2012;26(3):1218-1227. doi:10.1096/fj.11-193334 \n27. Tan J, Paria BC, Dey SK, Das SK. Differential \nuterine expression of estrogen and progesterone \nreceptors correlates with uterine preparation for \nimplantation and decidualization in the mouse. \nEndocrinology. 1999;140(11):5310-5321. doi:10.1210/\nendo.140.11.7148 \n28. Large MJ, DeMayo FJ. The regulation of embryo \nimplantation and endometrial decidualization by \nprogesterone receptor signaling. Mol Cell Endocrinol. \n2012;358(2):155-165. doi:10.1016/j.mce.2011.07.027 \n29. Zeitoun KM, Bulun SE. Aromatase: a key molecule \nin the pathophysiology of endometriosis and a \ntherapeutic target. Fertil Steril. 1999;72(6):961-969. d\noi:10.1016/s0015-0282(99)00393-3 \n30. Patel BG, Rudnicki M, Yu J, Shu Y, Taylor RN. \nProgesterone resistance in endometriosis: origins, \nconsequences and interventions. Acta Obstet Gynecol \nScand. 2017;96(6):623-632. doi:10.1111/aogs.13156 \n31. Macer ML, Taylor HS. Endometriosis and \ninfertility: a review of the pathogenesis and \ntreatment of endometriosis-associated infertility. \nObstet Gynecol Clin North Am. 2012;39(4):535-549. do\ni:10.1016/j.ogc.2012.10.002 \n32. Bulun SE, Cheng YH, Yin P, et al. Progesterone \nresistance in endometriosis: link to failure to \nmetabolize estradiol. Mol Cell Endocrinol. \n2006;248(1-2):94-103. doi:10.1016/j.mce.2005.11.041 \n33. Vegeto E, Shahbaz MM, Wen DX, Goldman ME, \nO’Malley BW, McDonnell DP. Human progesterone \nreceptor A form is a cell- and promoter-specific \nrepressor of human progesterone receptor B function. \nMol Endocrinol. 1993;7(10):1244-1255. doi:10.1210/m\nend.7.10.8264658 \n34. Tung L, Mohamed MK, Hoeffler JP, Takimoto GS, \nHorwitz KB. Antagonist-occupied human \nprogesterone B-receptors activate transcription \nwithout binding to progesterone response elements \nand are dominantly inhibited by A-receptors. Mol \nEndocrinol. 1993;7(10):1256-1265. doi:10.1210/men\nd.7.10.8123133 \n35. Attia GR, Zeitoun K, Edwards D, Johns A, Carr BR, \nBulun SE. Progesterone receptor isoform A but not B \nis expressed in endometriosis. J Clin Endocrinol \nMetab. 2000;85(8):2897-2902. doi:10.1210/jcem.8\n5.8.6739 \n36. Igarashi TM, Bruner-Tran KL, Yeaman GR, et al. \nReduced expression of progesterone receptor-B in the \nendometrium of women with endometriosis and in \ncocultures of endometrial cells exposed to \n2,3,7,8-tetrachlorodibenzo-p-dioxin. Fertil Steril. \n2005;84(1):67-74. doi:10.1016/j.fertnstert.2005.01.11\n3 \n37. Ishihara H, Kitawaki J o, Kado N, Koshiba H, \nFushiki S, Honjo H. Gonadotropin-releasing hormone \nagonist and danazol normalize aromatase \ncytochrome P450 expression in eutopic endometrium \nfrom women with endometriosis, adenomyosis, or \nleiomyomas. Fertil Steril. 2003;79(Suppl 1):735-742. d\noi:10.1016/s0015-0282(02)04813-6 \n38. Revel A. Defective endometrial receptivity. Fertil \nSteril. 2012;97(5):1028-1032. doi:10.1016/j.fertnster\nt.2012.03.039 \n39. Thomas K, Thomson A, Wood S, Kingsland C, \nVince G, Lewis-Jones I. Endometrial integrin \nexpression in women undergoing in vitro fertilization \nand the association with subsequent treatment \noutcome. Fertil Steril. 2003;80(3):502-507. doi:10.101\n6/s0015-0282(03)00792-1 \nEvaluating the Impact of Long-Term GnRH Agonist Therapy on Pregnancy Outcomes in Endometriosis-Ass…\nJournal of IVF-Worldwide 7\n\n40. Cavagna M, Mantese JC. Biomarkers of \nendometrial receptivity--a review. Placenta. \n2003;24(Suppl B):S39-S47. doi:10.1016/s0143-4004(0\n3)00184-x \n41. Casals G, Ordi J, Creus M, et al. Osteopontin and \nαvβ3 integrin as markers of endometrial receptivity: \nthe effect of different hormone therapies. Reprod \nBiomed Online. 2010;21(3):349-359. doi:10.1016/j.rbm\no.2010.04.012 \n42. Revel A, Koler M, Prus D, Tsafrir A, Laufer N, \nReich R. Implementation of integrin beta 3 level as \npredictor of implantation in IVF program. Fertil Steril. \n2005;84:S144. doi:10.1016/j.fertnstert.2005.07.352 \n43. Surrey ES, Minjarez DA, Schoolcraft WB. The \nincidence of aberrant endometrial αvβ3 vitronectin \nexpression in a high risk infertility population: could \nprolonged GnRH agonist therapy play a role? J Assist \nReprod Genet. 2007;24(11):553-556. doi:10.1007/s108\n15-007-9164-3 \n44. Nezhat C, Rambhatla A, Miranda-Silva C, et al. \nBCL-6 Overexpression as a Predictor for \nEndometriosis in Patients Undergoing In Vitro \nFertilization. JSLS. 2020;24(4):e2020.00064. doi:10.42\n93/jsls.2020.00064 \n45. Yoo JY, Kim TH, Fazleabas AT, et al. KRAS \nActivation and over-expression of SIRT1/BCL6 \nContributes to the Pathogenesis of Endometriosis \nand Progesterone Resistance. Sci Rep. 2017;7(1):6765. \ndoi:10.1038/s41598-017-04577-w \n46. Almquist LD, Likes CE, Stone B, et al. Endometrial \nBCL6 testing for the prediction of in vitro \nfertilization outcomes: a cohort study. Fertil Steril. \n2017;108(6):1063-1069. doi:10.1016/j.fertnstert.201\n7.09.017 \n47. Likes CE, Cooper LJ, Efird J, et al. Medical or \nsurgical treatment before embryo transfer improves \noutcomes in women with abnormal endometrial BCL6 \nexpression. J Assist Reprod Genet. 2019;36(3):483-490. \ndoi:10.1007/s10815-018-1388-x \n48. Agarwal SK, Chapron C, Giudice LC, et al. Clinical \ndiagnosis of endometriosis: a call to action. Am J \nObstet Gynecol. 2019;220(4):354.e1-354.e12. doi:10.1\n016/j.ajog.2018.12.039 \n49. Becker CM, Bokor A, Heikinheimo O, et al. ESHRE \nguideline: endometriosis. Hum Reprod Open. \n2022;2022(2):hoac009. doi:10.1093/hropen/hoac009 \n50. Kim MR, Chapron C, Römer T, et al. Clinical \nDiagnosis and Early Medical Management for \nEndometriosis: Consensus from Asian Expert Group. \nHealthcare. 2022;10(12):2515. doi:10.3390/healthcare\n10122515 \nEvaluating the Impact of Long-Term GnRH Agonist Therapy on Pregnancy Outcomes in Endometriosis-Ass…\nJournal of IVF-Worldwide 8","source_license":"CC0","license_restricted":false}