Impact of endometriosis on female fertility and the management options for endometriosis-related infertility in reproductive age women: a scoping review with recent evidences

Background: Endometriosis is a chronic inflammatory condition with varied presentation, which ultimately leads to chronic pelvic pain and infertility. It is a psychological and economic burden to the women and their families. Main body of abstract: The literature search was performed on the following databases: MEDLINE, Google Scholar, Scopus, EMBASE, Global health, the COCHRANE library, and Web of Science. We searched the entirety of those data- bases for studies published until July 2020 and in English language. The literature search was conducted using the combination of the Medical Subject heading (MeSH) and any relevant keywords for “endometriosis related infertility and management” in different orders. The modalities of treatment of infertility in these patients are heterogene- ous and inconclusive among the infertility experts. In this article, we tried to review the literature and look for the evidences for management of infertility caused by endometriosis. In stage I/II endometriosis, laparoscopic ablation leads to improvement in LBR. In stage III/IV, operative laparoscopy better than expectant management, to increase spontaneous pregnancy rates. Repeat surgery in stage III/IV rarely increases fecundability as it will decrease the ovar- ian reserve, and IVF will be better in these patients. The beneficial impact of GnRH agonist down-regulation in ART is undisputed. Dienogest is an upcoming and new alternative to GnRH agonist, with a better side effect profile. IVF + ICSI may be beneficial as compared to IVF alone. Younger patients planned for surgery due to pain or any other reason should be given the option of fertility preservation. Short conclusion: In women with endometriosis-related infertility, clinician should individualize management, with patient-centred, multi-modal, and interdisciplinary integrated approach.

Endometriosis, Endometriotic cystectomy, Medical management, Infertility, IVF © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.

Endometriosis is a state of chronic inflammation in the pelvis and is characterized by endometrial-type tis - sue outside of the uterus. Although exact prevalence of endometriosis is unknown, it roughly affects 2 to 10% of the female population, but 30 to 45% of females with infertility [1]. This condition leads to two main prob - lems—pain, infertility, or both. Endometriosis also has significant impact on the quality of life of the patients and negative influence on the sexual function and interper - sonal relationships. This article will deal with endometri - osis-related infertility in detail. Open Access Middle East Fertility Society Journal *Correspondence: [email protected] Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi, India Page 2 of 12Vatsa and Sethi Middle East Fertil Soc J (2021) 26:36 Main text The literature search was performed on the following databases: MEDLINE, Google Scholar, Scopus, EMBASE, Global health, the COCHRANE library, and Web of Sci - ence. We searched the entirety of those databases for studies published until July 2020 and in English language. The literature search was conducted using the combina - tion of the following Medical Subject heading (MeSH) and any relevant keywords in different orders: “endo - metriosis” , “endometrioma” , “endometriotic cystectomy” , “diagnosis” , “grading” , “management” , “surgical manage- ment” , “medical management” , “fertility preservation” , “mechanism” , “infertility” , “pathophysiology” , “ ASRM clas- sification” , “Endometriosis fertility index (EFI)” , “ovulation induction” , “intrauterine insemination (IUI)” , “Controlled ovarian hyperstimulation (COH)” , “ Assisted reproduction Techniques (ART)” , “In vitro fertilization (IVF)” , “clinical pregnancy rate” , “Dienogest” , “GnRH agonist” , “live birth” , “pregnancy outcome” , “minimal-mild endometriosis” , “severe endometriosis” , and “decreased ovarian reserve” . The reference lists of the included studies were also checked to look for studies that were not found in the electronic literature search. A total of 2208 articles were found pertaining to endometriosis. Original articles and some review articles, published in recent 5 years, were given priority. All the articles were accessible in full text. In this review, individual data sources were not sought for, and a descriptive analysis was done. The data were summarized in a form of descriptive review. Diagnosis of endometriosis The main symptoms of endometriosis are chronic pel - vic pain, dysmenorrhoea, dyspareunia, infertility, and cyclical bowel or urinary complaints. It is often missed at young age because of the non-specific complaints, causing a long diagnostic delay [2]. The imaging modal - ity of choice is transvaginal sonography (TVS) which can detect both ovarian endometrioma, rectal endometriosis, and associated adenomyosis [3]. In case of doubt in the diagnosis of ovarian endometrioma on TVS, magnetic resonance imaging (MRI) can be used, but its diagnostic accuracy is limited for peritoneal endometriosis [4, 5]. Further, evaluation for the involvement of other organs should be done if history and examination suggest deep infiltrating endometriosis (DIE). MRI or CT abdomen may help in evaluation when there is clinical suspicion of other organs being affected like ureter, bladder, and/or bowel [6]. More specific investigations like CT urogram or transrectal sonography may be required for mapping the endometriosis prior to surgery to see involvement of ureter or bladder and bowel respectively [7, 8]. There have been extensive studies on biomarkers (including CA125) for endometriosis; none has been validated for diagnosis of endometriosis [5]. The use of diagnostic laparoscopy and histopathologi - cal confirmation of endometrial glands and stromal tis - sue is gold standard for the diagnosis of endometriosis, but since the advancement of imaging, laparoscopy only to diagnose endometriosis may not be required. Quality of laparoscopy depends on surgical skills, expertise, and experience. Retroperitoneal and localized vaginal endo - metriosis can be easily missed. A negative laparoscopy reliably excludes the diagnosis of endometriosis, but pos - itive laparoscopy is less informative and of limited value when used in isolation without histology [9, 10]. Negative histology also does not exclude endometriosis [5] due to the possibility of inadequate or squeezed samples, which may have been taken from wrong location. Grading of endometriosis In 1996, ASRM proposed a revised classification of endo - metriosis and is currently the most widely used grading system for severity of endometriosis, but it has many

[11]. It does not correlate with the severity of symptoms, does not predict the treatment outcome, and poorly correlates with the pregnancy outcomes. Endo - metriosis fertility index (EFI) was developed by Adamson and Pasta [12], to address this problem. This system helps in predicting the treatment outcomes in infertile patients with laparoscopically proven endometriosis attempting standard non-IVF conception. Vesali et  al. conducted a meta-analysis to evaluate the accuracy of EFI for predicting non-ART pregnan - cies. There was a significant difference between all cat - egories, especially EFI 0-2 had a cumulative non-ART pregnancy rate at 36 months of 10%, which increased to approximately 70% for EFI of 9–10 (P < 0.001). They concluded that EFI was a useful index in predicting the non-ART pregnancy rate [13]. Though developed for calculating the non-IVF pregnancy rate, prediction stud - ies have shown that EFI is better at predicting the IVF outcomes as well [14]. This system does not account for uterine abnormality like presence of adenomyosis along with endometriosis, which is very common in infertile patients. Uterine pathology should be included in the system and for predicting pregnancy rate. Further, it does not help in prediction of post-surgery endometriosis- associated pain [12]. Moreover, EFI can be calculated for only those patients who underwent surgery. It is rec - ommended that all women with endometriosis have the r-ASRM classification, and patients with infertility should have EFI [15]. This classification and scoring system helps in counselling and prognosticating the patients about the treatment options and the outcomes expected. Page 3 of 12 Vatsa and Sethi Middle East Fertil Soc J (2021) 26:36 Mechanism of infertility in endometriosis The factors responsible for sub-fertility in endometrio - sis have been attributed to distorted pelvic anatomy and molecular alteration leading to excess production of prostaglandins, oestrogen, growth factors, reactive oxy - gen species, cytokines, etc. [16]. There is a debate on how minimal or mild endometriosis can lead to infertil - ity without distorting the pelvic anatomy. Various studies have shown that the molecular alterations in endome - triosis lead to ovarian, tubal, or endometrial dysfunc - tion, which leads to infertility [17–19]. The progesterone resistance and hyperestrogenic state lead to chronic inflammation making the endometrium non-receptive for normal embryo implantation and has been suggested as a significant contributor to infertility [20]. In women with endometriosis, inflammatory markers present in peritoneal fluid hamper oocyte competence; impair sperm motility, function, and oocyte-sperm interaction; and can cause sperm DNA fragmentation and abnormal acrosome reaction [21]. Xu et al. found that even in mini- mal to mild endometriosis, oocyte quality is impaired because the mitochondrial structure and function are hampered [22]. Immunological dysfunction is seen in infertile women with endometriosis [23]. Adenomyosis is associated with endometriosis in 90% of cases [24]. Surgeries performed for endometriosis lead to decreased ovarian reserve and pelvic adhesions contributing to infertility. In endometriosis, the granulosa cells are resist- ant to luteinizing hormone (LH) to some extent; there is hypothalamic-pituitary-ovarian axis dysfunction with abnormal LH production [25], which affects ovulation. Hyperprolactinemia may be associated with endome - triosis and its progression, with a significant association between the severity of endometriosis and prolactin lev - els [26]. So, distorted tubo-ovarian relationship, impaired folliculogenesis, hormonal dysfunction, disturbed local milieu, fertilization failure, and impaired endometrial receptivity are causes of endometriosis-related infertility. Medical management of infertility The treatment of endometriosis-related infertility must be individualized. Medical, surgical, and ART treatment alone or combinations can be used in these patients. Medical management, which includes various hor - monal treatments, deals with ovulation suppression and, therefore, does not have much role for infertility treatment. This is useful for only pain relief in infertile women. Cochrane review by Hughes et al. concluded that there is no role for suppressing ovulation in women with endometriosis who plan to conceive [27]. Neither pre - operative nor postoperative hormonal therapy increases the chances of spontaneous conception [27, 28]. The Cochrane review which included three RCTs, a total of 165 patients, showed the benefit of GnRH agonist pre IVF. The authors concluded that odds of clinical preg - nancy in endometriosis patients increased by fourfold when GnRH agonists were given for 3–6 months before IVF or ICSI [29]. GnRH agonists should be given for 3–6 months prior to IVF as per ESHRE recommendations to increase the clinical pregnancy rates [5]. In recent years, numerous studies have been done to find out the role of dienogest in treating endometriosis- related infertility. Dienogest has an effect on multiple receptors like the oestrogen, androgen, glucocorticoid, and mineralocorticoid and little impact on the metabolic parameters, and is having a significant impact on endo - metriotic lesions locally [30]. A systematic review by Grandi et al. in 2016 analysed studies on dienogest ther - apy and its effects on the inflammatory reaction of endo - metriotic tissue [31]. Dienogest is anti-inflammatory and causes modulation of the pro-inflammatory cytokine and chemokine production, which is mediated via PR in pro - gesterone receptor-expressing epithelial cells. Muller et  al. conducted study on 144 women planned for IVF after their endometriotic cystectomy and recruited the patients prospectively [32]. They divided patients into three groups: those receiving dienogest, GnRH agonist, and those without hormonal therapy within 6 months before IVF. They concluded that pre-IVF hormonal treatment is required in patients with endo - metriosis, and dienogest will probably be a better pre- treatment option as compared to GnRH agonist. Tamura et al. conducted a study on subjects with stage III or IV endometriosis, recruited 68 women in two groups: dien - ogest (n = 33) and control group (n = 35) [33]. Dienogest was given for 3 months prior to the ART cycle followed by GnRH agonist long protocol for ovarian stimulation. They concluded that administering Dienogest just before IVF did not increase IVF success rates. Therefore, more extensive studies are required to see whether dienogest therapy before IVF can help improve the clinical out - come of patients. Surgical management The decision for surgery in endometriosis-associated infertility depends on age, previous ovarian surgery, ovarian reserve, duration of infertility, grade of endome - triosis, tubal status, cost of treatment, expected outcome of the procedure, and priorities of the patient. The recon- struction of the normal pelvic anatomy to achieve an excellent tubo-ovarian relationship and remove all mac - roscopically visible disease is the main aim of the surgery. Minimally invasive surgery is preferred over laparotomy for obvious reasons [34]. Page 4 of 12Vatsa and Sethi Middle East Fertil Soc J (2021) 26:36 Leonardi et al. conducted a meta-analysis to determine if operative laparoscopy is an effective treatment in grade I-IV endometriosis compared with other therapies [10]. They found 1990 studies that were included in the anal - ysis. When operative laparoscopy was compared with diagnostic, it was found that operative did not improve the clinical pregnancy rate (CPR) (p = 0.06). Surgery for minimal to mild endometriosis There are two ways of removing peritoneal endometriotic lesions, first is by excision or ablation; both have compa - rable cumulative pregnancy rates. Ablative techniques involve bipolar coagulation and laser methods like CO2 or argon laser. ESHRE recommends CO2 laser vapori - zation is better than monopolar electrocoagulation [5]. Cochrane review by Duffy et al. has reported higher live birth or ongoing pregnancy rates and reduced overall pain scale after laparoscopic surgery for mild-moderate endometriosis [35]. ESHRE concluded that the ongoing pregnancy rates are increased in infertile women with AFS/ASRM stage I/II endometriosis after laparoscopy. Excision or ablation of endometriotic lesions on laparos - copy is better than diagnostic laparoscopy alone. Surgi - cal removal of peritoneal endometriosis may prevent the progression of the disease further [36]. Surgery for moderate to severe endometriosis Moderate to severe endometriosis (r-ASRM III-IV) dis - torts normal pelvic anatomy; surgery restores this dis - torted pelvic anatomy and the tubo-ovarian relationship hampered because of the pelvic adhesions. This form of endometriosis may involve rectovaginal or colorectal and can be deep infiltrating endometriosis [37]. Maheux-Lacroix et  al. conducted retrospective study on women with stage III–IV endometriosis who attempted pregnancy after laparoscopic resection; 63% had live birth following surgery, 64% without ART. EFI was significantly correlated with live-births (P < 0.001). EFI of 0–2 vs. 9–10, cumulative non-ART LBR at 5 years was 0%VS 91%, which was statistically significant. The chance of having live birth steadily increased from 38 to 71% among the same EFI strata in women who attempted ART (P = 0.1) [38]. A significant problem after any pelvic surgery is post- operative adhesion formation. Oxidized regenerated cel - lulose during operative laparoscopy for endometriosis has been proved useful for prevention of adhesion forma- tion [5]. After laparoscopic surgery, suspending the ovary temporarily will help reduce post-operative ovarian adhe- sions in cases with severe pelvic endometriosis. A recent meta-analysis concluded that there is a reduced chance and severity of adhesion formation in patients with stage III–IV endometriosis if the ovaries are temporarily sus - pended post laparoscopic resection [39]. Ovarian endometrioma Clinical data has suggested that ovarian endometrioma damages surrounding healthy ovarian tissue. The patho - physiology of which may be the presence of proteolytic enzyme, inflammatory mediators, reactive oxygen spe - cies, and iron in concentrations many times higher than those present in serum or other types of cysts; all of these lead to cell damage. The decision to operate on ovar - ian endometrioma depends on the patient’s age, ovarian reserve, and prior surgery on the ovary [37]. Depending on surgical skill, patient profile, and resources available ovarian endometrioma can be managed by either lapa - rotomy or laparoscopy, with excision of endometrioma capsule or drainage and ablation (electrocautery, CO2 laser, or plasma energy) of cyst wall [5]. Recent pro - spective study concluded that there was no difference in post-operative pregnancy rates after either ablation using plasma energy or cystectomy of the ovarian endo - metrioma [40]. Both techniques can compromise ovarian reserve, excision by removal, and coagulation by thermal damage of normal ovarian tissue. In infertility patients, accepting the increased chance of recurrence due to incomplete treatment of ovarian lesions is better than severe reduction of ovarian reserve following complete resection of endometriomas. A less damaging approach in terms of ovarian reserve for large endometrioma is a three-step approach. This includes laparoscopic drain - age of endometrioma, followed by the use of GnRH for 3 months to reduce cyst diameter, and then laparoscopic CO2 laser vaporization of the cyst [41]. Surgery before Assisted Reproductive Technology (ART) It was discussed in the previous section; spontaneous pregnancy rates can improve with surgery for endome - triosis. There have not been prospective, randomized studies on the effects of surgery for endometriosis on ART outcomes. A retrospective study on women with minimal-mild endometriosis had shown that surgery before IVF resulted in significantly higher implantation, pregnancy, and live birth rate (LBR) [42]. Bianchi et  al., in their study in women with DIE, found that extensive laparoscopic excision of endometriotic lesions before ART improves pregnancy rate, but LBR did not differ [43]. Another study found that surgery in patients with DIE did not improve IVF outcomes [44]. A retrospec - tive study done on 115 patients has shown that spon - taneous conception rate and IVF outcome improves after laparoscopic excision of DIE in moderate to severe endometriosis [45]. Retrospective analysis of 110 colo - rectal endometriosis patients showed that cumulative Page 5 of 12 Vatsa and Sethi Middle East Fertil Soc J (2021) 26:36 LBR at the first ART cycle after surgery as compared to the first-line ART was 33% vs. 13.0% [46]. There has been no evidence to support endometrioma removal before IVF as it does not enhance the outcome; instead, it can lead to decreased ovarian reserve and increase the dose of gonadotropins for stimulation in ART. Cochrane review showed no difference in clinical pregnancy rate with either surgery or expectant management before ART [ 47]. Liang et  al. conducted a prospective study where women with endometriosis-associated infertility were recruited; 13 had surgery to remove the endome - trioma before IVF, and 28 did not undergo surgery [48]. The chemokines, growth factors, inflammatory media - tors, implantation rate, and CPR were similar between the surgery and non-surgery groups. Ovarian reserve in terms of AMH levels was lower in the surgery group. Magnien et  al. conducted a retrospective cohort study in which IVF outcomes were evaluated for patients with and without previous surgery for Endometriosis. Past history of surgery for endometriosis (p = 0.001) was an independent risk factor for lower pregnancy rates [49]. But, in cases where normal ovarian tissue is not acces - sible for oocyte retrieval, cystectomy may be considered [5]. In diminished ovarian reserve patients, preoperative embryo cryopreservation followed by laparoscopic sur - gery (“surgery-assisted-IVF combination/Hybrid ther - apy”) can be done [50]. Table  1 summarizes surgery vs ART in endometriosis. Medically assisted reproduction Medically assisted reproduction (MAR) includes ovula - tion induction, controlled ovarian stimulation (COS), ovulation triggering, ART procedures, and intrauterine (IUI), intracervical, and intravaginal insemination as per World Health Organization (WHO) Revised Glossary on ART Terminology. Young women with minimal to mild disease and short duration of infertility can be managed expectantly for 6–9 months [51] If the above treatments fail or in patients with long standing infertility, dimin - ished ovarian reserve, or in cases with compromised tubal function or male factor infertility, IVF should be considered [52]. Controlled ovarian stimulation (COS) and intrauterine insemination (IUI) COS and IUI is a cost-effective and first-line treatment for many types of infertility, but its utility is not entirely clear in endometriosis. A retrospective analysis of COS and IUI demonstrated a per cycle fecundity rate of 6%, 11.8%, and 15.3% for endometriosis, malefactor, and unexplained infertility, respectively [53]. A meta-analy - sis has shown that endometriosis decreases the odds of pregnancy by half [54]. Keresztúri et al. compared preg - nancy rate after COS+IUI on 238 patients of all stages of endometriosis and concluded that surgery followed by COH+IUI is more effective than surgery alone [55]. So, COS with IUI can be considered as a first-line strategy for infertile women with early-stage endometriosis. Aro - matase inhibitors (AI) and clomiphene citrate both can be used for COS in women who underwent surgery for minimal to mild endometriosis. In a study, a small group of surgically diagnosed endometriosis patients were rand- omized to OVI with human menopausal gonadrotrophin (HMG) + IUI vs no treatment for four cycles showed that cumulative live birth rate over 4 cycles was 11% versus 2% (p=0.002) suggesting that COH may improve preg - nancy rates [56]. A multicenter trial included patients with unexplained infertility, endometriosis, or mild male factor infertility and who were randomized to intracervi - cal insemination (ICI), IUI, FSH with ICI, or FSH with IUI [57]. They concluded that FSH +IUI had higher preg- nancy rates than the other groups (33% v 10%, p <0.0001) and suggested that in a woman with endometriosis and subfertility, it may be reasonable to start with OVI + IUI. A retrospective study by Houwen et al., who performed IUI in moderate-to-severe endometriosis patients, found that long-term pituitary down-regulation prior to OVI+IUI tend to result in higher ongoing pregnancy rate (adjusted HR 1.8) [58]. A larger RCT is required to see the utility of OVI+IUI in moderate to severe endometri - osis, at present not recommended. Endometriosis and assisted reproductive technology (ART) ESHRE recommends using ART in endometriosis if there is tubal or male factor infertility, and/or other treat - ments have failed. Studies to date on effect of endome - triosis on IVF outcome have shown mixed results. After a meta-analysis, Senapati et  al. concluded that women with endometriosis who undergo IVF have half the preg - nancy rate compared to those who get IVF done for other Table 1 Surgery vs ART in endometriosis [37] Factor In favour of surgery In favour of ART • Age Young Old • Associated infertility fac- tors (tubal or male factor) [5] No Yes • Infertility duration Short Long • Ovarian reserve Satisfactory Decreased • Patients choice Patient choice Patient choice • Pelvic pain intensity Severe Mild • Ovarian endometrioma especially bilateral No Yes • Previous surgery No Yes • Associated adenomyosis No Yes Page 6 of 12Vatsa and Sethi Middle East Fertil Soc J (2021) 26:36 indications [59]. Ovarian endometrioma, its surgery, and peritoneal endometriosis damage oocyte maturation and adversely affect the ovarian reserve, which leads to inad - equate ovarian response [59]. Data suggests that endo - metriosis affects not only the endometrial receptivity but also the oocyte and embryo development [59]. However, other studies have shown that endometriosis in isolation has LBR after IVF similar to other causes of infertility [60]. A recent meta-analysis which included 36 studies has shown that women with and without endometriosis have comparable ART outcomes in terms of live births. In contrast, those with severe endometriosis have inferior outcomes [61]. A retrospective cohort study on approxi - mately 3600 women with endometriosis and 19,000 women as control has shown that there was not much difference in terms of live birth, clinical pregnancy, and miscarriage rates. Still, women with endometriosis had a lesser number of oocytes retrieved [60]. Various studies have been done to compare the effi - cacy of GnRH agonist and antagonist in endometrio - sis patients. GnRH agonists suppress the endometriotic lesions and are thought to increase the IVF success rate. A prospective randomized trial by Recai et  al. reported that implantation and CPR are similar for patients with mild to moderate endometriosis with both agonist and antagonist protocols and endometrioma who did not undergo surgery for endometriosis. However, GnRH agonists had a significantly higher number of surplus embryos available for cryopreservation [62]. Kolanska et  al. has done a retrospective analysis of prospective data of 284 COH cycles, 165 with GnRH-agonist and 119 with GnRH-antagonist protocol. The pregnancy rate was similar in both groups while the live-birth rate was higher in the agonist group [63]. In the study by Zhao et al., patients were divided into three groups according to the IVF protocols, GnRH-agonist, GnRH-antagonist, and long GnRH-agonist. Total gonadotrophin dosage and duration required for stimulation was less in the GnRH- antagonist group than in the others. Still, there were no significant differences in the implantation rate and clini - cal pregnancy rate, oocytes retrieved, fertilization rate, embryo utilization rate, and LBR in the three groups [64]. ESHRE recommends, IVF pretreatment with GnRH agonist for a period of 3–6 months [29]. For COS in endometriosis patients both agonist and antagonist pro - tocols seem to be equally effective [65]. A study suggests that GnRHa agonist ovulation triggering, which is possi - ble in antagonist protocols, limits pain symptom progres- sion in the period immediately after ART [66]. In women with endometriosis, there are increased chances of ovarian abscess formation following oocyte pickup; although overall risk is low, antibiotic prophy - laxis has been suggested [5]. Boucret et  al. conducted a retrospective study intending to evaluate the impact of endometriosis on embryo quality and IVF outcomes. There was no association between endometriosis and the number of top-quality embryos, but the implanta - tion rate and LBR were lower in the endometriosis group. The lower number of cryopreserved embryos decreases the cumulative LBR by reducing number of embryos, not their quality [67]. Lower implantation rate after IVF in endometriosis patients compared to tubal factor and unexplained infertility patients may be due to the asso - ciation of endometriosis and adenomyosis. Prolonged downregulation with GnRH agonist or oral contraceptive pills may help overcome the negative effect of adenomyo- sis on implantation and endometrial receptivity [68]. Recent research favours IVF/ICSI over IVF alone in endometriosis patients. Komsky-Elbaz et  al. compared conventional IVF versus IVF-ICSI in sibling oocytes from couples with endometriosis and normozoosper - mic semen; a total of 786 sibling cumulus-oocyte com - plexes (COC) were randomized between insemination by conventional IVF or ICSI. The authors concluded that ICSI has higher fertilization rate and reduced rate of total fertilization failure [69]. Therefore, IVF/ICSI can be considered as a practical approach for managing endometriosis-associated infertility. Wu et al. conducted a retrospective study and found that implantation, clini - cal pregnancy, and LBR were statistically significantly higher in the freeze-all group compared with new trans - fer groups (P < 0.001) [70]. Yilmaz et al. conducted a retrospective study and found that between unilateral and bilateral endometrioma groups, AMH, oocyte, and embryo quality, the numbers of embryos, PR, and LBR are similar. They concluded that the presence of endometrioma negatively effects fertility parameters but whether it is unilateral or bilateral does not affect the outcome [71]. There has been a concern of increased recurrence rate of endometriosis after COS for IVF/ICSI due to the supra-physiologic surge of E2. Some studies suggested that endometriosis recurrence rates are not increased after COS for IVF/ICSI [52]. Stud- ies have proven that ART did not exacerbate the symp - toms of endometriosis or negatively impact quality of life [72]. Table 2 summarizes guidelines/recommendations in endometriosis-related infertility. Fertility Preservation in Endometriosis The technique of ovarian tissue, oocyte, and embryo cryopreservation is widely used in oncology patients for fertility preservation (FP). Therefore, oocyte and embryo cryopreservation can be good options for fertility pres - ervation in young endometriosis patients at risk of pre - mature ovarian failure. The women with endometriosis may benefit from fertility preservation, but because of Page 7 of 12 Vatsa and Sethi Middle East Fertil Soc J (2021) 26:36 Table 2 Summary of guidelines/recommendations in endometriosis-related infertility ESHRE 2014 [5] ASRM 2012 [73] NICE 2017 [74] Imaging TVS is useful to diagnose ovarian endometrioma and to rule out rectal endometriosis (level A) 3D USG to diagnose rectovaginal endometriosis: useful- ness not well established (level D) MRI to diagnose peritoneal endometriosis: usefulness not proven (level D) TVS is useful to diagnose suspected endometriosis and to identify endometriomas and deep endometriosis involv- ing bowel, bladder, or ureter (low evidence) MRI—as primary investigation to diagnose endometriosis (very low evidence) Diagnosis Perform laparoscopy to diagnose endometriosis and confirm by histology. (GPP) CA-125 for diagnosis of endometriosis is not recom- mended (level A) Laparoscopy with histological confirmation is required for definitive diagnosis of endometriosis, especially when it is not apparent visually on surgery CA-125—not used to diagnose endometriosis (very low evidence) Diagnostic laparoscopy to diagnose endometriosis by systematic inspection of pelvis (moderate to very low evidence) Medical management No role in endometriosis-related infertility (level A) No evidence that it improves fertility No role in endometriosis-related infertility Surgical management Stage I/II Either excise or ablate lesions including adhesiolysis, to increase OPRa (level A) CO2 laser vaporization is preferred over monopolar electrocoagulation (level C) Excision of capsule, better than drainage and electroco- agulation (level A) Counsel about risks of reduced ovarian function after surgery (GPP) ASRM stage III/IV Operative laparoscopy better than expectant manage- ment, to increase spontaneous pregnancy rates (level B) Stage I/II: laparoscopic ablation leads to improvement in LBR. Stage III/IV: repeat surgery rarely increases fecundability, and IVF will be better in these patients Management of endometriosis-related subfertility should have multidisciplinary team approach. Combination of medical and surgical treatment No hormonal treatment before surgery (GPP) No hormonal treatment after surgery (level A) Preoperative and postoperative hormonal therapy does not enhances fertility Superovulation and IUI AFS/ASRM Stage I/II endometriosis, IUI + COSb, instead of expectant management (level C) SO/IUIc may be given to stage I or II endometriosis as an alternative to IVF or further surgical therapy (level II) Insufficient evidence that SO/IUI is more successful after endometriosis is diagnosed and treated vs untreated minimal or mild endometriosis ART Preferred modality if other factors of infertility coexists. Recurrence rates of endometriosis are not increased after COS for IVF/ICSI (level C) GnRH agonists for a period of 3–6 months prior to treat- ment with ART to improve CPR (level B) IVF likely maximizes cycle fecundity, especially in those with distortion of pelvic anatomy due to moderate or severe disease. Page 8 of 12Vatsa and Sethi Middle East Fertil Soc J (2021) 26:36 Table 2 (continued) ESHRE 2014 [5] ASRM 2012 [73] NICE 2017 [74] Surgery before ART AFS/ASRM stage I/II—If undergoing laparoscopy prior to ART, may consider complete surgical removal of endometriosis, to improve LBR, benefit not well estab- lished (level C) Endometrioma larger than 3 cm: no evidence that cystectomy prior to treatment with ART improve preg- nancy rate (level A) Endometrioma larger than 3 cm: consider cystectomy prior to ART only to improve endometriosis-associated pain or the accessibility of follicles.(GPP) No benefit of surgery in asymptomatic women with endometrioma prior to IVF No studies evaluating impact of size of endometrioma on outcome. a OPR Overall pregnancy rate b IUI + COS Intrauterine insemination+ controlled ovarian stimulation c SO/IUI Superovulation+ intrauterine insemination Page 9 of 12 Vatsa and Sethi Middle East Fertil Soc J (2021) 26:36 the paucity of data, fertility preservation counselling of patients with endometriosis should be individualized. Cobo et  al. conducted a retrospective observational study to observe the outcome of FP using cryopreserved oocytes in patients with endometriosis with or without a history of surgery [75]. They found that patients without a history of surgery had a higher number of cryopreserved oocytes per cycle than the unilateral or bilateral surgery groups, but was comparable among the surgical patients. Fertility preservation gives patients with endometriosis a chance to increase their reproductive chances. Therefore, performing surgery after oocyte pickup for FP in young women is a good option [75].

Endometriosis is an enigmatic disease, and so is its treat - ment. The data on various modalities of treatment of infertility in these patients is heterogeneous and incon - clusive. Medical treatment is not helpful for the treat - ment of infertility. ART has emerged as a ray of hope for infertile endometriosis patients where conception by other means is difficult. But the beneficial effect of GnRH agonist downregulation in ART is undisputed. Dienogest is an upcoming/new alternative to GnRH agonist, with a better side effect profile. IVF/ICSI may be a better option than IVF alone. With the current evidence available, role of surgery prior to ART is inconclusive. Patients with endometriosis-related infertility should be offered the option of fertility preservation. Randomized, prospective studies in relation to endometriosis-related infertility are lacking. For women presenting with main complaint of infertility, the clinician should individualize the manage - ment, with patient-centred, multi-modal and interdisci - plinary integrated approach. Abbreviations ART : Assisted reproductive techniques; IVF/ICSI: In vitro fertilization/intra-cyto- plasmic sperm insemination; GnRH: Gonadotrophin-releasing hormone; EFI: Endometriosis fertility index; IUI: Intrauterine insemination; COH: Controlled ovarian hyperstimulation; TVS: Transvaginal sonography; MRI: Magnetic resonance imaging; DIE: Deep infiltrating endometriosis; ASRM: American Society of Reproductive Medicine; AFS: American Fertility Society; LH: Lutein- izing hormone; COC: Cumulus-oocyte complexes; LBR: Live birth rate; OVI: Ovulation induction; ESHRE: European Society of Human Reproduction and Embryology; FP: Fertility preservation; MAR: Medically assisted reproduction; COS: Controlled ovarian stimulation; WHO: World Health Organization; CPR: Clinical pregnancy rate; AMH: Antimullerian hormone; PR: Progesterone recep- tors; CPR: Clinical pregnancy rate; COC: Cumulus oocyte complexes.

No acknowledgments. Authors’ contributions RV and AS both collected and reviewed the literature related to endometriosis and endometriosis-related infertility and wrote the scoping review. All authors have read and approved the manuscript. Funding No funding. Availability of data and materials Scoping review of the literature is available in the following databases: MED- LINE, Google Scholar, Scopus, EMBASE, Global health, the COCHRANE library, and Web of Science. Declarations Ethics approval and consent to participate Not applicable as it is a scoping review of the recent literature. Consent for publication Not applicable. Competing interests No financial and non-financial competing interests. Received: 17 July 2021 Accepted: 18 September 2021

1. Meuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D’Hooghe T (2009) High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril 92(1):68–74. https:// doi. org/ 10. 1016/j. fertn stert. 2008. 04. 056 Epub 2008 Aug 5. PMID: 18684448 2. Ghai V, Jan H, Shakir F, Haines P , Kent A (2020) Diagnostic delay for super- ficial and deep endometriosis in the United Kingdom. J Obstet Gynaecol 40(1):83–89. https:// doi. org/ 10. 1080/ 01443 615. 2019. 16032 17 Epub 2019 Jul 22. PMID: 31328629 3. Guerriero S, Condous G, van den Bosch T, Valentin L, Leone FPG, Van Schoubroeck D et al (2016) Systematic approach to sonographic evalu- ation of the pelvis in women with suspected endometriosis, including terms, definitions and measurements: a consensus opinion from the International Deep Endometriosis Analysis (IDEA) group. Ultrasound Obstet Gynecol 48(3):318–332. https:// doi. org/ 10. 1002/ uog. 15955 Epub 2016 Jun 28. PMID: 27349699 4. Stratton P , Winkel C, Premkumar A, Chow C, Wilson J, Hearns-Stokes R et al (2003) Diagnostic accuracy of laparoscopy, magnetic resonance imaging, and histopathologic examination for the detection of endometriosis. Fer- til Steril 79(5):1078–1085. https:// doi. org/ 10. 1016/ s0015- 0282(03) 00155-9 PMID: 12738499 5. Dunselman GAJ, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, De Bie B et al (2014) ESHRE guideline: management of women with endo- metriosis. Hum Reprod 29(3):400–412. https:// doi. org/ 10. 1093/ humrep/ det457 Epub 2014 Jan 15. PMID: 24435778 6. Chapron C, Tosti C, Marcellin L, Bourdon M, Lafay-Pillet M-C, Millischer A-E et al (2017) Relationship between the magnetic resonance imaging appearance of adenomyosis and endometriosis phenotypes. Hum Reprod 32(7):1393–1401. https:// doi. org/ 10. 1093/ humrep/ dex088 PMID: 28510724 7. Bazot M, Malzy P , Cortez A, Roseau G, Amouyal P , Daraï E (2007) Accuracy of transvaginal sonography and rectal endoscopic sonography in the diagnosis of deep infiltrating endometriosis. Ultrasound Obstet Gynecol 30(7):994–1001. https:// doi. org/ 10. 1002/ uog. 4070 PMID: 17992706 8. Zannoni L, Del Forno S, Coppola F, Papadopoulos D, Valerio D, Golfieri R et al (2017) Comparison of transvaginal sonography and computed tomography–colonography with contrast media and urographic phase for diagnosing deep infiltrating endometriosis of the posterior compart- ment of the pelvis: a pilot study. Jpn J Radiol 35(9):546–554. https:// doi. org/ 10. 1007/ s11604- 017- 0665-4 Epub 2017 Jul 12. PMID: 28702886 9. Bafort C, Beebeejaun Y, Tomassetti C, Bosteels J, Duffy JM (2020) Laparoscopic surgery for endometriosis. Cochrane Database Syst Rev 10:CD011031. https:// doi. org/ 10. 1002/ 14651 858. CD011 031. pub3 PMID: 33095458 Page 10 of 12Vatsa and Sethi Middle East Fertil Soc J (2021) 26:36 10. Leonardi M, Gibbons T, Armour M, Wang R, Glanville E, Hodgson R et al (2020) When to do surgery and when not to do surgery for endome- triosis: a systematic review and meta-analysis. J Minim Invasive Gynecol 27(2):390–407.e3. https:// doi. org/ 10. 1016/j. jmig. 2019. 10. 014 Epub 2019 Oct 31. PMID: 31676397 11. American Society for Reproductive (1997) Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 67(5):817–821. https:// doi. org/ 10. 1016/ s0015- 0282(97) 81391-x PMID: 9130884 12. Adamson GD, Pasta DJ (2010) Endometriosis fertility index: the new, vali- dated endometriosis staging system. Fertil Steril 94(5):1609–1615. https:// doi. org/ 10. 1016/j. fertn stert. 2009. 09. 035 PMID: 19931076 13. Vesali S, Razavi M, Rezaeinejad M, Maleki-Hajiagha A, Maroufizadeh S, Sepidarkish M (2020) Endometriosis fertility index for predicting non- assisted reproductive technology pregnancy after endometriosis surgery: a systematic review and meta-analysis. BJOG 127(7):800–809 14. Wang W, Li R, Fang T, Huang L, Ouyang N, Wang L et al (2013) Endo- metriosis fertility index score maybe more accurate for predicting the outcomes of in vitro fertilisation than r-AFS classification in women with endometriosis. Reprod Biol Endocrinol 11:112. https:// doi. org/ 10. 1186/ 1477- 7827- 11- 112 PMID: 24330552; PMCID: PMC3866946 15. Johnson NP , Hummelshoj L, Adamson GD, Keckstein J, Taylor HS, Abrao MS et al (2017) World Endometriosis Society consensus on the classifica- tion of endometriosis. Hum Reprod 32(2):315–324. https:// doi. org/ 10. 1093/ humrep/ dew293 Epub 2016 Dec 5. PMID: 27920089 16. de Ziegler D, Borghese B, Chapron C (2010) Endometriosis and infertility: pathophysiology and management. Lancet 376(9742):730–738. https:// doi. org/ 10. 1016/ S0140- 6736(10) 60490-4 PMID: 20801404 17. Kobayashi H, Yamada Y, Kanayama S, Furukawa N, Noguchi T, Haruta S et al (2009) The role of iron in the pathogenesis of endometriosis. Gynecol Endocrinol 25(1):39–52. https:// doi. org/ 10. 1080/ 09513 59080 23662 04 PMID: 19165662 18. Singh AK, Chattopadhyay R, Chakravarty B, Chaudhury K (2013) Markers of oxidative stress in follicular fluid of women with endometriosis and tubal infertility undergoing IVF. Reprod Toxicol 42:116–124. https:// doi. org/ 10. 1016/j. repro tox. 2013. 08. 005 Epub 2013 Aug 29. PMID: 23994512 19. Sanchez AM, Viganò P , Somigliana E, Panina-Bordignon P , Vercellini P , Candiani M (2014) The distinguishing cellular and molecular features of the endometriotic ovarian cyst: from pathophysiology to the potential endometrioma-mediated damage to the ovary. Hum Reprod Update 20(2):217–230. https:// doi. org/ 10. 1093/ humupd/ dmt053 Epub 2013 Oct 14. PMID: 24129684 20. Lessey BA, Kim JJ (2017) Endometrial receptivity in the eutopic endome- trium of women with endometriosis: it is affected, and let me show you why. Fertil Steril 108(1):19–27. https:// doi. org/ 10. 1016/j. fertn stert. 2017. 05. 031 Epub 2017 Jun 14. PMID: 28602477; PMCID: PMC5629018 21. Carli C, Leclerc P , Metz CN, Akoum A (2007) Direct effect of macrophage migration inhibitory factor on sperm function: possible involvement in endometriosis-associated infertility. Fertil Steril 88(4 Suppl):1240–1247. https:// doi. org/ 10. 1016/j. fertn stert. 2007. 04. 002 Epub 2007 Jul 20. PMID: 17658526 22. Xu B, Guo N, Zhang X, Shi W, Tong X, Iqbal F et al (2015) Oocyte quality is decreased in women with minimal or mild endometriosis. Sci Rep 5(1):10779 23. Miller JE, Ahn SH, Monsanto SP , Khalaj K, Koti M, Tayade C (2017) Implica- tions of immune dysfunction on endometriosis associated infertility. Oncotarget 8(4):7138–7147. https:// doi. org/ 10. 18632/ oncot arget. 12577 PMID: 27740937; PMCID: PMC5351695 24. Kunz G, Beil D, Huppert P , Noe M, Kissler S, Leyendecker G (2005) Adeno- myosis in endometriosis—prevalence and impact on fertility. Evidence from magnetic resonance imaging. Hum Reprod 20(8):2309–2316. https:// doi. org/ 10. 1093/ humrep/ dei021 Epub 2005 May 26. PMID: 15919780 25. Cahill DJ, Harlow CR, Wardle PG (2003) Pre-ovulatory granulosa cells of infertile women with endometriosis are less sensitive to luteinizing hormone: reduced LH sensitivity in endometriosis. Am J Reprod Immunol 49(2):66–69. https:// doi. org/ 10. 1034/j. 1600- 0897. 2003. 01156.x PMID: 12765343 26. Cahill DJ (2000) Pituitary-ovarian dysfunction and endometriosis. Hum Reprod Update 6(1):56–66. https:// doi. org/ 10. 1093/ humupd/ 6.1. 56 PMID: 10711830 27. Hughes E, Brown J, Collins JJ, Farquhar C, Fedorkow DM, Vanderkerchove P (2007) Ovulation suppression for endometriosis for women with subfer- tility. Cochrane Database Syst Rev 2007(3):CD000155. https:// doi. org/ 10. 1002/ 14651 858. CD000 155. pub2 PMID: 17636607; PMCID: PMC7045467 28. Furness S, Yap C, Farquhar C, Cheong YC (2004) Pre and post-operative medical therapy for endometriosis surgery. Cochrane Database Syst Rev 2004(3):CD003678. https:// doi. org/ 10. 1002/ 14651 858. CD003 678. pub2 Update in: Cochrane Database Syst Rev. 2020;11:CD003678. PMID: 15266496; PMCID: PMC6984629 29. Georgiou EX, Melo P , Baker PE, Sallam HN, Arici A, Garcia-Velasco JA et al (2019) Long-term GnRH agonist therapy before in vitro fertilisation (IVF) for improving fertility outcomes in women with endometriosis. Cochrane Database Syst Rev 2019(11):CD013240. https:// doi. org/ 10. 1002/ 14651 858. CD013 240. pub2 PMID: 31747470; PMCID: PMC6867786 30. Köhler G, Faustmann TA, Gerlinger C, Seitz C, Mueck AO (2010) A dose- ranging study to determine the efficacy and safety of 1, 2, and 4 mg of dienogest daily for endometriosis. Int J Gynaecol Obstet 108(1):21–25. https:// doi. org/ 10. 1016/j. ijgo. 2009. 08. 020 Erratum in: Int J Gynaecol Obstet. 2011;112(3):257. PMID: 19819448 31. Grandi G, Mueller M, Bersinger NA, Cagnacci A, Volpe A, McKinnon B (2016) Does dienogest influence the inflammatory response of endome- triotic cells? A systematic review. Inflamm Res 65(3):183–192. https:// doi. org/ 10. 1007/ s00011- 015- 0909-7 Epub 2015 Dec 9. PMID: 26650031 32. Muller V, Kogan I, Yarmolinskaya M, Niauri D, Gzgzyan A, Aylamazyan E (2017) Dienogest treatment after ovarian endometrioma removal in infer- tile women prior to IVF. Gynecol Endocrinol 33(sup1):18–21 33. Tamura H, Yoshida H, Kikuchi H, Josaki M, Mihara Y, Shirafuta Y et al (2019) The clinical outcome of Dienogest treatment followed by in vitro fertilization and embryo transfer in infertile women with endometriosis. J Ovarian Res 12(1):123. https:// doi. org/ 10. 1186/ s13048- 019- 0597-y PMID: 31831028; PMCID: PMC6909621 34. Vercellini P , Somigliana E, Vigano P , Abbiati A, Barbara G, Crosignani PG (2009) Surgery for endometriosis-associated infertility: a pragmatic approach. Hum Reprod 24(2):254–269. https:// doi. org/ 10. 1093/ humrep/ den379 Epub 2008 Oct 23. PMID: 18948311 35. Duffy JM, Arambage K, Correa FJ, Olive D, Farquhar C, Garry R et al (2014) Laparoscopic surgery for endometriosis. Cochrane Database Syst Rev (4):CD011031. https:// doi. org/ 10. 1002/ 14651 858. CD011 031. pub2 Update in: Cochrane Database Syst Rev. 2020;10:CD011031. PMID: 24696265 36. Healey M, Ang WC, Cheng C (2010) Surgical treatment of endometriosis: a prospective randomized double-blinded trial comparing excision and ablation. Fertil Steril 94(7):2536–2540. https:// doi. org/ 10. 1016/j. fertn stert. 2010. 02. 044 Epub 2010 Mar 31. PMID: 20356588 37. Chapron C, Marcellin L, Borghese B, Santulli P (2019) Rethinking mecha- nisms, diagnosis and management of endometriosis. Nat Rev Endocrinol 15(11):666–682. https:// doi. org/ 10. 1038/ s41574- 019- 0245-z Epub 2019 Sep 5. PMID: 31488888 38. Maheux-Lacroix S, Nesbitt-Hawes E, Deans R, Won H, Budden A, Adamson D et al (2017) Endometriosis fertility index predicts live births following surgical resection of moderate and severe endometriosis. Hum Reprod 32(11):2243–2249. https:// doi. org/ 10. 1093/ humrep/ dex291 PMID: 29040471 39. Giampaolino P , Della Corte L, Saccone G, Vitagliano A, Bifulco G, Calagna G et al (2019) Role of ovarian suspension in preventing postsurgical ovarian adhesions in patients with stage III-IV pelvic endometriosis: a systematic review. J Minim Invasive Gynecol 26(1):53–62. https:// doi. org/ 10. 1016/j. jmig. 2018. 07. 021 Epub 2018 Aug 6. PMID: 30092363 40. Mircea O, Puscasiu L, Resch B, Lucas J, Collinet P , von Theobald P et al (2016) Fertility outcomes after ablation using plasma energy versus cys- tectomy in infertile women with ovarian endometrioma: a multicentric comparative study. JJ Minim Invasive Gynecol 23(7):1138–1145. https:// doi. org/ 10. 1016/j. jmig. 2016. 08. 818 Epub 2016 Aug 20. PMID: 27553184 41. Hogg S, Vyas S (2018) Endometriosis update. Obstet Gynaecol Reprod Med 28(3):61–69 42. Opøien HK, Fedorcsak P , Åbyholm T, Tanbo T (2011) Complete surgical removal of minimal and mild endometriosis improves outcome of subse- quent IVF/ICSI treatment. Reprod Biomed Online 23(3):389–395. https:// doi. org/ 10. 1016/j. rbmo. 2011. 06. 002 Epub 2011 Jun 15. PMID: 21764382 43. Bianchi PHM, Pereira RMA, Zanatta A, Alegretti JR, Motta ELA, Serafini PC (2009) Extensive excision of deep infiltrative endometriosis before in vitro fertilization significantly improves pregnancy rates. J Minim Invasive Page 11 of 12 Vatsa and Sethi Middle East Fertil Soc J (2021) 26:36 Gynecol 16(2):174–180. https:// doi. org/ 10. 1016/j. jmig. 2008. 12. 009 Erra- tum in: J Minim Invasive Gynecol. 2009;16(5):663. PMID: 19249705 44. Papaleo E, Ottolina J, Viganò P , Brigante C, Marsiglio E, De Michele F et al (2011) Deep pelvic endometriosis negatively affects ovarian reserve and the number of oocytes retrieved for in vitro fertilization: pelvic endome- triosis and ovarian reserve. Acta Obstet Gynecol Scand 90(8):878–884. https:// doi. org/ 10. 1111/j. 1600- 0412. 2011. 01161.x Epub 2011 Jun 14. PMID: 21542809 45. Centini G, Afors K, Murtada R, Argay IM, Lazzeri L, Akladios CY et al (2016) Impact of laparoscopic surgical management of deep endometriosis on pregnancy rate. J Minim Invasive Gynecol 23(1):113–119. https:// doi. org/ 10. 1016/j. jmig. 2015. 09. 015 Epub 2015 Sep 30. PMID: 26427703 46. Bendifallah S, Roman H, Mathieu d’Argent E, Touleimat S, Cohen J, Darai E et al (2017) Colorectal endometriosis-associated infertility: should surgery precede ART? Fertil Steril 108(3):525–531.e4. https:// doi. org/ 10. 1016/j. fertn stert. 2017. 07. 002 Epub 2017 Aug 12. PMID: 28807397 47. Benschop L, Farquhar C, van der Poel N, Heineman MJ (2010) Interven- tions for women with endometrioma prior to assisted reproductive technology. Cochrane Database Syst Rev (11):CD008571. https:// doi. org/ 10. 1002/ 14651 858. CD008 571. pub2 PMID: 21069706 48. Liang Y, Yang X, Lan Y, Lei L, Li Y, Wang S (2019) Effect of Endometrioma cystectomy on cytokines of follicular fluid and IVF outcomes. J Ovarian Res 12(1):98. https:// doi. org/ 10. 1186/ s13048- 019- 0572-7 PMID: 31639028; PMCID: PMC6802315 49. Maignien C, Santulli P , Bourdon M, Korb D, Marcellin L, Lamau M-C et al (2020) Deep infiltrating endometriosis: a previous history of surgery for endometriosis may negatively affect assisted reproductive technology outcomes. Reprod Sci 27(2):545–554. https:// doi. org/ 10. 1007/ s43032- 019- 00052-1 Epub 2020 Jan 6. PMID: 32046438 50. Kuroda K, Ikemoto Y, Ochiai A, Ozaki R, Matsumura Y, Nojiri S et al (2019) Combination treatment of preoperative embryo cryopreservation and endoscopic surgery (surgery-ART hybrid therapy) in infertile women with diminished ovarian reserve and uterine myomas or ovarian endometrio- mas. J Minim Invasive Gynecol 26(7):1369–1375. https:// doi. org/ 10. 1016/j. jmig. 2019. 02. 008 Epub 2019 Feb 19. PMID: 30794888 51. Werbrouck E, Spiessens C, Meuleman C, D’Hooghe T (2006) No differ- ence in cycle pregnancy rate and in cumulative live-birth rate between women with surgically treated minimal to mild endometriosis and women with unexplained infertility after controlled ovarian hyperstimu- lation and intrauterine insemination. Fertil Steril 86(3):566–571. https:// doi. org/ 10. 1016/j. fertn stert. 2006. 01. 044 PMID: 16952506 52. Benaglia L, Somigliana E, Santi G, Scarduelli C, Ragni G, Fedele L (2011) IVF and endometriosis-related symptom progression: insights from a prospective study. Hum Reprod 26(9):2368–2372. https:// doi. org/ 10. 1093/ humrep/ der208 Epub 2011 Jun 29. PMID: 21715451 53. Nuojua-Huttunen S (1999) Intrauterine insemination treatment in subfer- tility: an analysis of factors affecting outcome. Hum Reprod 14(3):698– 703. https:// doi. org/ 10. 1093/ humrep/ 14.3. 698 PMID: 10221698 54. Hughes EG (1997) The effectiveness of ovulation induction and intrauter- ine insemination in the treatment of persistent infertility: a meta-analysis. Hum Reprod 12(9):1865–1872. https:// doi. org/ 10. 1093/ humrep/ 12.9. 1865 PMID: 9363697 55. Keresztúri A, Kozinszky Z, Daru J, Pásztor N, Sikovanyecz J, Zádori J et al (2015) Pregnancy rate after controlled ovarian hyperstimulation and intrauterine insemination for the treatment of endometriosis following surgery. Biomed Res Int 2015:282301. https:// doi. org/ 10. 1155/ 2015/ 282301 Epub 2015 Jul 12. PMID: 26247014; PMCID: PMC4515270 56. Tummon IS, Asher LJ, Martin JSB, Tulandi T (1997) Randomized controlled trial of superovulation and insemination for infertility associated with minimal or mild endometriosis. Fertil Steril 68(1):8–12. https:// doi. org/ 10. 1016/ s0015- 0282(97) 81467-7 PMID: 9207576 57. Guzick DS, Carson SA, Coutifaris C, Overstreet JW, Factor-Litvak P , Steinkampf MP et al (1999) Efficacy of superovulation and intrauterine insemination in the treatment of infertility. N Engl J Med 340(3):177–183. https:// doi. org/ 10. 1056/ NEJM1 99901 21340 0302 PMID: 9895397 58. van der Houwen LEE, Schreurs AMF, Schats R, Heymans MW, Lambalk CB, Hompes PGA et al (2014) Efficacy and safety of intrauterine insemina- tion in patients with moderate-to-severe endometriosis. Reprod Biomed Online 28(5):590–598. https:// doi. org/ 10. 1016/j. rbmo. 2014. 01. 005 Epub 2014 Jan 27. PMID: 24656562 59. Senapati S, Sammel MD, Morse C, Barnhart KT (2016) Impact of endome- triosis on in vitro fertilization outcomes: an evaluation of the Society for Assisted Reproductive Technologies Database. Fertil Steril 106(1):164– 171.e1. https:// doi. org/ 10. 1016/j. fertn stert. 2016. 03. 037 Epub 2016 Apr 7. PMID: 27060727; PMCID: PMC5173290 60. González-Comadran M, Schwarze JE, Zegers-Hochschild F, Souza MDCB, Carreras R, Checa MÁ (2017) The impact of endometriosis on the outcome of Assisted Reproductive Technology. Reprod Biol Endocrinol 15(1):8. https:// doi. org/ 10. 1186/ s12958- 016- 0217-2 PMID: 28118836; PMCID: PMC5260022 61. Barbosa MAP , Teixeira DM, Navarro PAAS, Ferriani RA, Nastri CO, Martins WP (2014) Impact of endometriosis and its staging on assisted reproduc- tion outcome: systematic review and meta-analysis: impact of endome- triosis on assisted reproduction outcome. Ultrasound Obstet Gynecol 44(3):261–278. https:// doi. org/ 10. 1002/ uog. 13366 Epub 2014 Aug 13. PMID: 24639087 62. Pabuccu R, Onalan G, Kaya C (2007) GnRH agonist and antagonist proto- cols for stage I–II endometriosis and endometrioma in in vitro fertiliza- tion/intracytoplasmic sperm injection cycles. Fertil Steril 88(4):832–839. https:// doi. org/ 10. 1016/j. fertn stert. 2006. 12. 046 Epub 2007 Apr 10. PMID: 17428479 63. Kolanska K, Cohen J, Bendifallah S, Selleret L, Antoine J-M, Chabbert- Buffet N et al (2017) Pregnancy outcomes after controlled ovarian hyperstimulation in women with endometriosis-associated infertility: GnRH-agonist versus GnRH-antagonist. J Gynecol Obstet Hum Reprod 46(9):681–686. https:// doi. org/ 10. 1016/j. jogoh. 2017. 09. 007 Epub 2017 Sep 29. PMID: 28970135 64. Zhao F, Lan Y, Chen T, Xin Z, Liang Y, Li Y et al (2020) Live birth rate comparison of three controlled ovarian stimulation protocols for in vitro fertilization-embryo transfer in patients with diminished ovarian reserve after endometrioma cystectomy: a retrospective study. J Ovarian Res 13(1):23. https:// doi. org/ 10. 1186/ s13048- 020- 00622-x PMID: 32113477; PMCID: PMC7049193 65. Drakopoulos P , Rosetti J, Pluchino N, Blockeel C, Santos-Ribeiro S, de Brucker M et al (2018) Does the type of GnRH analogue used, affect live birth rates in women with endometriosis undergoing IVF/ICSI treatment, according to the rAFS stage? Gynecol Endocrinol 34(10):884–889. https:// doi. org/ 10. 1080/ 09513 590. 2018. 14603 46 Epub 2018 Apr 12. PMID: 29648476 66. Bourdon M, Santulli P , de Ziegler D, Gayet V, Maignien C, Marcellin L et al (2017) Does GnRH agonist triggering control painful symptom scores during assisted reproductive technology? A retrospective study. Reprod Sci 24(9):1325–1333. https:// doi. org/ 10. 1177/ 19337 19116 687659 Epub 2017 Jan 5. PMID: 28056703 67. Boucret L, Bouet P-E, Riou J, Legendre G, Delbos L, Hachem HE et al (2020) Endometriosis lowers the cumulative live birth rates in IVF by decreasing the number of embryos but not their quality. J Clin Med 9(8):2478. https:// doi. org/ 10. 3390/ jcm90 82478 PMID: 32752267; PMCID: PMC7464781 68. Niu Z, Chen Q, Sun Y, Feng Y (2013) Long-term pituitary downregula- tion before frozen embryo transfer could improve pregnancy outcomes in women with adenomyosis. Gynecol Endocrinol 29(12):1026–1030. https:// doi. org/ 10. 3109/ 09513 590. 2013. 824960 Epub 2013 Sep 5. PMID: 24006906 69. Komsky-Elbaz A, Raziel A, Friedler S, Strassburger D, Kasterstein E, Komarovsky D et al (2013) Conventional IVF versus ICSI in sibling oocytes from couples with endometriosis and normozoospermic semen. J Assist Reprod Genet 30(2):251–257. https:// doi. org/ 10. 1007/ s10815- 012- 9922-8 Epub 2012 Dec 28. PMID: 23271211; PMCID: PMC3585678 70. Wu J, Yang X, Huang J, Kuang Y, Wang Y (2019) Fertility and neonatal outcomes of freeze-all vs. fresh embryo transfer in women with advanced endometriosis. Front Endocrinol (Lausanne) 10:770. https:// doi. org/ 10. 3389/ fendo. 2019. 00770 PMID: 31787933; PMCID: PMC6856047 71. Yilmaz N, Ceran MU, Ugurlu EN, Gulerman HC, Ustun YE (2021) Impact of endometrioma and bilaterality on IVF / ICSI cycles in patients with endometriosis. J Gynecol Obstet Hum Reprod 50(3):101839. https:// doi. org/ 10. 1016/j. jogoh. 2020. 101839 Epub 2020 Jun 30. PMID: 32619727 72. Santulli P , Bourdon M, Presse M, Gayet V, Marcellin L, Prunet C et al (2016) Endometriosis-related infertility: assisted reproductive technol- ogy has no adverse impact on pain or quality-of-life scores. Fertil Steril Page 12 of 12Vatsa and Sethi Middle East Fertil Soc J (2021) 26:36 105(4):978–987.e4. https:// doi. org/ 10. 1016/j. fertn stert. 2015. 12. 006 Epub 2015 Dec 30. PMID: 26746132 73. Practice Committee of the American Society for Reproductive Medicine (2012) Endometriosis and infertility: a committee opinion. Fertil Steril 98(3):591–598. https:// doi. org/ 10. 1016/j. fertn stert. 2012. 05. 031 Epub 2012 Jun 15. PMID: 22704630 74. Kuznetsov L, Dworzynski K, Davies M, Overton C, Guideline Committee (2017) Diagnosis and management of endometriosis: summary of NICE guidance. BMJ 358:j3935. https:// doi. org/ 10. 1136/ bmj. j3935 Erratum in: BMJ. 2017;358:j4227. PMID: 28877898 75. Cobo A, Giles J, Paolelli S, Pellicer A, Remohí J, García-Velasco JA (2020) Oocyte vitrification for fertility preservation in women with endometrio- sis: an observational study. Fertil Steril 113(4):836–844. https:// doi. org/ 10. 1016/j. fertn stert. 2019. 11. 017 Epub 2020 Mar 4. PMID: 32145929 Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations.