{"paper_id":"8d7cc04c-3d00-4a64-b753-dbe23e353f9b","body_text":"Vatsa and Sethi  Middle East Fertil Soc J           (2021) 26:36  \nhttps://doi.org/10.1186/s43043-021-00082-3\nREVIEW\nImpact of endometriosis on female \nfertility and the management options \nfor endometriosis-related infertility \nin reproductive age women: a scoping review \nwith recent evidences\nRicha Vatsa and Ankita Sethi*  \nAbstract \nBackground: Endometriosis is a chronic inflammatory condition with varied presentation, which ultimately leads to \nchronic pelvic pain and infertility. It is a psychological and economic burden to the women and their families.\nMain body of abstract: The literature search was performed on the following databases: MEDLINE, Google Scholar, \nScopus, EMBASE, Global health, the COCHRANE library, and Web of Science. We searched the entirety of those data-\nbases for studies published until July 2020 and in English language. The literature search was conducted using the \ncombination of the Medical Subject heading (MeSH) and any relevant keywords for “endometriosis related infertility \nand management” in different orders. The modalities of treatment of infertility in these patients are heterogene-\nous and inconclusive among the infertility experts. In this article, we tried to review the literature and look for the \nevidences for management of infertility caused by endometriosis. In stage I/II endometriosis, laparoscopic ablation \nleads to improvement in LBR. In stage III/IV, operative laparoscopy better than expectant management, to increase \nspontaneous pregnancy rates. Repeat surgery in stage III/IV rarely increases fecundability as it will decrease the ovar-\nian reserve, and IVF will be better in these patients. The beneficial impact of GnRH agonist down-regulation in ART \nis undisputed. Dienogest is an upcoming and new alternative to GnRH agonist, with a better side effect profile. IVF \n+ ICSI may be beneficial as compared to IVF alone. Younger patients planned for surgery due to pain or any other \nreason should be given the option of fertility preservation.\nShort conclusion: In women with endometriosis-related infertility, clinician should individualize management, with \npatient-centred, multi-modal, and interdisciplinary integrated approach.\nKeywords: Endometriosis, Endometriotic cystectomy, Medical management, Infertility, IVF\n© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.\nBackground\nEndometriosis is a state of chronic inflammation in the \npelvis and is characterized by endometrial-type tis -\nsue outside of the uterus. Although exact prevalence of \nendometriosis is unknown, it roughly affects 2 to 10% \nof the female population, but 30 to 45% of females with \ninfertility [1]. This condition leads to two main prob -\nlems—pain, infertility, or both. Endometriosis also has \nsignificant impact on the quality of life of the patients and \nnegative influence on the sexual function and interper -\nsonal relationships. This article will deal with endometri -\nosis-related infertility in detail.\nOpen Access\nMiddle East Fertility\nSociety Journal\n*Correspondence:  drankita32@gmail.com\nDepartment of Obstetrics and Gynaecology, All India Institute of Medical \nSciences, New Delhi, India\n\nPage 2 of 12Vatsa and Sethi  Middle East Fertil Soc J           (2021) 26:36 \nMain text\nThe literature search was performed on the following \ndatabases: MEDLINE, Google Scholar, Scopus, EMBASE, \nGlobal health, the COCHRANE library, and Web of Sci -\nence. We searched the entirety of those databases for \nstudies published until July 2020 and in English language. \nThe literature search was conducted using the combina -\ntion of the following Medical Subject heading (MeSH) \nand any relevant keywords in different orders: “endo -\nmetriosis” , “endometrioma” , “endometriotic cystectomy” , \n“diagnosis” , “grading” , “management” , “surgical manage-\nment” , “medical management” , “fertility preservation” , \n“mechanism” , “infertility” , “pathophysiology” , “ ASRM clas-\nsification” , “Endometriosis fertility index (EFI)” , “ovulation \ninduction” , “intrauterine insemination (IUI)” , “Controlled \novarian hyperstimulation (COH)” , “ Assisted reproduction \nTechniques (ART)” , “In vitro fertilization (IVF)” , “clinical \npregnancy rate” , “Dienogest” , “GnRH agonist” , “live birth” , \n“pregnancy outcome” , “minimal-mild endometriosis” , \n“severe endometriosis” , and “decreased ovarian reserve” . \nThe reference lists of the included studies were also \nchecked to look for studies that were not found in the \nelectronic literature search. A total of 2208 articles were \nfound pertaining to endometriosis. Original articles and \nsome review articles, published in recent 5 years, were \ngiven priority. All the articles were accessible in full text. \nIn this review, individual data sources were not sought \nfor, and a descriptive analysis was done. The data were \nsummarized in a form of descriptive review.\nDiagnosis of endometriosis\nThe main symptoms of endometriosis are chronic pel -\nvic pain, dysmenorrhoea, dyspareunia, infertility, and \ncyclical bowel or urinary complaints. It is often missed \nat young age because of the non-specific complaints, \ncausing a long diagnostic delay [2]. The imaging modal -\nity of choice is transvaginal sonography (TVS) which can \ndetect both ovarian endometrioma, rectal endometriosis, \nand associated adenomyosis [3]. In case of doubt in the \ndiagnosis of ovarian endometrioma on TVS, magnetic \nresonance imaging (MRI) can be used, but its diagnostic \naccuracy is limited for peritoneal endometriosis [4, 5]. \nFurther, evaluation for the involvement of other organs \nshould be done if history and examination suggest deep \ninfiltrating endometriosis (DIE). MRI or CT abdomen \nmay help in evaluation when there is clinical suspicion \nof other organs being affected like ureter, bladder, and/or \nbowel [6]. More specific investigations like CT urogram \nor transrectal sonography may be required for mapping \nthe endometriosis prior to surgery to see involvement \nof ureter or bladder and bowel respectively [7, 8]. There \nhave been extensive studies on biomarkers (including \nCA125) for endometriosis; none has been validated for \ndiagnosis of endometriosis [5].\nThe use of diagnostic laparoscopy and histopathologi -\ncal confirmation of endometrial glands and stromal tis -\nsue is gold standard for the diagnosis of endometriosis, \nbut since the advancement of imaging, laparoscopy only \nto diagnose endometriosis may not be required. Quality \nof laparoscopy depends on surgical skills, expertise, and \nexperience. Retroperitoneal and localized vaginal endo -\nmetriosis can be easily missed. A negative laparoscopy \nreliably excludes the diagnosis of endometriosis, but pos -\nitive laparoscopy is less informative and of limited value \nwhen used in isolation without histology [9, 10]. Negative \nhistology also does not exclude endometriosis [5] due to \nthe possibility of inadequate or squeezed samples, which \nmay have been taken from wrong location.\nGrading of endometriosis\nIn 1996, ASRM proposed a revised classification of endo -\nmetriosis and is currently the most widely used grading \nsystem for severity of endometriosis, but it has many \nlimitations [11]. It does not correlate with the severity of \nsymptoms, does not predict the treatment outcome, and \npoorly correlates with the pregnancy outcomes. Endo -\nmetriosis fertility index (EFI) was developed by Adamson \nand Pasta [12], to address this problem. This system helps \nin predicting the treatment outcomes in infertile patients \nwith laparoscopically proven endometriosis attempting \nstandard non-IVF conception.\nVesali et  al. conducted a meta-analysis to evaluate \nthe accuracy of EFI for predicting non-ART pregnan -\ncies. There was a significant difference between all cat -\negories, especially EFI 0-2 had a cumulative non-ART \npregnancy rate at 36 months of 10%, which increased \nto approximately 70% for EFI of 9–10 (P < 0.001). They \nconcluded that EFI was a useful index in predicting the \nnon-ART pregnancy rate [13]. Though developed for \ncalculating the non-IVF pregnancy rate, prediction stud -\nies have shown that EFI is better at predicting the IVF \noutcomes as well [14]. This system does not account for \nuterine abnormality like presence of adenomyosis along \nwith endometriosis, which is very common in infertile \npatients. Uterine pathology should be included in the \nsystem and for predicting pregnancy rate. Further, it does \nnot help in prediction of post-surgery endometriosis-\nassociated pain [12]. Moreover, EFI can be calculated \nfor only those patients who underwent surgery. It is rec -\nommended that all women with endometriosis have the \nr-ASRM classification, and patients with infertility should \nhave EFI [15]. This classification and scoring system helps \nin counselling and prognosticating the patients about the \ntreatment options and the outcomes expected.\n\nPage 3 of 12\nVatsa and Sethi  Middle East Fertil Soc J           (2021) 26:36 \n \nMechanism of infertility in endometriosis\nThe factors responsible for sub-fertility in endometrio -\nsis have been attributed to distorted pelvic anatomy and \nmolecular alteration leading to excess production of \nprostaglandins, oestrogen, growth factors, reactive oxy -\ngen species, cytokines, etc. [16]. There is a debate on \nhow minimal or mild endometriosis can lead to infertil -\nity without distorting the pelvic anatomy. Various studies \nhave shown that the molecular alterations in endome -\ntriosis lead to ovarian, tubal, or endometrial dysfunc -\ntion, which leads to infertility [17–19]. The progesterone \nresistance and hyperestrogenic state lead to chronic \ninflammation making the endometrium non-receptive \nfor normal embryo implantation and has been suggested \nas a significant contributor to infertility [20]. In women \nwith endometriosis, inflammatory markers present in \nperitoneal fluid hamper oocyte competence; impair \nsperm motility, function, and oocyte-sperm interaction; \nand can cause sperm DNA fragmentation and abnormal \nacrosome reaction [21]. Xu et al. found that even in mini-\nmal to mild endometriosis, oocyte quality is impaired \nbecause the mitochondrial structure and function are \nhampered [22]. Immunological dysfunction is seen in \ninfertile women with endometriosis [23]. Adenomyosis \nis associated with endometriosis in 90% of cases [24]. \nSurgeries performed for endometriosis lead to decreased \novarian reserve and pelvic adhesions contributing to \ninfertility. In endometriosis, the granulosa cells are resist-\nant to luteinizing hormone (LH) to some extent; there \nis hypothalamic-pituitary-ovarian axis dysfunction with \nabnormal LH production [25], which affects ovulation. \nHyperprolactinemia may be associated with endome -\ntriosis and its progression, with a significant association \nbetween the severity of endometriosis and prolactin lev -\nels [26]. So, distorted tubo-ovarian relationship, impaired \nfolliculogenesis, hormonal dysfunction, disturbed local \nmilieu, fertilization failure, and impaired endometrial \nreceptivity are causes of endometriosis-related infertility.\nMedical management of infertility\nThe treatment of endometriosis-related infertility must \nbe individualized. Medical, surgical, and ART treatment \nalone or combinations can be used in these patients.\nMedical management, which includes various hor -\nmonal treatments, deals with ovulation suppression \nand, therefore, does not have much role for infertility \ntreatment. This is useful for only pain relief in infertile \nwomen. Cochrane review by Hughes et al. concluded that \nthere is no role for suppressing ovulation in women with \nendometriosis who plan to conceive [27]. Neither pre -\noperative nor postoperative hormonal therapy increases \nthe chances of spontaneous conception [27, 28]. The \nCochrane review which included three RCTs, a total of \n165 patients, showed the benefit of GnRH agonist pre \nIVF. The authors concluded that odds of clinical preg -\nnancy in endometriosis patients increased by fourfold \nwhen GnRH agonists were given for 3–6 months before \nIVF or ICSI [29]. GnRH agonists should be given for 3–6 \nmonths prior to IVF as per ESHRE recommendations to \nincrease the clinical pregnancy rates [5].\nIn recent years, numerous studies have been done to \nfind out the role of dienogest in treating endometriosis-\nrelated infertility. Dienogest has an effect on multiple \nreceptors like the oestrogen, androgen, glucocorticoid, \nand mineralocorticoid and little impact on the metabolic \nparameters, and is having a significant impact on endo -\nmetriotic lesions locally [30]. A systematic review by \nGrandi et al. in 2016 analysed studies on dienogest ther -\napy and its effects on the inflammatory reaction of endo -\nmetriotic tissue [31]. Dienogest is anti-inflammatory and \ncauses modulation of the pro-inflammatory cytokine and \nchemokine production, which is mediated via PR in pro -\ngesterone receptor-expressing epithelial cells.\nMuller et  al. conducted study on 144 women planned \nfor IVF after their endometriotic cystectomy and \nrecruited the patients prospectively [32]. They divided \npatients into three groups: those receiving dienogest, \nGnRH agonist, and those without hormonal therapy \nwithin 6 months before IVF. They concluded that pre-IVF \nhormonal treatment is required in patients with endo -\nmetriosis, and dienogest will probably be a better pre-\ntreatment option as compared to GnRH agonist. Tamura \net al. conducted a study on subjects with stage III or IV \nendometriosis, recruited 68 women in two groups: dien -\nogest (n = 33) and control group (n = 35) [33]. Dienogest \nwas given for 3 months prior to the ART cycle followed \nby GnRH agonist long protocol for ovarian stimulation. \nThey concluded that administering Dienogest just before \nIVF did not increase IVF success rates. Therefore, more \nextensive studies are required to see whether dienogest \ntherapy before IVF can help improve the clinical out -\ncome of patients.\nSurgical management\nThe decision for surgery in endometriosis-associated \ninfertility depends on age, previous ovarian surgery, \novarian reserve, duration of infertility, grade of endome -\ntriosis, tubal status, cost of treatment, expected outcome \nof the procedure, and priorities of the patient. The recon-\nstruction of the normal pelvic anatomy to achieve an \nexcellent tubo-ovarian relationship and remove all mac -\nroscopically visible disease is the main aim of the surgery. \nMinimally invasive surgery is preferred over laparotomy \nfor obvious reasons [34].\n\nPage 4 of 12Vatsa and Sethi  Middle East Fertil Soc J           (2021) 26:36 \nLeonardi et al. conducted a meta-analysis to determine \nif operative laparoscopy is an effective treatment in grade \nI-IV endometriosis compared with other therapies [10]. \nThey found 1990 studies that were included in the anal -\nysis. When operative laparoscopy was compared with \ndiagnostic, it was found that operative did not improve \nthe clinical pregnancy rate (CPR) (p = 0.06).\nSurgery for minimal to mild endometriosis\nThere are two ways of removing peritoneal endometriotic \nlesions, first is by excision or ablation; both have compa -\nrable cumulative pregnancy rates. Ablative techniques \ninvolve bipolar coagulation and laser methods like CO2 \nor argon laser. ESHRE recommends CO2 laser vapori -\nzation is better than monopolar electrocoagulation [5]. \nCochrane review by Duffy et al. has reported higher live \nbirth or ongoing pregnancy rates and reduced overall \npain scale after laparoscopic surgery for mild-moderate \nendometriosis [35]. ESHRE concluded that the ongoing \npregnancy rates are increased in infertile women with \nAFS/ASRM stage I/II endometriosis after laparoscopy. \nExcision or ablation of endometriotic lesions on laparos -\ncopy is better than diagnostic laparoscopy alone. Surgi -\ncal removal of peritoneal endometriosis may prevent the \nprogression of the disease further [36].\nSurgery for moderate to severe endometriosis\nModerate to severe endometriosis (r-ASRM III-IV) dis -\ntorts normal pelvic anatomy; surgery restores this dis -\ntorted pelvic anatomy and the tubo-ovarian relationship \nhampered because of the pelvic adhesions. This form of \nendometriosis may involve rectovaginal or colorectal and \ncan be deep infiltrating endometriosis [37].\nMaheux-Lacroix et  al. conducted retrospective \nstudy on women with stage III–IV endometriosis who \nattempted pregnancy after laparoscopic resection; 63% \nhad live birth following surgery, 64% without ART. EFI \nwas significantly correlated with live-births (P < 0.001). \nEFI of 0–2 vs. 9–10, cumulative non-ART LBR at 5 years \nwas 0%VS 91%, which was statistically significant. The \nchance of having live birth steadily increased from 38 to \n71% among the same EFI strata in women who attempted \nART (P = 0.1) [38].\nA significant problem after any pelvic surgery is post-\noperative adhesion formation. Oxidized regenerated cel -\nlulose during operative laparoscopy for endometriosis \nhas been proved useful for prevention of adhesion forma-\ntion [5]. After laparoscopic surgery, suspending the ovary \ntemporarily will help reduce post-operative ovarian adhe-\nsions in cases with severe pelvic endometriosis. A recent \nmeta-analysis concluded that there is a reduced chance \nand severity of adhesion formation in patients with stage \nIII–IV endometriosis if the ovaries are temporarily sus -\npended post laparoscopic resection [39].\nOvarian endometrioma\nClinical data has suggested that ovarian endometrioma \ndamages surrounding healthy ovarian tissue. The patho -\nphysiology of which may be the presence of proteolytic \nenzyme, inflammatory mediators, reactive oxygen spe -\ncies, and iron in concentrations many times higher than \nthose present in serum or other types of cysts; all of these \nlead to cell damage. The decision to operate on ovar -\nian endometrioma depends on the patient’s age, ovarian \nreserve, and prior surgery on the ovary [37]. Depending \non surgical skill, patient profile, and resources available \novarian endometrioma can be managed by either lapa -\nrotomy or laparoscopy, with excision of endometrioma \ncapsule or drainage and ablation (electrocautery, CO2 \nlaser, or plasma energy) of cyst wall [5]. Recent pro -\nspective study concluded that there was no difference \nin post-operative pregnancy rates after either ablation \nusing plasma energy or cystectomy of the ovarian endo -\nmetrioma [40]. Both techniques can compromise ovarian \nreserve, excision by removal, and coagulation by thermal \ndamage of normal ovarian tissue. In infertility patients, \naccepting the increased chance of recurrence due to \nincomplete treatment of ovarian lesions is better than \nsevere reduction of ovarian reserve following complete \nresection of endometriomas. A less damaging approach \nin terms of ovarian reserve for large endometrioma is a \nthree-step approach. This includes laparoscopic drain -\nage of endometrioma, followed by the use of GnRH for \n3 months to reduce cyst diameter, and then laparoscopic \nCO2 laser vaporization of the cyst [41].\nSurgery before Assisted Reproductive Technology (ART)\nIt was discussed in the previous section; spontaneous \npregnancy rates can improve with surgery for endome -\ntriosis. There have not been prospective, randomized \nstudies on the effects of surgery for endometriosis on \nART outcomes. A retrospective study on women with \nminimal-mild endometriosis had shown that surgery \nbefore IVF resulted in significantly higher implantation, \npregnancy, and live birth rate (LBR) [42]. Bianchi et  al., \nin their study in women with DIE, found that extensive \nlaparoscopic excision of endometriotic lesions before \nART improves pregnancy rate, but LBR did not differ \n[43]. Another study found that surgery in patients with \nDIE did not improve IVF outcomes [44]. A retrospec -\ntive study done on 115 patients has shown that spon -\ntaneous conception rate and IVF outcome improves \nafter laparoscopic excision of DIE in moderate to severe \nendometriosis [45]. Retrospective analysis of 110 colo -\nrectal endometriosis patients showed that cumulative \n\nPage 5 of 12\nVatsa and Sethi  Middle East Fertil Soc J           (2021) 26:36 \n \nLBR at the first ART cycle after surgery as compared \nto the first-line ART was 33% vs. 13.0% [46]. There has \nbeen no evidence to support endometrioma removal \nbefore IVF as it does not enhance the outcome; instead, \nit can lead to decreased ovarian reserve and increase the \ndose of gonadotropins for stimulation in ART. Cochrane \nreview showed no difference in clinical pregnancy rate \nwith either surgery or expectant management before \nART [ 47]. Liang et  al. conducted a prospective study \nwhere women with endometriosis-associated infertility \nwere recruited; 13 had surgery to remove the endome -\ntrioma before IVF, and 28 did not undergo surgery [48]. \nThe chemokines, growth factors, inflammatory media -\ntors, implantation rate, and CPR were similar between \nthe surgery and non-surgery groups. Ovarian reserve \nin terms of AMH levels was lower in the surgery group. \nMagnien et  al. conducted a retrospective cohort study \nin which IVF outcomes were evaluated for patients with \nand without previous surgery for Endometriosis. Past \nhistory of surgery for endometriosis (p = 0.001) was an \nindependent risk factor for lower pregnancy rates [49]. \nBut, in cases where normal ovarian tissue is not acces -\nsible for oocyte retrieval, cystectomy may be considered \n[5]. In diminished ovarian reserve patients, preoperative \nembryo cryopreservation followed by laparoscopic sur -\ngery (“surgery-assisted-IVF combination/Hybrid ther -\napy”) can be done [50]. Table  1 summarizes surgery vs \nART in endometriosis.\nMedically assisted reproduction\nMedically assisted reproduction (MAR) includes ovula -\ntion induction, controlled ovarian stimulation (COS), \novulation triggering, ART procedures, and intrauterine \n(IUI), intracervical, and intravaginal insemination as per \nWorld Health Organization (WHO) Revised Glossary on \nART Terminology. Young women with minimal to mild \ndisease and short duration of infertility can be managed \nexpectantly for 6–9 months [51] If the above treatments \nfail or in patients with long standing infertility, dimin -\nished ovarian reserve, or in cases with compromised \ntubal function or male factor infertility, IVF should be \nconsidered [52].\nControlled ovarian stimulation (COS) and intrauterine \ninsemination (IUI)\nCOS and IUI is a cost-effective and first-line treatment \nfor many types of infertility, but its utility is not entirely \nclear in endometriosis. A retrospective analysis of COS \nand IUI demonstrated a per cycle fecundity rate of 6%, \n11.8%, and 15.3% for endometriosis, malefactor, and \nunexplained infertility, respectively [53]. A meta-analy -\nsis has shown that endometriosis decreases the odds of \npregnancy by half [54]. Keresztúri et al. compared preg -\nnancy rate after COS+IUI on 238 patients of all stages \nof endometriosis and concluded that surgery followed by \nCOH+IUI is more effective than surgery alone [55]. So, \nCOS with IUI can be considered as a first-line strategy \nfor infertile women with early-stage endometriosis. Aro -\nmatase inhibitors (AI) and clomiphene citrate both can \nbe used for COS in women who underwent surgery for \nminimal to mild endometriosis. In a study, a small group \nof surgically diagnosed endometriosis patients were rand-\nomized to OVI with human menopausal gonadrotrophin \n(HMG) + IUI vs no treatment for four cycles showed that \ncumulative live birth rate over 4 cycles was 11% versus \n2% (p=0.002) suggesting that COH may improve preg -\nnancy rates [56]. A multicenter trial included patients \nwith unexplained infertility, endometriosis, or mild male \nfactor infertility and who were randomized to intracervi -\ncal insemination (ICI), IUI, FSH with ICI, or FSH with \nIUI [57]. They concluded that FSH +IUI had higher preg-\nnancy rates than the other groups (33% v 10%, p <0.0001) \nand suggested that in a woman with endometriosis and \nsubfertility, it may be reasonable to start with OVI + IUI. \nA retrospective study by Houwen et al., who performed \nIUI in moderate-to-severe endometriosis patients, \nfound that long-term pituitary down-regulation prior to \nOVI+IUI tend to result in higher ongoing pregnancy rate \n(adjusted HR 1.8) [58]. A larger RCT is required to see \nthe utility of OVI+IUI in moderate to severe endometri -\nosis, at present not recommended.\nEndometriosis and assisted reproductive technology (ART)\nESHRE recommends using ART in endometriosis if there \nis tubal or male factor infertility, and/or other treat -\nments have failed. Studies to date on effect of endome -\ntriosis on IVF outcome have shown mixed results. After \na meta-analysis, Senapati et  al. concluded that women \nwith endometriosis who undergo IVF have half the preg -\nnancy rate compared to those who get IVF done for other \nTable 1 Surgery vs ART in endometriosis [37]\nFactor In favour of surgery In favour of ART \n• Age Young Old\n• Associated infertility fac-\ntors (tubal or male factor) [5]\nNo Yes\n• Infertility duration Short Long\n• Ovarian reserve Satisfactory Decreased\n• Patients choice Patient choice Patient choice\n• Pelvic pain intensity Severe Mild\n• Ovarian endometrioma \nespecially bilateral\nNo Yes\n• Previous surgery No Yes\n• Associated adenomyosis No Yes\n\nPage 6 of 12Vatsa and Sethi  Middle East Fertil Soc J           (2021) 26:36 \nindications [59]. Ovarian endometrioma, its surgery, and \nperitoneal endometriosis damage oocyte maturation and \nadversely affect the ovarian reserve, which leads to inad -\nequate ovarian response [59]. Data suggests that endo -\nmetriosis affects not only the endometrial receptivity but \nalso the oocyte and embryo development [59]. However, \nother studies have shown that endometriosis in isolation \nhas LBR after IVF similar to other causes of infertility \n[60]. A recent meta-analysis which included 36 studies \nhas shown that women with and without endometriosis \nhave comparable ART outcomes in terms of live births. \nIn contrast, those with severe endometriosis have inferior \noutcomes [61]. A retrospective cohort study on approxi -\nmately 3600 women with endometriosis and 19,000 \nwomen as control has shown that there was not much \ndifference in terms of live birth, clinical pregnancy, and \nmiscarriage rates. Still, women with endometriosis had a \nlesser number of oocytes retrieved [60].\nVarious studies have been done to compare the effi -\ncacy of GnRH agonist and antagonist in endometrio -\nsis patients. GnRH agonists suppress the endometriotic \nlesions and are thought to increase the IVF success rate. \nA prospective randomized trial by Recai et  al. reported \nthat implantation and CPR are similar for patients with \nmild to moderate endometriosis with both agonist and \nantagonist protocols and endometrioma who did not \nundergo surgery for endometriosis. However, GnRH \nagonists had a significantly higher number of surplus \nembryos available for cryopreservation [62]. Kolanska \net  al. has done a retrospective analysis of prospective \ndata of 284 COH cycles, 165 with GnRH-agonist and \n119 with GnRH-antagonist protocol. The pregnancy rate \nwas similar in both groups while the live-birth rate was \nhigher in the agonist group [63]. In the study by Zhao \net al., patients were divided into three groups according \nto the IVF protocols, GnRH-agonist, GnRH-antagonist, \nand long GnRH-agonist. Total gonadotrophin dosage and \nduration required for stimulation was less in the GnRH-\nantagonist group than in the others. Still, there were no \nsignificant differences in the implantation rate and clini -\ncal pregnancy rate, oocytes retrieved, fertilization rate, \nembryo utilization rate, and LBR in the three groups [64].\nESHRE recommends, IVF pretreatment with GnRH \nagonist for a period of 3–6 months [29]. For COS in \nendometriosis patients both agonist and antagonist pro -\ntocols seem to be equally effective [65]. A study suggests \nthat GnRHa agonist ovulation triggering, which is possi -\nble in antagonist protocols, limits pain symptom progres-\nsion in the period immediately after ART [66].\nIn women with endometriosis, there are increased \nchances of ovarian abscess formation following oocyte \npickup; although overall risk is low, antibiotic prophy -\nlaxis has been suggested [5]. Boucret et  al. conducted a \nretrospective study intending to evaluate the impact of \nendometriosis on embryo quality and IVF outcomes. \nThere was no association between endometriosis and \nthe number of top-quality embryos, but the implanta -\ntion rate and LBR were lower in the endometriosis group. \nThe lower number of cryopreserved embryos decreases \nthe cumulative LBR by reducing number of embryos, \nnot their quality [67]. Lower implantation rate after IVF \nin endometriosis patients compared to tubal factor and \nunexplained infertility patients may be due to the asso -\nciation of endometriosis and adenomyosis. Prolonged \ndownregulation with GnRH agonist or oral contraceptive \npills may help overcome the negative effect of adenomyo-\nsis on implantation and endometrial receptivity [68].\nRecent research favours IVF/ICSI over IVF alone in \nendometriosis patients. Komsky-Elbaz et  al. compared \nconventional IVF versus IVF-ICSI in sibling oocytes \nfrom couples with endometriosis and normozoosper -\nmic semen; a total of 786 sibling cumulus-oocyte com -\nplexes (COC) were randomized between insemination \nby conventional IVF or ICSI. The authors concluded \nthat ICSI has higher fertilization rate and reduced rate \nof total fertilization failure [69]. Therefore, IVF/ICSI \ncan be considered as a practical approach for managing \nendometriosis-associated infertility. Wu et al. conducted \na retrospective study and found that implantation, clini -\ncal pregnancy, and LBR were statistically significantly \nhigher in the freeze-all group compared with new trans -\nfer groups (P < 0.001) [70].\nYilmaz et al. conducted a retrospective study and found \nthat between unilateral and bilateral endometrioma \ngroups, AMH, oocyte, and embryo quality, the numbers \nof embryos, PR, and LBR are similar. They concluded that \nthe presence of endometrioma negatively effects fertility \nparameters but whether it is unilateral or bilateral does \nnot affect the outcome [71]. There has been a concern \nof increased recurrence rate of endometriosis after COS \nfor IVF/ICSI due to the supra-physiologic surge of E2. \nSome studies suggested that endometriosis recurrence \nrates are not increased after COS for IVF/ICSI [52]. Stud-\nies have proven that ART did not exacerbate the symp -\ntoms of endometriosis or negatively impact quality of life \n[72]. Table 2 summarizes guidelines/recommendations in \nendometriosis-related infertility.\nFertility Preservation in Endometriosis\nThe technique of ovarian tissue, oocyte, and embryo \ncryopreservation is widely used in oncology patients for \nfertility preservation (FP). Therefore, oocyte and embryo \ncryopreservation can be good options for fertility pres -\nervation in young endometriosis patients at risk of pre -\nmature ovarian failure. The women with endometriosis \nmay benefit from fertility preservation, but because of \n\nPage 7 of 12\nVatsa and Sethi  Middle East Fertil Soc J           (2021) 26:36 \n \nTable 2 Summary of guidelines/recommendations in endometriosis-related infertility\nESHRE 2014 [5] ASRM 2012 [73] NICE 2017 [74]\nImaging TVS is useful to diagnose ovarian endometrioma and to \nrule out rectal endometriosis (level A)\n3D USG to diagnose rectovaginal endometriosis: useful-\nness not well established (level D)\nMRI to diagnose peritoneal endometriosis: usefulness \nnot proven (level D)\nTVS is useful to diagnose suspected endometriosis and to \nidentify endometriomas and deep endometriosis involv-\ning bowel, bladder, or ureter (low evidence)\nMRI—as primary investigation to diagnose endometriosis \n(very low evidence)\nDiagnosis Perform laparoscopy to diagnose endometriosis and \nconfirm by histology. (GPP)\nCA-125 for diagnosis of endometriosis is not recom-\nmended (level A)\nLaparoscopy with histological confirmation is required \nfor definitive diagnosis of endometriosis, especially \nwhen it is not apparent visually on surgery\nCA-125—not used to diagnose endometriosis (very low \nevidence)\nDiagnostic laparoscopy to diagnose endometriosis by \nsystematic inspection of pelvis (moderate to very low \nevidence)\nMedical management No role in endometriosis-related infertility (level A) No evidence that it improves fertility No role in endometriosis-related infertility\nSurgical management Stage I/II\nEither excise or ablate lesions including adhesiolysis, to \nincrease  OPRa (level A)\nCO2 laser vaporization is preferred over monopolar \nelectrocoagulation (level C)\nExcision of capsule, better than drainage and electroco-\nagulation (level A)\nCounsel about risks of reduced ovarian function after \nsurgery (GPP)\nASRM stage III/IV\nOperative laparoscopy better than expectant manage-\nment, to increase spontaneous pregnancy rates (level B)\nStage I/II: laparoscopic ablation leads to improvement \nin LBR.\nStage III/IV: repeat surgery rarely increases fecundability, \nand IVF will be better in these patients\nManagement of endometriosis-related subfertility should \nhave multidisciplinary team approach.\nCombination of \nmedical and surgical \ntreatment\nNo hormonal treatment before surgery (GPP)\nNo hormonal treatment after surgery (level A)\nPreoperative and postoperative hormonal therapy does \nnot enhances fertility\nSuperovulation and IUI AFS/ASRM Stage I/II endometriosis, IUI +  COSb, instead \nof expectant management (level C)\nSO/IUIc may be given to stage I or II endometriosis as an \nalternative to IVF or further surgical therapy (level II)\nInsufficient evidence that SO/IUI is more successful after \nendometriosis is diagnosed and treated vs untreated \nminimal or mild endometriosis\nART Preferred modality if other factors of infertility coexists.\nRecurrence rates of endometriosis are not increased \nafter COS for IVF/ICSI (level C)\nGnRH agonists for a period of 3–6 months prior to treat-\nment with ART to improve CPR (level B)\nIVF likely maximizes cycle fecundity, especially in those \nwith distortion of pelvic anatomy due to moderate or \nsevere disease.\n\nPage 8 of 12Vatsa and Sethi  Middle East Fertil Soc J           (2021) 26:36 \nTable 2 (continued)\nESHRE 2014 [5] ASRM 2012 [73] NICE 2017 [74]\nSurgery before ART AFS/ASRM stage I/II—If undergoing laparoscopy prior \nto ART, may consider complete surgical removal of \nendometriosis, to improve LBR, benefit not well estab-\nlished (level C)\nEndometrioma larger than 3 cm: no evidence that \ncystectomy prior to treatment with ART improve preg-\nnancy rate (level A)\nEndometrioma larger than 3 cm: consider cystectomy \nprior to ART only to improve endometriosis-associated \npain or the accessibility of follicles.(GPP)\nNo benefit of surgery in asymptomatic women with \nendometrioma prior to IVF\nNo studies evaluating impact of size of endometrioma \non outcome.\na OPR Overall pregnancy rate\nb IUI + COS Intrauterine insemination+ controlled ovarian stimulation\nc SO/IUI Superovulation+ intrauterine insemination\n\nPage 9 of 12\nVatsa and Sethi  Middle East Fertil Soc J           (2021) 26:36 \n \nthe paucity of data, fertility preservation counselling of \npatients with endometriosis should be individualized. \nCobo et  al. conducted a retrospective observational \nstudy to observe the outcome of FP using cryopreserved \noocytes in patients with endometriosis with or without a \nhistory of surgery [75]. They found that patients without a \nhistory of surgery had a higher number of cryopreserved \noocytes per cycle than the unilateral or bilateral surgery \ngroups, but was comparable among the surgical patients. \nFertility preservation gives patients with endometriosis a \nchance to increase their reproductive chances. Therefore, \nperforming surgery after oocyte pickup for FP in young \nwomen is a good option [75].\nConclusions\nEndometriosis is an enigmatic disease, and so is its treat -\nment. The data on various modalities of treatment of \ninfertility in these patients is heterogeneous and incon -\nclusive. Medical treatment is not helpful for the treat -\nment of infertility. ART has emerged as a ray of hope \nfor infertile endometriosis patients where conception by \nother means is difficult. But the beneficial effect of GnRH \nagonist downregulation in ART is undisputed. Dienogest \nis an upcoming/new alternative to GnRH agonist, with a \nbetter side effect profile. IVF/ICSI may be a better option \nthan IVF alone. With the current evidence available, role \nof surgery prior to ART is inconclusive. Patients with \nendometriosis-related infertility should be offered the \noption of fertility preservation. Randomized, prospective \nstudies in relation to endometriosis-related infertility are \nlacking. For women presenting with main complaint of \ninfertility, the clinician should individualize the manage -\nment, with patient-centred, multi-modal and interdisci -\nplinary integrated approach.\nAbbreviations\nART : Assisted reproductive techniques; IVF/ICSI: In vitro fertilization/intra-cyto-\nplasmic sperm insemination; GnRH: Gonadotrophin-releasing hormone; EFI: \nEndometriosis fertility index; IUI: Intrauterine insemination; COH: Controlled \novarian hyperstimulation; TVS: Transvaginal sonography; MRI: Magnetic \nresonance imaging; DIE: Deep infiltrating endometriosis; ASRM: American \nSociety of Reproductive Medicine; AFS: American Fertility Society; LH: Lutein-\nizing hormone; COC: Cumulus-oocyte complexes; LBR: Live birth rate; OVI: \nOvulation induction; ESHRE: European Society of Human Reproduction and \nEmbryology; FP: Fertility preservation; MAR: Medically assisted reproduction; \nCOS: Controlled ovarian stimulation; WHO: World Health Organization; CPR: \nClinical pregnancy rate; AMH: Antimullerian hormone; PR: Progesterone recep-\ntors; CPR: Clinical pregnancy rate; COC: Cumulus oocyte complexes.\nAcknowledgements\nNo acknowledgments.\nAuthors’ contributions\nRV and AS both collected and reviewed the literature related to endometriosis \nand endometriosis-related infertility and wrote the scoping review. All authors \nhave read and approved the manuscript.\nFunding\nNo funding.\nAvailability of data and materials\nScoping review of the literature is available in the following databases: MED-\nLINE, Google Scholar, Scopus, EMBASE, Global health, the COCHRANE library, \nand Web of Science.\nDeclarations\nEthics approval and consent to participate\nNot applicable as it is a scoping review of the recent literature.\nConsent for publication\nNot applicable.\nCompeting interests\nNo financial and non-financial competing interests.\nReceived: 17 July 2021   Accepted: 18 September 2021\nReferences\n 1. Meuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman \nD, D’Hooghe T (2009) High prevalence of endometriosis in infertile \nwomen with normal ovulation and normospermic partners. Fertil Steril \n92(1):68–74. https:// doi. org/ 10. 1016/j. fertn stert. 2008. 04. 056 Epub 2008 \nAug 5. PMID: 18684448\n 2. 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Cobo A, Giles J, Paolelli S, Pellicer A, Remohí J, García-Velasco JA (2020) \nOocyte vitrification for fertility preservation in women with endometrio-\nsis: an observational study. Fertil Steril 113(4):836–844. https:// doi. org/ 10. \n1016/j. fertn stert. 2019. 11. 017 Epub 2020 Mar 4. PMID: 32145929\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in pub-\nlished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}