{"paper_id":"d903dc34-0fef-44a4-ad77-e31a356597e8","body_text":"Endometriosis is an inflammatory oestrogen-dependent disease characterized by\nendometrial-like tissue found outside of the uterus. Endometriosis lesions are often\nlocated in the peritoneum, ovaries (endometrioma) and uterus, but lesions can also\nbe found in the bowel, urinary tract and vagina. Endometriosis is associated with a\nwide range of symptoms including visceral syndrome (e.g. pelvic pain, painful\nurination, dyschezia), dysmenorrhoea and subfertility. Traditionally, endometriosis\nclassification is based on the location of endometrial tissue lesions, and the three\nmost prevalent types are ovarian endometriomas, superficial peritoneal endometriosis\nor deep endometriosis. 1 , 2 \nEndometriosis is commonly graded on the revised American Society for Reproductive\nMedicine (r-ASRM) classification scale. Depending on the extent of lesions, it is\nclassified according to the four stages: minimal (stage I), mild (stage II),\nmoderate (stage III) and severe (stage IV). 1 , 2\nEndometriosis lesions can alter the pelvic anatomy, lead to excess inflammation and\ncan negatively impact the reproductive cycle resulting in subfertility in 30–50% of\naffected women. 3 , 4 \nIn women with endometriosis desiring to become pregnant, around 10–25% require\nassisted reproductive technology (ART), such as  in vitro \nfertilization (IVF) and intracytoplasmic sperm injection (ICSI). \n 5 \n  Since the 1980s, the long gonadotrophin-releasing hormone (GnRH) agonist\nprotocol has been the gold standard for controlled ovarian stimulation (COS) to\nprevent a premature luteinizing hormone (LH) surge and improve ART outcomes.\nHowever, this protocol requires an extensive treatment period which is associated\nwith more frequent side effects (such as hot flushes/flashes, bleeding, cyst\ndevelopment and headache) and has a higher risk of ovarian hyperstimulation syndrome\n(OHSS), which can be life-threatening. \n 6 \n  The GnRH-antagonist protocol is a promising alternative with a reduced risk\nof OHSS, shorter treatment time and often requires a reduced gonadotrophin dose as a\nresult of GnRH antagonists being able to rapidly inhibit GnRH receptors within hours\nof administration. \n 7 \n  However, previous studies report poorer pregnancy outcomes in infertile\ncouples after the GnRH-antagonist protocol. 8 , 9\nCompared to other causes of infertility, little research has focused on patients with\nendometriosis specifically, and it remains uncertain whether patients with\nendometriosis respond similarly to the long GnRH-agonist and GnRH-antagonist COS\nprotocols. Furthermore, the fertilization rate is often overlooked, and it has\nrecently been shown that fertilization rate positively correlates with cumulative\nlive birth rate (LBR). \n 10 \n  In this systematic review, we aim to compare ART outcomes following the long\nGnRH-agonist COS protocol with the GnRH-antagonist COS protocol specifically for\nwomen with endometriosis.\n\nThe patient populations consisted of women diagnosed with any form of\nendometriosis undergoing IVF/ICSI with ovarian stimulation using the long\nGnRH-agonist protocol compared to the GnRH-antagonist protocol.\nThe primary outcomes were related to pregnancy [clinical pregnancy rate (CPR) and\nLBR]. Secondary outcomes included the number of oocytes retrieved [total and\nmetaphase II (MII)], fertilization rate, COS parameters (treatment duration and\ngonadotrophin dose) and adverse ART outcomes (miscarriage rate, cycle\ncancellation rate and OHSS).\nA systematic search of the published literature up to 10 June 2022 was\nundertaken on MEDLINE, Embase and Web of Science databases using the\nPreferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. \n 11 \n  The following keywords and medical subject headings (MeSH) were\nqueried: endometriosis, endometrioma, infertility, GnRH agonist, GnRH\nantagonist,  in vitro  fertilization and ICSI (the full\nsearch strategy is detailed in  Supplementary Table 1 ). Database search results were\nimported into EndNote (X9, Clarivate Analytics) prior to title and abstract\nscreening. The PRISMA flowchart can be found in  Figure 1 .\nPRISMA flow diagram summarizing the search strategy used to identify\nqualifying studies.\nDuplicate studies were removed and two authors (K.K.W.K. and S.O.)\nindependently screened titles and abstracts, and excluded obviously\nirrelevant studies. Equivocal studies were independently screened by the\nthird author (J.A.T.) until a consensus could be reached. Full manuscripts\nof studies meeting the selection criteria were retrieved and reviewed by\nK.K.W.K., S.O. and J.A.T. for the final decision. Studies that used other\nGnRH-agonist protocols (i.e. ultralong or short) or had patients without\nendometriosis were excluded. Case reports, conference abstracts with\nunavailable data and trial protocols were also excluded.\nData extraction was completed by K.K.W.K. and S.O. All data from randomized\ncontrolled trials (RCTs) and observational studies (and their relevant\nsubgroups) comparing the long GnRH-agonist protocol  versus \nthe GnRH-antagonist COS protocol for women with endometriosis were included\n( Supplementary Table 2 ). Data were synthesized into outcome\ntables.\nThe rigour of study methodology and risk of bias was critically appraised\nusing the relevant Scottish Intercollegiate Guidelines Network (SIGN)\ncriteria for cohort studies and RCTs (description of criteria are available\non the SIGN website). \n 12 \n  For cohort studies, this tool aims to assess the internal validity\n(selection of subjects, assessment of exposure and outcomes, confounding\nfactors, statistical analysis) and overall study quality. Statements 1.3,\n1.5, 1.6, 1.11 and 1.12 of the SIGN cohort study tool were excluded as all\nthe studies were retrospective in nature and outcomes were objective in\naccordance with the SIGN’s checklist notes. \n 12 \n  The RCT tool assesses for a focused research question, patient\nrandomization, blinding methods, interventions, attrition bias, analysis\nmethods and overall study quality.\n\nUsing a systematic searching approach, 744 titles were identified from database\nsearches. After 59 duplicate titles were removed, 608 titles and abstracts were\nexcluded. Ultimately, eight studies were included for the final analysis with a\ntotal of 2695 women and 2761 cycles (study characteristics are summarized in\n Table\n1 ). 13 – 20  In these studies, 1721\ncycles used the long GnRH-agonist protocol and 1040 cycles used the\nGnRH-antagonist protocol. Six retrospective analyses, 13 – 17 , 20  one cross-sectional study \n 18 \n  and one RCT \n 19 \n  were identified. Each study was undertaken at a single centre, and all\ninclusion/exclusion criteria were available.\nSummary table of characteristics of included endometriosis studies.\n♀, female; #, number; ASRM, American Society for Reproductive\nMedicine Classification; COS, controlled ovarian stimulation; CP,\nclinical pregnancy; CPR, clinical pregnancy rate; d, days; DOR,\ndiminished ovarian reserve; ET, embryo transfer; FR, fertilization\nrate; GnRH-a, gonadotrophin-releasing hormone agonist; GnRH-ant,\ngonadotrophin-releasing hormone antagonist; Hx, history; hMG, human\nmenopausal gonadotrophin; IN, intranasal; ICSI, intracytoplasmic\nsperm injection; IR, implantation rate; IU, units; IVF,  in\nvitro  fertilization; MRI, magnetic resonance imaging;\nN, number of patients; OCP, oral contraceptive pills; OR, oocytes\nretrieved; PCOS, polycystic ovarian syndrome; Prev., previous;\nr-AFS, revised American Fertility Society classification system;\nRCT, randomised controlled trial; SC, subcutaneous.\nFor the long GnRH-agonist protocol, four studies administered\ntriptorelin, 14 , 15 , 18 , 19  two studies administered leuprorelin 16 , 17  and one\nstudy administered decapeptyl \n 13 \n  daily starting from day 20 to 21 of the previous menstrual cycle. One study \n 20 \n  did not specify which GnRH agonist was used and started treatment after\nday 21 of the preceding cycle. Seven studies in the GnRH-antagonist arm\nadministered subcutaneous cetrorelix or ganirelix. 13 – 19  Five of which followed a\nflexible multiple dosing protocol 13 , 15 – 17 , 19  and two of which followed\na fixed protocol from day 5 or day 6. 14 , 18  One study also gave\npatients in the GnRH-antagonist arm an oral contraceptive pill pretreatment\ntaken for 14–24 days in the preceding cycle followed by a 3- to 5-day washout period. \n 16 \n  One study did not specify the antagonist used and started the protocol\nafter at least 6 weeks of oral contraceptives. \n 20\nThe completed SIGN assessments for observational studies and the RCT can be found\nin  Tables 2  and\n 3 ,\nrespectively. Since the study by Hosseini  et al.  was a\ncross-sectional study, a SIGN \n 12 \n  checklist was not required (as described by SIGN’s study design\nalgorithm). As mentioned earlier, Statements 1.3, 1.5, 1.6, 1.11 and 1.12 were\nnot applicable for retrospective studies. Statements 1.3, 1.8 and 1.9 did not\napply since patients did not have the outcome before starting the intervention\n(1.4) and the primary outcomes of interest (pregnancy and LBRs) were objective\nand would not be affected by blinding (1.8 and 1.9). All studies had a clearly\nfocused question, had representative patient characteristics and clearly defined\noutcomes. All studies had overall acceptable quality and were eligible for\nreview. Two observational studies mentioned that the assignment of the\nGnRH-agonist protocol or the GnRH-antagonist protocol varied between\nclinicians. 15 , 16  Kolanska  et al. \n 20 \n  were the only observational study to exclusively offer either the\nGnRH-agonist protocol or the antagonist protocol during specific timelines\nminimizing selection bias to either protocol. Although Rodriguez-Purata\n et al. \n 16 \n  mentioned that poorer responders tended to use the antagonist protocol, a\npropensity score matching statistical method was used to compare CPRs. This\nmethod adjusts for covariates such as disease severity and comorbidities that\nmay affect the probability of patients allocated to a certain treatment. As\nsuch, only patients with similar characteristics were compared for this outcome\nwhich helped mitigate selection bias. Two studies performed multivariate\nlogistic regression to identify predictive factors affecting pregnancy or birth\nrates. 13 , 18  The inclusion of a small number of women with\npolycystic ovary syndrome, tubal infertility or adenomyosis alongside\nendometriosis also raised concerns for additional confounding factors. 14 , 20  Four of\nthe studies only included women undergoing their first IVF/ICSI cycle, which\nreduced the risk of confounders from women who require multiple IVF cycles due\nto poorer ART outcomes. 14 , 15 , 18 , 19  Since the primary outcomes of interest were objective,\nthe studies were at lower risk of measurement bias. For the RCT, randomization\nmethods were adequate, although there was a lack of blinding. An adequate sample\nsize for pretest power estimation could not be calculated since there was a lack\nof studies comparing the long GnRH-agonist  versus  the\nGnRH-antagonist protocol prior to this RCT. \n 19\nQuality of evidence for GnRH-agonist and GnRH-antagonist COS protocols in\nendometriosis observational studies using the SIGN checklist.\nQuality of evidence for GnRH-agonist and GnRH-antagonist COS protocols in\nendometriosis RCTs using the SIGN checklist.\nCPR was reported by all eight studies and was calculated by CPR per embryo\ntransfer (ET) in three studies 13 , 17 , 18  or CPR per\npatient/cycle in four studies, 14 – 16 , 19  (see  Table 4 ).\nKolanska  et al. \n 20 \n  were the only study to report both CPR per cycle with ET and CPR per\npatient and analysed fresh/frozen ETs separately. Most studies found no\nsignificant difference in CPR 13 – 20  between the long\nGnRH-agonist and GnRH-antagonist protocols except for two subgroup\nanalyses. 18 , 20  For advanced endometriosis, Hosseini  et\nal. \n 18 \n  reported a significantly higher pregnancy rate with the GnRH agonist\nwhen anti-Müllerian hormone (AMH) levels were between 1.1 and 2.7 ng/ml\n( p  = 0.04). Kolanska  et al. \n 20 \n  found significantly higher CPR per started cycle with the GnRH\nagonist when analysing fresh ETs from women with all forms of endometriosis\ncombined ( p  = 0.02) but no significant difference for CPR\nper cycle with ET only or freeze–thaw cycles. No difference\n( p  > 0.05) was found when analysing deep or ovarian\nendometriosis in isolation regardless of fresh or freeze–thaw cycles. \n 20 \n  Multivariate logistic regression analysis was performed by two\nstudies which identified maternal age ( p  = 0.006) and\nnumber of embryos ( p  = 0.03) as main factors that may\npredict pregnancy rate. 13 , 18\nCPR outcome data for GnRH-agonist and GnRH-antagonist COS protocols\nin women with endometriosis.\nAMH, anti-Müllerian hormone; CPR, clinical pregnancy rate; DE,\ndeep endometriosis; ET, embryo transfer; Hx, history; NS, not\nstatistically significant.\nAll values shown as percentage (absolute number).\nLBR was included in three studies 13 , 14 , 20  (see  Table 5 ). The LBR\nwas calculated as either births per ET cycles 13 , 20  or births per started\ncycle regardless of the number of embryos transferred. 14 , 20  Two\nstudies found no significant difference in LBR between protocols. 13 , 14 \nKolanska  et al.  performed subgroup analyses by\nendometriosis subtype and fresh/freeze–thaw embryos and found no significant\ndifference between protocols in LBR for patients with DE or endometriomas in\nisolation regardless of ET methods. However, the LBR per started cycle\n(regardless of whether embryos were transferred) was significantly higher\n( p  = 0.02) in the long GnRH-agonist group. \n 20 \n  Zhao  et al. \n 13 \n  were the only study to perform regression analysis and found maternal\nage to be the strongest predictive factor for women with diminished ovarian\nreserve (DOR) following ovarian cystectomy.\nLBR outcome data for GnRH-agonist and GnRH-antagonist COS protocols\nin women with endometriosis.\nAll values shown as percentage (absolute number).\nCPR, clinical pregnancy rate; DE, deep endometriosis; ET, embryo\ntransfer; LBR, live birth rate; NS, not statistically\nsignificant.\nSix studies assessed the total number of oocytes retrieved 13 , 14 , 16 – 19  (see\n Table 6 ).\nTwo studies included women with resected endometrioma and found no\ndifference in the number of oocytes retrieved between COS\nprotocols. 13 , 19  However, in women with active endometriomas,\nPabuccu  et al.  reported a higher number of oocytes\n( p  = 0.002) retrieved using the GnRH-agonist protocol.\nThe number of oocytes retrieved from patients with stage I–II endometriosis\nwas reported by two studies, and both found no significant difference\nbetween protocols. 14 , 19  Three studies included women with stage III–IV\nendometriosis and two found no significant difference. 14 , 17  In a\nsubgroup analysis of advanced endometriosis grouped by AMH levels, women\nwith AMH levels between 1.1 and 2.7 ng/ml did not differ in the number of\noocytes retrieved between the two COS protocols. However, in women with AMH\nless than 1.1 ng/ml, the long GnRH-agonist protocol yielded more oocytes,\nwhile in women with AMH greater than 2.7 ng/ml, the GnRH-antagonist protocol\nled to an increased number of oocytes retrieved. \n 18 \n  Rodriguez-Purata  et al. \n 16 \n  included all stages of endometriosis and found a significantly higher\nnumber of oocytes retrieved using the long GnRH-agonist protocol\n( p  = 0.001). However, the propensity score was not\napplied to this outcome.\nNumber of oocytes retrieved for GnRH-agonist and GnRH-antagonist COS\nprotocols in women with endometriosis.\n#, number; AMH, anti-Müllerian hormone; Hx, history; IQR,\ninterquartile range; NS, not statistically significant.\nAll number of oocytes retrieved shown as mean ± standard\ndeviation unless * [mean (IQR)].\nFour studies included the number of MII oocytes retrieved 15 – 17 , 19  (see\n Table 6 ).\nPabuccu  et al.  were the only study to analyse patients with\nstage I–II endometriosis and found no difference between the two protocols.\nIn severe stages of endometriosis, Ruggiero  et al. \n 17 \n  reported a significantly higher number of MII oocytes retrieved when\nthe GnRH-antagonist protocol was used. Two studies included patients with\nactive/resected endometrioma and found a significantly higher number of MII\noocytes retrieved when GnRH-agonist COS was used\n( p  = 0.0001–0.01). 15 , 19  Rodriguez-Purata\n et al. \n 16 \n  did not apply the propensity score matching for this outcome but also\nfound a significantly higher number of MII oocyte yield using the\nGnRH-agonist protocol.\nFertilization rate (FR) was reported by four studies 13 , 15 , 17 , 19  (see\n Table 7 ).\nPabuccu  et al. \n 19 \n  were the only study to compare FR in women with stage I–II\nendometriosis and found no difference between COS protocols. Also, no\nsignificant difference was found in women with severe endometriosis. \n 17 \n  Two observational studies of women with endometrioma\nresection 13 , 15  reported no significant difference in FR although\nthe RCT found a significantly higher FR when the long GnRH-agonist was used\nin resected endometrioma ( p  = 0.001) but not in active endometrioma. \n 19\nFertilization rate outcome data for GnRH-agonist and GnRH-antagonist\nCOS protocols in women with endometriosis.\nHx, history; NS, not statistically significant.\nAll values shown as mean ± standard deviation.\nAmong the seven studies that reported COS duration 13 – 17 , 19 , 20  (see  Table 8 ), only\none found a significant difference in the COS duration \n 14 \n  with the agonist protocol having a longer duration compared to the\nantagonist protocol ( p  = 0.001). Drakopoulos  et\nal. \n 14 \n  found a significant difference between the GnRH-agonist and\nGnRH-antagonist duration in women with stage III–IV endometriosis\n( p  < 0.001) but no difference in women with stage\nI–II endometriosis.\nSummary of COS parameters for GnRH-agonist and GnRH-antagonist COS\nprotocols in women with endometriosis.\nCOS, controlled ovarian stimulation; Hx, history; IQR,\ninterquartile range; SD, standard deviation.\nIn the majority of the papers reviewed, there were no significant differences\nin the total gonadotrophin dose (IU) required for COS treatment between the\ntwo protocols (see  Table 8 ). Drakopoulos  et al. \n 14 \n  reported that both women with stage I–II and stage III–IV\nendometriosis required a greater gonadotrophin dose when using the long\nGnRH-agonist protocol ( p  < 0.001) as opposed to the\nGnRH-antagonist protocol. Ruggerio  et al. \n 17 \n  also found that the gonadotrophin dose between the two protocols was\ngreater in the agonist arm ( p  = 0.05) when observing women\nwith stage III–IV endometriosis. Whereas two studies that only included\nwomen with resected endometriomas found no difference in gonadotrophin dose\nbetween the protocols. 13 , 15\nPabuccu  et al. \n 19 \n  reported the amount of gonadotrophin used by the number of\nrecombinant follicle-stimulating hormone (FSH) ampoules and no significant\ndifferences were observed in women with stage I–II endometriosis, resected\nendometriomas or active endometriomas.\nThe risk of developing OHSS was not explicitly reported as an outcome in any of\nthe studies. The miscarriage rate was reported by three studies but there was no\nsignificant difference between the outcomes of the GnRH-agonist or antagonist\nprotocols 17 , 19 , 20  (see  Table 9 ). Pabuccu  et\nal.  observed no significant difference between the two protocols in\nthe miscarriage rate in women with stage I–II endometriosis, resected\nendometrioma or active endometrioma. Interestingly, this study included the\ntotal number of cycle cancellations due to the risk of developing OHSS or\ninsufficient ovarian response but did not specify how the cancellations were\ndistributed between the two protocols nor were  p -values specified. \n 19 \n  Three papers measured the cycle cancellation rate in patients taking\nthese two protocols and found that cycles were cancelled due to a variety of\nreasons, including insufficient ovarian response, risk of ovarian\nhyperstimulation, elevated progesterone levels and a low number of oocytes or\nembryos. 17 , 18 , 20  Of these three studies, all found that the cancellation\nrate did not differ significantly between the two protocols.\nSummary of adverse ART outcome data for GnRH-agonist and GnRH-antagonist\nCOS protocols in women with endometriosis.\nAll values shown as percentage (absolute number).\nAMH, anti-Müllerian hormone; CCR, cycle cancellation rate; DE, deep\nendometriosis; ET, embryo transfer; Hx, history; MR, miscarriage\nrate; NS, not statistically significant.\n\nMost studies found comparable clinical pregnancy and live birth rates between the\nlong GnRH-agonist and GnRH-antagonist ovarian stimulation protocols. This is\nsimilar to that of women in the general IVF population and poor ovarian\nresponders. 21 – 23  In\naddition, fertilization rates were similar although the long GnRH-agonist\nprotocol might be beneficial for some women with specific endometriosis subtypes\nand those with low ovarian reserve.\nWhen comparing COS parameters, the GnRH-agonist protocol generally required\ngreater gonadotrophin dose and longer treatment duration although this did not\nalways reach significance. Adverse ART outcomes such as cycle cancellation rate\nand miscarriage rate were similar between the two protocols. The direct risk of\ndeveloping OHSS could not be assessed because data regarding OHSS were not\nreported in these studies.\nHow pregnancy and LBRs are reported in studies is important to consider when\ndiscussing ART outcomes with patients. Since the number of embryos retrieved\ncould be a predictive factor for pregnancy rate, \n 24 \n  excluding the patients who do not have a sufficient ovarian response\nby calculating the CPR per ET cycles 13 , 17 , 18  would result in\nhigher CPR as demonstrated by Kolanska  et al . \n 20 \n  Future studies may consider reporting both CPR per cycle initiation\nand CPR per ET cycle as it provides better comparability between studies and\nmore accuracy when discussing the chance of pregnancy at each stage of ART.\nTwo multivariate regression analyses 13 , 18  also identified the\nnumber of embryos and maternal age as predictive factors for IVF success\nwhich has been previously reported. \n 25\nThe precise mechanism by which GnRH analogues affect extra-pituitary\nreproductive tissues remains a topic of ongoing debate. Although most\nstudies found no significant difference in CPR/LBR, 13 , 15 – 20 \nKolanska  et al. \n 20 \n  were the only study to analyse both fresh and freeze–thaw cycles and\nfound that the long GnRH-agonist protocol led to a significantly higher\npregnancy rate in patients with endometriosis regardless of subtype. The\nauthors suggested that this difference may be explained by the action of\nGnRH antagonists on the endometrium rather than ovaries which is in line\nwith previous studies. In 2006, Ruan  et al.  using an IVF\nmice model compared GnRH-agonist  versus  GnRH-antagonist COS\nprotocols and found that the expression of two uterine receptivity\nbiomarkers (integrin β3 and leukaemia-inhibitory factor) during the\nimplantation window was significantly lower in the GnRH-antagonist group.\nThis correlated with a significantly lower implantation rate. \n 26 \n  A later case-control study in 2008 evaluated another receptivity\nmarker, homeobox A10 (HOXA10) expression, from human endometrial biopsies\nand found decreased stromal and glandular cell HOXA10 expression in the\nGnRH-antagonist group. \n 27 \n  Although laboratory studies have found that the GnRH-antagonist\nprotocol can reduce endometrial receptivity, in the clinic, pregnancy and\nbirth rates in endometriosis patients are similar between both\nprotocols 13 – 20  and\nthis is in agreement with meta-analyses that include poor and normal ovarian\nresponders who have other causes of infertility. 9 , 21 , 22 , 28\nLaboratory studies have also found that the GnRH-antagonist protocol may lead\nto a poorer follicular microenvironment (higher nitric oxide concentration,\nincreased superoxide dismutase expression and decreased insulin growth\nfactor 1 and 2) 29 , 30  which could impact oocyte yield. However, this is\nnot necessarily reflected in human studies. Trials in women from other IVF\npopulations comparing long GnRH-agonist protocols with GnRH-antagonist\nprotocols report mixed findings on total and mature oocyte yield. In the\ngeneral IVF population, the long GnRH-agonist may yield a higher number of\noocytes, CPR and LBR. 9 , 13  Meanwhile, in women\nwith polycystic ovary syndrome who have a poor ovarian response,\nmeta-analyses have shown that there is no significant difference in the\ntotal number of oocytes and mature oocytes retrieved. 9 , 22  Our\nreview found heterogeneous results among endometriosis patients similar to\nthe results from meta-analyses on other infertile IVF populations. This\ndemonstrates the variable effects of GnRH analogues on the ovaries.\nWhile the well-known benefit of the GnRH-antagonist protocol is a reduced\ndosage of exogenous gonadotrophins required for ovarian stimulation, this\nmay do more harm than good, especially in patients with a history of ovarian\nendometriomas. A comparative study by Al-Azemi  et al. \n 31 \n  found that the presence of endometriomas significantly diminished\novarian reserve. Moreover, the surgical techniques during endometrioma\ncystectomy could damage the surrounding healthy ovarian tissue and\nvasculature increasing gonadotrophin resistance and negatively impact\novarian reserve. \n 32 \n  Hence, women with endometriomas usually require higher doses of\nrecombinant FSH during ovarian stimulation due to a poorer ovarian response.\nSince the GnRH-agonist protocols are associated with higher gonadotrophin\ndoses and longer COS duration, this may be advantageous for women with\nongoing or resected endometriomas 15 , 19  or with diminished\novarian reserve.\nFertilization rate is defined as the number of 2 pronuclear (2PN) oocytes\nthat contain genetic information from both sperm and egg divided by the\nnumber of inseminated oocytes. Interestingly, fertilization rate has not\nbeen included in prior analyses comparing these two COS protocols. However,\nit can be a valuable parameter for women considering embryo cryopreservation\nsince it can be a marker for cumulative pregnancy rate. 10 , 33 \nFurthermore, higher fertilization rates can be an independent predictor for\nimplantation rates. This is relevant when deciding the number of embryos to\ntransfer, which is often problematic for IVF/ICSI providers. 34 , 35 \nAlthough the fertilization rates of the two protocols were generally no\ndifferent, this may be due to the selection of higher quality (mature)\noocytes for fertilization. Therefore, the higher number of mature oocytes\navailable for fertilization with the long GnRH-agonist protocol in\nconjunction with having a similar fertilization rate results in an increased\ncumulative pregnancy rate.\nART is an expensive treatment and the cost should be considered especially\nwhen ART is not subsidized or covered by insurance. A recent\ncost-effectiveness analysis comparing GnRH-agonist and GnRH-antagonist COS\nin the general IVF population by Jing  et al.  found that the\nGnRH-antagonist protocol is economically advantageous per fresh embryo\ncycles due to the shorter treatment duration, lower gonadotrophin dose\nrequired and lower incidence of OHSS. However, the cumulative ongoing\npregnancy rate in both fresh and frozen embryo cycles is higher with the\nGnRH-agonist protocol due to the higher number of oocytes retrieved. \n 36 \n  Furthermore, the significantly shorter treatment duration with the\nGnRH-antagonist protocol would require fewer injections and lead to reduced\ntreatment cost. Although most studies in our review found no significant\ndifferences in pregnancy or birth outcomes between the two protocols, the\nlong GnRH-agonist protocol may still be favoured especially in patients with\na history of ovarian endometriomas or diminished ovarian reserve. Thus, a\npatient-tailored approach should be sought, incorporating the patient’s\ndisease characteristics and reproductive goals as a priority. As mentioned,\nthe risk of developing OHSS could not be assessed due to the lack of\navailable evidence and should be explored in future studies.\nTo our knowledge, this is the first systematic review comparing ART outcomes\nfollowing COS using the long GnRH-agonist protocol  versus \nthe GnRH-antagonist protocol specifically for women with endometriosis in\naccordance with PRISMA guidelines. Two authors (K.K.W.K. and S.O.) screened\nall the titles and completed bias/study quality assessment increasing the\nstrength of our methodology. Several databases were searched without date\nrestrictions minimizing the risk of selection bias. Authors were also sought\nfor additional data and were provided by Drakopoulos  et al . \n 14\nThe single RCT and relatively small number of studies were the main\nlimitations for this review. In addition, the small study numbers and\nheterogeneity of endometriosis stages/subtypes in each study did not allow\nfor meta-analysis as one must consider the varying structural changes to the\nfemale reproductive anatomy. Due to the nature of observational studies,\nselection of endometriosis patients to either the GnRH-agonist or\nGnRH-antagonist protocol may be influenced by the clinician’s preferences.\nFertility centres have also gained more experience with the GnRH-antagonist\nprotocol throughout the years and an updated RCT would be preferred to\nminimize selection bias.\n\nThis systematic review compared the long GnRH-agonist and GnRH-antagonist ovarian\nstimulation protocols and found similar CPRs and LBRs. However, the cumulative\npregnancy rate may favour the long GnRH-agonist protocol due to the higher number of\nretrieved oocytes available for subsequent embryo cryopreservation. Women with\novarian endometriomas or poor ovarian reserve may benefit from the GnRH-agonist\nprotocol due to greater gonadotrophin exposure resulting in an improved ovarian\nresponse. The GnRH-antagonist protocol is a sensible option for women with\nendometriosis, who want to lower the costs and duration of treatment. The risk of\ndeveloping OHSS in endometriosis patients specifically could not be assessed and\nthis outcome should be reported as a priority in future studies. A larger,\nwell-powered RCT analysing patients according to endometriosis stage/subtype is\nneeded. Ultimately, this review’s findings could help clinicians make an\nevidence-based decision when choosing a GnRH-analogue ovarian stimulation protocol\nwhile balancing treatment costs, stage/subtype of endometriosis and pregnancy goals\nof their patients.\n\nClick here for additional data file.\nSupplemental material, sj-docx-1-tae-10.1177_20420188231173325 for Comparing ART\noutcomes in women with endometriosis after GnRH agonist versus GnRH antagonist\novarian stimulation: a systematic review by Kevin K.W. Kuan, Sean Omoseni and\nJavier A. Tello in Therapeutic Advances in Endocrinology and Metabolism\nClick here for additional data file.\nSupplemental material, sj-docx-2-tae-10.1177_20420188231173325 for Comparing ART\noutcomes in women with endometriosis after GnRH agonist versus GnRH antagonist\novarian stimulation: a systematic review by Kevin K.W. Kuan, Sean Omoseni and\nJavier A. Tello in Therapeutic Advances in Endocrinology and Metabolism","source_license":"CC0","license_restricted":false}