{"paper_id":"2110a79f-bc04-48fd-ab4d-0ff3cd4c6633","body_text":"Katta et al. Middle East Fertility Society Journal           (2024) 29:27  \nhttps://doi.org/10.1186/s43043-024-00189-3\nREVIEW Open Access\n© The Author(s) 2024. 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://creativecommons.org/licenses/by/4.0/.\nMiddle East Fertility\nSociety Journal\nImpact of treatment interventions \nof endometriomas prior to in vitro fertilization: \na systematic review and meta-analysis\nMaha Katta1, Ahmed M. Maged2*  , Asmaa I. Ogila2 and Wael S. Ragab3 \nAbstract \nBackground Treatment of endometrioma before in vitro fertilization (IVF) is challenging as it may affect ovarian \nresponse to induction.\nObjective A systematic review to search for the available optimal management of ovarian endometrioma \nbefore ovulation induction in IVF.\nSearch strategy Screening of the MEDLINE, Web of Science, EMBASE, Cochrane database, and the clinical trial \nregistration sites, covering the period from their inception up to June 2023 was done by two reviewers independently \nusing the keywords ovarian endometrioma, ovarian endometriosis, endometrioma/surgery, endometrioma/hormonal \ntreatment, randomized controlled trial(s), case-controlled studies, and cohort studies.\nSelection criteria All types of studies were included. Participants included were women with unilateral or bilateral \novarian endometriomas candidate for IVF/ICSI. We included 18 studies in the review. Three studies were randomized \ncontrolled parallel studies, six were prospective cohort, and nine were retrospective cohort studies.\nData collection and analysis Data from all included studies were extracted by two authors (A. M., A. O.) indepen-\ndently. Data extracted included sample size, population characteristics including age, BMI, duration of infertility, ovar-\nian reserve markers, cyst size, and bilaterality and induction protocol used.\nMain results We found 18 studies. Women with untreated endometrioma had significantly higher numbers \nof MII oocytes (the mean difference (MD) effect estimate was − 0.53 with [− 1.04, − 0.01] 95% CI and 0.04 P-value), \nhigher number of obtained embryos (MD effect estimate was − 0.25 with [− 0.38, − 0.11] 95%CI and < 0.001 P-value), \nand required lower doses of gonadotropins for induction (MD effect estimate was 361.14 with [168.13, 5554.15] 95% \nCI and < 0.001 P-value) compared to those who had undergone surgical management of endometrioma. How-\never, live birth (OR effect estimate was 0.79 with [0.54, 1.18] 95% CI and 0.25 P-value), clinical pregnancy (OR effect \nestimate was 0.95 with [0.72, 1.26] 95% CI and 0.73 P-value), miscarriage (OR effect estimate was 0.74 with [0.33, \n1.63] 95% CI and 0.45 P-value), cancellation rates (OR effect estimate was 1.62 with [0.57, 4.66] 95% CI and 0.37 \nP-value), and the duration of stimulation (MD effect estimate was 0.19 with [− 0.42, − 0.81] 95% CI and 0.54 P-value) \ndid not show any significant difference between the two groups of women. Hormonal treatment of endome-\ntrioma was associated with higher ongoing pregnancy rate (OR effect estimate was 3.39 with [1.83, 6.26] 95% CI \nand < 0.001 P-value), higher clinical pregnancy rate (OR effect estimate was 3.36 with [2.01, 5.63] 95% CI and < 0.001 \nP-value), and higher numbers of MII oocytes (MD effect estimate was 2.04 with [0.72, 3.36] 95% CI and 0.003 P-value) \n*Correspondence:\nAhmed M. Maged\nprof.ahmedmaged@gmail.com; ahmedmaged@cu.edu.eg\nFull list of author information is available at the end of the article\n\nPage 2 of 15Katta et al. Middle East Fertility Society Journal           (2024) 29:27 \nwhen compared to women who did not receive such therapy. These effects were evident in treatment with GnRH \nagonists, OCPs (oral contraceptive pills), and dienogest, while the miscarriage and cycle cancellation rates did \nnot show these differences.\nConclusions The optimal approach for treating endometrioma prior to IVF is not clear yet due to lack of well-\ndesigned randomized controlled trials.\nRegistration number CRD42020151736.\nKeywords Ovarian endometrioma, Ovarian endometriosis, Endometrioma/surgery, Endometrioma/hormonal \ntreatment, Endometrioma/GnRH agonist, Endometrioma/aspiration, Endometrioma/laparoscopy, IVF outcome\nIntroduction\nEndometriosis is a benign gynecological pathology char -\nacterized by the existence of endometrium outside the \nuterine cavity and was commonly diagnosed by surgery \n[1]. Recently, ESHRE in 2022 stated that diagnosis of \nendometriosis with laparoscopy showed to be restricted \nto only to those with negative different imaging find -\nings, and women with failed empirical treatment and the \ngroup stated that laparoscopy is no longer considered \nas the gold standard for diagnosis of endometriosis [2]. \nEndometriosis is an estrogen-dependent chronic inflam -\nmatory pathology that affects between 10 and 15% of \nwomen during their childbearing period. It is commonly \nassociated with pain, infertility [3, 4], chronic stress, and \nanxiety [5]. Difficult conception is observed in 30 to 50% \nof women diagnosed with endometriosis [6], and many \nof them are trying to conceive through different assisted \nreproductive techniques [7].\nUnfortunately, the pathogenesis of endometriosis \nassociated with infertility remains unclear. Endome -\ntriosis causes infertility through various mechanisms: \ndistortion of the normal pelvic anatomy, scarring of \nthe fallopian tubes, inflammation of different pelvic \norgans with adhesion formation, alteration of immune \nresponse and hormonal environment of ova, impair -\nment of implantation of a pregnancy, and alteration of \noocytes quality [8]. Various inflammatory changes have \nbeen proposed to be the reasons behind endometriosis-\nassociated infertility including alteration of macrophages \nproliferation and its phagocytic activity, increasing the \nnumbers of malfunctioning natural killer cells and T \nlymphocytes with enhancement of proinflammatory \nand angiogenic cytokines release [9, 10]. Ovarian endo -\nmetrioma decreases the volume of functioning ovarian \ntissue through its space-occupying action and/or the \nlocal inflammatory and immune reactions or both. This \nreduction in functioning ovarian tissue is aggravated \nby surgery. Clinical examination has low sensitivity and \nspecificity for diagnosis of endometriosis, and laparos -\ncopy remains the gold standard for diagnosis; however, \nrecent studies look promising for new sonographic and \nmagnetic resonance imaging (MRI) techniques [11].\nEndometrioma could be managed by either medical \nor surgical modalities, and both affect the reproductive \npotential of the women. Women should be counselled \nabout behavioral changes that creates optimum patients’ \ncharacteristics and healthy lifestyle before they started \nmedical and/or surgical treatments. One of these is the \nmaintenance of ideal body weight to decrease the endo -\nmetriosis cancer risk and to improve the success of IVF \n[2]. The best management of endometriomas before \nstarting IVF/ICSI trial is unknown. Medical treatment \nfor endometrioma includes mainly hormonal therapy \nwith progestogens, combined oral contraceptives, aro -\nmatase enzyme inhibitors, and gonadotropin-releasing \nhormone analogues. Their mode of action depends on \ntheir ability to decrease ovarian activity [12]. Surgical \ntreatment includes cyst aspiration, laparoscopic ovar -\nian cystectomy, ovarian cystectomy via laparotomy, or \nrobotic surgery. Laparoscopic management is currently \nthe most accepted approach being associated with lower \ncosts and faster recovery compared to other approaches \n[13]. The aim of current review is to evaluate the impact \nof medical and surgical interventions to endometriomas \nprior to IVF-ET as there was no similar review to assess \nthe effects of different treatment modalities of ovarian \nendometriomas on IVF outcomes.\nMethodology\nThis study protocol was prospectively registered follow -\ning the guidelines of the Preferred Reporting Items for \nSystematic reviews and Meta-Analyses (PRISMA) with \nCRD42020151736 number.\nResearch question\n• Population: Women with unilateral or bilateral ovar -\nian endometrioma\n• Intervention: Surgical (including cystectomy and \naspiration) and medical (including GnRH, progester -\n\nPage 3 of 15\nKatta et al. Middle East Fertility Society Journal           (2024) 29:27 \n \none, and aromatase inhibitors) management of endo-\nmetrioma before IVF\n• Comparison: Surgical treatment and medical treat -\nment compared to no intervention\n• Outcome: Outcomes of IVF cycles\nIn this systematic review, the following databases: \nMEDLINE, Web of Science, Embase, Cochrane Library, \nand the clinical trial registry were searched from incep -\ntion up to June 2023. The search used the keywords \nas follows: endometriosis; endometrioma, ovarian \nendometriosis, and ovarian endometrioma; ovarian \nendometriosis; endometriotic ovarian cyst; endome -\ntrioma/surgery; endometrioma/hormonal treatment, \nGnRH agonist, letrozole, aromatase inhibitors, OCPs \n(oral contraceptive pills)), IVF/ICSI, and in  vitro fer -\ntilization; intracytoplasmic sperm injection; assisted \nreproductive technologies; ART; oocytes; live birth; \nfertilization; and live birth rate, pregnancy rate, miscar -\nriage rate, number of oocytes, cancellation rate, rand -\nomized controlled trial(s), case-controlled studies, and \ncohort studies. As only few randomized controlled tri -\nals were available, the authors agreed to include other \ntypes of studies as case controlled and cohort studies \nwhether prospective or retrospective. Review articles \nand case reports, editorial opinion, and commentary \nwere excluded. We analyzed the references and cita -\ntions of all available studies (both primary and sec -\nondary), narrative and systematic reviews, abstracts of \ngynecology, and infertility seminars. We emailed the \nauthors directly for any missing or unclear informa -\ntion. If necessary, all studies written in English compar -\ning different surgical and medical modalities against no \ntreatment or other modalities were included. Surgical \nmodalities include laparoscopic cystectomy, open cys -\ntectomy, or cyst aspiration. Medical modalities include \nprogestogens, aromatase inhibitors, GnRH agonists, or \noral contraceptive pills (OCPs).\nCystectomy is the stripping of the cyst wall away from \nthe healthy ovarian tissues through either laparoscopy \nor laparotomy. Aspiration procedure is the transvaginal \naspiration of the cyst content guided by ultrasound. Med-\nical treatment acts through antagonizing estrogen secre -\ntion and/or action.\nTwo authors (A. O. and A. M.) independently assessed \nthe titles, abstracts, and the full articles and then \nextracted the data of the included studies, and disa -\ngreements were discussed further with other authors. \nExtracted data included study type, settings, participants \ncharacteristics, details of intervention, and outcome \nparameters.\nThe risk of bias was assessed using the Cochrane Hand-\nbook of Systematic Reviews recommendations for the \n3 RCTs [14]. These recommendations include random \nsequence generation, allocation concealment, partici -\npants and outcome assessors blinding, incomplete data of \noutcomes, selective reporting, and other biases.\nThe outcome parameters of this review included live \nbirth, clinical pregnancy, miscarriage, cancellation rates, \nnumber of MII follicles, duration of stimulation, total \ndose of gonadotropin used for induction, and number of \nobtained embryos.\nStatistical analysis\nFor analysis of continuous and dichotomous data, the \nmean difference and odd ratio with 95% confidence inter-\nval (CI) analysis were used, respectively. The random \neffect model was used to calculate the effect size, and I 2 \nstatistic and Cochran’s Q test were calculated to evalu -\nate the studies heterogeneity. Significant P-value was \nconsidered when < 0.05, and significant I 2 was consid -\nered when > 40%. Analyses were done using the Review \nManager (RevMan) version 5.4.1 (The Nordic Cochrane \nCentre, Cochrane Collaboration, 2020, Copenhagen, \nDenmark).\nResults\nThe PRISMA flow chart is shown in Fig. 1.\nStudy characteristics\nTable  1 describes the characteristics of the included \nstudies.\nEighteen studies were included in this review [15–32]. \nFive were conducted in Turkey [15, 16, 18, 25, 26], 3 in \nJapan [19, 27, 28], and 1 in each of the following coun -\ntries: Canada [31], China [21], Denmark [22], Egypt [23], \nFrance [32], Italy [30], Russia [24], Spain [17], South \nKorea [20], and the USA [29]. Three studies were RCTs \n[16, 23, 26], six were prospective cohort [21, 22, 24, 25, \n30, 32], and nine were retrospective cohort studies [15, \n17–20, 27–29, 31]. All were single center except three tri-\nals [17, 31, 32] that were conducted in two centers. Six \nstudies compared laparoscopic surgery to no treatment \n[16–19, 21, 27], five compared surgery to no treatment \n[15, 20, 25, 26, 29], and three compared cyst aspiration to \nno treatment [20, 25, 27]. Medical treatment was GnRH \nin two studies [23, 24], OCPs in one study [15], and dien -\nogest in one study [24], while aromatase inhibitors were \nstudied in two trials [22, 31].\nRisk of bias of included studies\nRisk of bias in the three RCTs is described in Table 2. The \nrisk of bias for non-RCTs was evaluated using the New -\ncastle–Ottawa scale (Table 3).\n\nPage 4 of 15Katta et al. Middle East Fertility Society Journal           (2024) 29:27 \nSynthesis of results\nEighteen studies with 3063 participants were included in \nour review.\nSurgical intervention versus no treatment\nLive birth rate was evaluated in 4 studies (565 par -\nticipants). The OR effect estimate was 0.79 with [0.54, \n1.18] 95% CI and 0.25 P -value (Fig. 2 ).\nClinical pregnancy rate was evaluated in 11 studies \n(1447 participants). The OR effect estimate was 0.95 \nwith [0.72, 1.26] 95% CI and 0.73 P -value (Fig. 3 ).\nMiscarriage rate was evaluated in 6 studies (333 par -\nticipants). The OR effect estimate was 0.74 with [0.33, \n1.63] 95% CI and 0.45 P -value (Figure S1).\nCycle cancellation rate was evaluated in 4 studies \n(551 participants). The OR effect estimate was 1.62 with \n[0.57, 4.66] 95% CI and 0.37 P -value (Figure S2).\nNumber of MII oocytes was evaluated in 11 studies \n(1475 participants). The mean difference (MD) effect \nestimate was − 0.53 with [−  1.04, − 0.01] 95% CI and \n0.04 P-value (Figure S3).\nNumber of obtained embryos was evaluated in 4 stud -\nies (569 participants). The MD effect estimate was − 0.25 \nwith [− 0.38, − 0.11] 95% CI and < 0.001 P-value (Figure \nS4).\nDuration of stimulation was evaluated in 6 studies \n(881 participants). The MD effect estimate was 0.19 with \n[− 0.42, 0.81] 95% CI and 0.54 P-value (Figure S5).\nThe total dose of gonadotropins was evaluated in 9 \nstudies (1255 participants). The MD effect estimate was \n361.14 with [168.13, 554.15] 95% CI and < 0.001 P-value \n(Figure S6).\nFig. 1 Prisma flow chart\n\nPage 5 of 15\nKatta et al. Middle East Fertility Society Journal           (2024) 29:27 \n \nTable 1 Characteristics of the included studies\nStudy Settings Design Size Participants Intervention Outcome\nCandiani (2020) Single center, Italy Prospective cohort 142 Inclusion criteria\n○ Previous surgery for unilateral\nor bilateral endometriomas > 3 cm\nExclusion criteria\n• Age ≥ 40 years\n• Previous bilateral ovarian surgery\nor more at the time of surgery\n• Previous salpingectomy or\nhysterectomy\n• Follow-up < 12 months\n2 arms\ngroup 1: patients underwent \na standardized laparoscopic stripping \ntechnique\ngroup 2: patients underwent cyst co2 \nlaser vaporization\nPostoperative pregnancy rate (sponta-\nneous or assisted)\nIdentification of independent predic-\ntors of pregnancy\nCanton (2018) 2 centers, Canada Retrospective cohort 126 Inclusion criteria\n• Age 21–39 years\n• Ground-glass cysts persistent \nfor at least 3 months and not enlarg-\ning\n• Previous IVF failed cycle with frozen \nembryo transfers\nExclusion criteria\n• Hydrosalpinges\n• Intracavitary lesion\n• Severe male factor\n• Previous surgery for endometriosis\n• First IVF cycle\n• Lack of an endometrioma\n2 arms\n• Group 1 received 3.75-mg intramus-\ncular depo-leuprolide treatment alone \nfor 60 days\n• Group 2 received 5 mg of oral \nletrozole daily beside leuprolide \nwith the same regimen and duration\nCPR\nLBR\nAFC\nLargest mean endometrioma diameter\nTotal Gn dose\nNo. of mature oocytes retrieved\nNo. of pronuclear (2PN)\nembryos\nNo. of blastocysts\nDemirdag (2021) [15] Single center, Turkey Retrospective cohort 179 P\n259 C\nInclusion criteria\n• History of ovarian endometrioma \nbefore the IVF/ICSI cycle\nExclusion criteria\n• Polycystic ovarian syndrome\n• Male factor infertility\n• Thaw cycles\n3 arms\n• Group 1 (n = 81): Previous endome-\ntrioma surgery\n• Group 2 (n = 98): Non-operated \nendometrioma\n• Group 3 (n = 1757): Other infertility \ncauses as unexplained and tubal fac-\ntor infertility without\nendometrioma\nCPR\nLBR\nAFC, NOR\nE2 levels on the day of hCG trigger\nTotal Gn dose\nCancellation rates\nDemirol (2006) [16] Single center, Turkey RCT 99 Inclusion criteria\n• Single or multiple\n• Unilateral ovarian endometriomas \nbetween •\n3 and 6 cm referred to ICSI\nExclusion criteria\n• Bilateral endometrioma\n• Patients with laparoscopic suturing\n2 arms\n○ Group 1 (n = 49) underwent con-\nservative\n○\novarian surgery before ICSI\n• Group 2 (n = 50) underwent ICSI \ndirectly\nStimulation duration\nPeak E2 level\nNo. of mature oocytes retrieved\nFR\nIR\nCPR\n\nPage 6 of 15Katta et al. Middle East Fertility Society Journal           (2024) 29:27 \nTable 1 (continued)\nStudy Settings Design Size Participants Intervention Outcome\nDeZiegler (2010) 2 centers, France Prospective cohort 60 Endometriosis was diagnosed \neither surgically or by ultrasound\n4 arms\n• Group 1 (n = 540) received OCP0 \n.03 mg of EE and 0.125 mg of LNG \nbefore ART for 6 to 8 weeks subdi-\nvided to endometriosis (n = 114, 29 \nendometrioma) and control (n = 426)\n• Group 1 (n = 255) received no OC \npretreatment subdivided to endo-\nmetriosis (n = 172, 31 endometrioma) \nand control (n = 83)\nCPR\nNo. of mature oocytes retrieved\nNo. of embryos\nGarcia-Velasco (2004) \n[17]\n2 centers, Spain Retrospective cohort 189 P\n210 C\nInclusion criteria\n• Ovarian endometriomas underwent \nIVF-ET cycles\nExclusion criteria\n• Any other known infertility factor \nbesides endometriosis\n2 arms\n• Study group (n = 133 women, 147 \ncycles): Previous laparoscopic cystec-\ntomy for an ovarian endometrioma\n• Control group (n = 56 women, \n63 cycles): Non-operated ovarian \nendometrioma(s)\nNo. of oocytes retrieved\nNo. of mature oocytes\nNo. of embryos\nFR\nIR\nCPR\nMPR\nChPR\nMiscarriage rate\nCancellation rate\nGuler (2017) [18] Single center, Turkey Retrospective ohort 150 P\n257 C\nExclusion criteria\nUnexplained infertility without endo-\nmetriosis, endometriosis-related tubal \nfactor, male factor infertility\n• Previous laparotomy or oophorec-\ntomy for endometrioma\n• Recurrent endometrioma\n4 arms\n257 ICSI cycles of 150 patients\n• Group 1 (n = 84 women, 91 cycles): \nMinimal endometriosis\n• Group 2 (n = 25 women, 57 cycles): \nEndometrioma removal\n• Group 3 (n = 53 women, 65 cycles): \nNon-operated endometrioma\nGroup 4 (n = 24 women, 44 cycles): \nTubal factor infertility\nCPR\nLBR\nTotal Gn dose\nNo. of oocytes retrieved\nStimulation duration\nKuroda (2009)[19] Single center, Japan Retrospective cohort 61 P\n97 C\nInclusion criteria\n• Women with endometriosis or endo-\nmetrioma\nExclusion criteria\nWomen with more than 4 IVF/ICSI \ncycles\n4 arms\n• Group A (n = 31 cycles): Unoperated \nendometrioma\n• Group B (n = 51 cycles): Postoperative\n• endometrioma\n• Group C (n = 15 cycles): No endo-\nmetrioma\nGroup D (n = 27 cycles): Tubal infertil-\nity\nNo. of oocytes retrieved\nFR\nCancellation rate\nIR\nCPR\nLBR\nMiscarriage rate\n\nPage 7 of 15\nKatta et al. Middle East Fertility Society Journal           (2024) 29:27 \n \nTable 1 (continued)\nStudy Settings Design Size Participants Intervention Outcome\nLee (2014) [20] Single center, Korea Retrospective cohort 101 Inclusion criteria\n• Women with pathologically \nconfirmed previous or current \nendometrioma(s) > 3 cm\n• Age: 20–45 years\n• Normal: 24–35-day ovulatory cycles\n• BMI: 18–25 kg/m2\nExclusion criteria\n• Endocrine abnormalities as diabetes \nmellitus, PCOS, hyperprolactinemia\n• Previous severe OHSS\n• Abnormalities interfering with stimu-\nlation\nPrevious (within 12 months) or current \ndrug or alcohol abuse\n3 arms\n• Resection group (n = 36): Surgical \nresection of endometrioma\n• Aspiration group (n = 29): Transvagi-\nnal endometrioma aspiration\nControl group (n = 36): No surgical \nintervention\nNo. of oocytes retrieved\nNo. of mature oocytes\nNo. of embryos\nTotal Gn dose\nCPR\nLBR\nMPR\nMiscarriage rate\nLiang (2019) [21] Single center, China Prospective cohort 41 Inclusion criteria\n○ Infertility due to stages III or IV \nendometriosis\n• Normal semen analysis\nExclusion criteria\n• Age: ≥ 40 years\n• BMI: ≥ 30 kg/m2\n• FSH: ≥ 12 mIU/mL\n• PCOS\n• Endocrinal disorders (thyroiddisease, \ndiabetes mellitus, and Cushing’s \nsyndrome)\nCycles with contaminated dominant \nFF with blood cycles with the domi-\nnant FF not yielding oocytes\n2 arms\n• Surgery group (n = 13): Surgery \nto remove the endometrioma\nSurgery group (n = 28): Untreated \nbefore IVF\nTotal Gn dose\nNo. of oocytes retrieved\nNo. of MII oocytes FR\nIR\nCPR\n\nPage 8 of 15Katta et al. Middle East Fertility Society Journal           (2024) 29:27 \nTable 1 (continued)\nStudy Settings Design Size Participants Intervention Outcome\nLossl (2009) [22] Single center, Denmark Prospective ohort 20 Inclusion criteria\n○ Ultrasonographic \ndiagnosedendometrioma(s) persisting \nfor three or more cycles between 20 \nand 70 mm and indicated for IVF \nor ICSI\n• Age: 20–39 years\n• Regular: 21–35-day menstrual cycle\n• BMI: 18–30 kg/m2\n• Negative urinary pregnancy test \non treatment day 1\nExclusion criteria\n○ GnRH-agonist treatment withinthe \nlast 3 months\nHistory of osteopenia, hepatic, \nrenal,cardiovascular, or thromboem-\nbolic disorder\n1 arm received goserelin 3.6 mg s \non treatment days 1, 28, and 56 \nand 1 mg of anastrozole from day \n1 to day 69. COH initiated from day \n70ncompared to a standard IVF/\nICSI treatment in 15 women who \nunderwent a previous or subse-\nquent standard cycle, with present \nendometrioma(s)\nEndometrioma volume changes\nSerum CA125 changes\nStimulation duration\nTotal Gn dose\nNo. of oocytes retrieved\nNo. of embryos\nTotal Gn dose\nFR\nIR\nCPR\nLBR\nMiscarriage rate\nMaged (2018) [23] Single center, Egypt RCT 90 Inclusion criteria\n○ Subfertile women indicated for ICSI \nand having a single endometrioma \nof 2–5 cm\n• Normal uterine cavity\nExclusion criteria\n• Bilateral or multiple endometriomas,\n• FSH > 10\n• BMI > 30 kg/m2\n• Age > 40 years\n• Cases who received GnRH \nwithin 12 months of the study\n• Patients who received OCPs or other \nhormones within 3 months\n• Previous surgical resection of endo-\nmetrioma\nSevere male factor\n2 arms\n• Group A (n = 45): Received standard \nlong protocol\nGroup B (n = 45): Received Intramus-\ncular injections of 3.75-mg triptorelin \nevery 28 days for 3 doses followed \nby thestandard long protocol 28 days \nafter the last injection\nCh PR\nCPR\nOngoing PR\nMiscarriage rate ectopic pregnancy\nMPR\n\nPage 9 of 15\nKatta et al. Middle East Fertility Society Journal           (2024) 29:27 \n \nTable 1 (continued)\nStudy Settings Design Size Participants Intervention Outcome\nMuller (2017) [24] Single center, Russia Prospective cohort 144 Inclusion criteria:\n• Age 23–42 years\n• Infertility\n• Surgical treatment of endometrioma\n• ≤ 4 months before enrollment\n• No endometriomas or other ovarian \ncysts at thestart of stimulation\n• FSH < 12.0 IU/L and AMH ≥ 0.5 ng/mL\nExclusion criteria\n• BMI ≥ 30 kg/m2\n• Uterine fibroids ≥ 2 cm in diameter \nand/or deforming the uterine cavity\n• III/IV stage ofadenomyosis\nContraindications to COS or gestation\n3 arms\n○ Group 1 (n = 38): Received 2-mg \ndienogest daily for 6 months \nbefore IVF\n• Group 2 (n = 70): Received 3.75-mg \ntriptorelin every 28 days for six doses \nbefore IVF\n• Group 3 (n = 38): Without any hor-\nmone therapy before IVF\nCPR\nLBR\nTotal Gn dose\nStimulation duration\nNo oocyte retrieved\nCancellation rate\nPabuccu (2004) [25] Single center, Turkey Prospective cohort 171 Inclusion criteria\n• Women candidate for ICSI\n• Normal uterine cavity\nExclusion criteria\n• Thaw cycles\n4 arms\n• Group 1 (n = 41): Aspiration of endo-\nmetriomas and no history of previous \nsurgery\n• Group 2 (n = 40): Nonaspirated \nendometriomas\n• Group 3 (n = 44): History of ovarian \nsurgery for endometriomas in patients \nwithout ovarian endometriomas \nat the beginning of COH\nGroup 4 (n = 46): Tubal factor infertility\nTotal Gn dose\nStimulation duration\nNo MII oocytes\nFR\nIR\nCPR\nMiscarriage rate\nPabuccu (2007) [26] Single center, Turkey RCT 246 Inclusion criteria\n• Women candidate for ICSI\n• Normal uterine cavity\nExclusion criteria\n• Patients with recurrent endometri-\noma or with advanced endometriosis \n(stages III–IV) without endometrioma \nwere excluded from group 1\n• Hydrosalpinx\n• Tuberculosis\n• Male factor infertility\n• Thaw cycles\n3 arms\n○ Group 1 (n = 98): Mild-to-moderate \nendometriosis\n• Group 2 (n = 81): Ovarian surgery \nfor endometrioma\n• Group 3 (n = 67): Non-operated \nendometrioma\nTotal Gn dose\nStimulation duration\nE2 levels on the day of hCG trigger\nNo oocytes retrieved\nNo MII oocytes\nFR\nChPR\nCPR\n\nPage 10 of 15Katta et al. Middle East Fertility Society Journal           (2024) 29:27 \nTable 1 (continued)\nStudy Settings Design Size Participants Intervention Outcome\nSuganuma (2002) \n[27]\nSingle center, Japan Retrospective cohort 79 P\n127 C\nInclusion: Infertile women with endo-\nmetrioma who underwent IVF-ET\n3 arms\n• Surgery group (n = 36 women, \n62 cycles) underwent laparotomy \nor laparoscopy\n• Cyst-aspirated group (n = 23 \nwomen, 35 cycles): Endometrioma \ncontent aspirated under transvagi-\nnal ultrasonic imaging andtreated \nwith or without alcohol fixation\nNo treatment group (n = 20 women, \n30 cycles): Nontreated endometrioma\nRetrieved oocytes, no. of mature \noocytes, fertilization, and pregnancy\nTakashima (2013)[28] Single center, Japan Retrospective cohort 44 Inclusion criteria\n○ Patients who had undergone \nlaparoscopic excision of ovarian endo-\nmetrioma followed by IVF treatment\n• Age 32–40 years\n• BMI 18–25 kg/m2\n• Both ovaries present\n• Menstrual cycle length between 25 \nand 35 days\nExclusion criteria\n• Hormonal treatment within 1 year \nprior to the laparoscopy\n• Previous adnexal surgery\nClinical hyperandrogenism\n2 arms\nWomen who had laparoscopic exci-\nsion for unilateral endometrioma \namong infertile women\n• Group 1 (n = 21): Hemostasis dur-\ning the surgery achieved by coagula-\ntion\n• Group 2 (n = 23): Hemostasis dur-\ning the surgery achieved by suture\nNo. of mature oocytes retrieved\nNo. of embryos\nTotal Gn dose\nStimulation duration CPR\nWong (2004) [29] Single center, USA Retrospective cohort 204 Inclusion criteria\n• Women candidate for ICSI\n• Couples with male factor infertility \ntreated by ICSI\nExclusion criteria\n• Tubal factor infertility\n• Ovulatory dysfunction\n3 arms\n• Group 1A (n = 36 cycles): Previous \nlaparoscopic ovarian cystectomy \nfor endometrioma\n• Group 1B (n = 38 cycles): Nontreated \nendometrioma\n• Group 2 (n = 183 cycles): Endome-\ntriosis without endometrioma\nCPR\nCancellation rate\nNo mature oocytes\nFR\nIR\nMiscarriage rate\nMPR\nC cycles, ChPR chemical pregnancy rate, CPR clinical pregnancy rate, FR fertilization rate, IR Implantation rate, LBR Live birth rate, P Participants\n\nPage 11 of 15\nKatta et al. Middle East Fertility Society Journal           (2024) 29:27 \n \nMedical intervention versus no treatment\nOngoing rate was evaluated in 2 studies (270 partici -\npants). The OR effect estimate was 3.39 with [1.83, 6.26] \n95% CI and < 0.001 P-value (Figure S7).\nClinical pregnancy rate was evaluated in 3 studies (330 \nparticipants). The OR effect estimate was 3.36 with [2.01, \n5.63] 95% CI and < 0.001 P-value (Figure S8).\nMiscarriage rate was evaluated in 2 studies (270 partic -\nipants). The OR effect estimate was 1.31 with [0.46, 3.72] \n95% CI and 0.61 P-value (Figure S9).\nCancellation rate was evaluated in 2 studies (270 par -\nticipants). The OR effect estimate was 0.48 with [0.21, \n1.10] 95% CI and 0.08 P-value (Figure S10).\nNumber of MII oocytes was evaluated in 3 studies (330 \nparticipants). The mean difference (MD) effect estimate \nwas 2.04 with [0.72, 3.36] 95% CI and 0.003 P-value (Fig -\nure S11).\nSubgroup analysis of all outcomes based on the type \nof surgical and medical intervention is shown in supple -\nmentary Table S1.\nCandiani and colleagues (2020) [30] conducted a ret -\nrospective study on 142 women diagnosed with sympto -\nmatic endometrioma who were subjected to laparoscopic \ncyst stripping or CO2 cyst vaporization and then tried to \nconceive spontaneously and if failed through IVF. They \nreported pregnancy rates of 72.2% vs 74.3% (55.6% vs. \n35.9% spontaneously;16.7% vs.38.5% through IVF) in \nstripping vs. laser respectively (P = 0.83), and 26.7% do \nnot achieve pregnancy. They identified age and duration \nof infertility as independent indicators for pregnancy. \nThey concluded that the pregnancy rate was not differ -\nent between the two groups and suggest that CO2 laser \none-step technique could be a good alternative to con -\nventional cystectomy.\nCantor et  al. in 2019 [31] conducted a retrospective \nstudy on 126 women with endometrioma and had a his -\ntory of previous IVF cycle. Participants were subjected to \neither two doses of intramuscular 3.75-mg intramuscu -\nlar depo-leuprolide with 1-month interval or daily 5-mg \noral letrozole for 60 days along with the same leuprolide \nTable 2 Risk of bias\nH High riskm L Low risk, U Unclear risk\nRandom sequence \ngeneration\nAllocation \nconcealment\nParticipants \nblinding\nOutcome \nassessor blinding\nIncomplete \ndata\nSelective \nreporting\nOther bias\nDemirol (2006) [16] U U H H L L L\nMaged (2018) [23] L L H H L L L\nPabuccu (2007) [26] L U H H L L L\nTable 3 Risk-of-bias assessment of non-RCTs\nStudy Selection Comparability Outcome/exposure Total score\nCase cohort Control Design Analysis Ascertainment \nof exposure\nOutcome \nnegative at \nstart\nOutcome \nassessment\nFollow-up \nduration\nCandiani (2020) * * ** * * * * * 9\nCanton (2018) * * ** * * * * * 9\nDemirdag (2021) [15] * * * * * * * * 8\nDeZiegler (2010) * * * * * * * X 7\nGarcia-Velasco (2004) \n[17]\n* * * * * * * * 8\nGuler (2017) [18] * * * * * * * X 7\nKuroda (2009) [19] * * ** * * * * * 9\nLee (2014) [20] * * * * * * * * 8\nLiang (2019) [21] * * * * * * * X 7\nLossl (2009) [22] * * * * * * * * 8\nMuller (2017) [24] * * * * * * * X 7\nPabuccu (2004)[25] * * ** * * * * * 9\nSuganuma (2002) [27] * * * * * * * * 8\nTakashima (2013) [28] * * * * * * * * 8\nWong (2004) [29] * * * * * * * * 8\n\nPage 12 of 15Katta et al. Middle East Fertility Society Journal           (2024) 29:27 \ntreatment before fresh IVF cycle. They reported a sig -\nnificantly higher AFC (10.3 ± 2.0 vs. 6.4 ± 2.5; P = 0.0001), \nlower required total doses of Gn (2079 ± 1119 ver -\nsus 3716 ± 1314; P = 0.0001), higher number of mature \noocytes (9.1 ± 2.4 versus 4.0 ± 1.7; P = 0.0001), clinical \npregnancy rate (50% versus 22%, P = 0.003), and live birth \nrate (40% versus 17%, P = 0.008) in letrozole GnRH group \ncompared to GnRH only group, respectively.\nLossl et al. in 2009 [22] conducted a prospective single \narm study on 20 women candidate for IVF and diagnosed \nwith endometrioma. They were subjected to three subcu-\ntaneous injections of 3.6 goserelin every 28 days in addi -\ntion to daily oral tablet of 1-mg anastrozole for 70 days. \nThey reported a significant decrease in endometriomal \nvolume by 29% (P = 0.007) and serum CA125 by 61% \n(P = 0.001).\nDiscussion\nIn this review, women with untreated endometrioma had \nsignificantly higher numbers of MII oocytes (P = 0.04), \nhigher number of obtained embryos (P < 0.001), and \nrequired lower doses of gonadotropins for induction \n(P < 0.001) compared to those who had undergone sur -\ngical management of endometrioma. However live birth \n(P = 0.25), clinical pregnancy (P = 0.73), miscarriage \n(P = 0.45), cancellation rates (P = 0.37), and the duration \nof stimulation (P = 0.54) did not show any significant dif -\nference between the two groups of women.\nOur systematic review also confirmed that hormo -\nnal treatment of endometrioma was associated with \nhigher ongoing pregnancy rate (P < 0.001), higher clini -\ncal pregnancy rate (P < 0.001), and higher numbers of \nMII oocytes (P = 0.003) when compared to women who \ndid not receive such therapy. These effects were evident \nin treatment with GnRH agonists, OCPs, and dienogest, \nwhile the miscarriage (P = 0.61) and cycle cancellation \nrates (P = 0.08) did not show these differences.\nGiven the thorough search strategy and clear inclusion \nand exclusion criteria, this review provides a comprehen-\nsive overview of the current scientific evidence regarding \nsurgical and medical treatment of endometriomas prior \nto IVF/ICSI. All 18 included studies included various \ncomparisons, different study designs, and heterogenous \nreporting of data. This marked heterogeneity in study \ndesign, sample size, included population characteristics, \nintervention differences in type and timing, and differ -\nent treatment modalities after intervention completion \nprevents the proper meta-analysis reporting of differ -\nent outcome parameters. The review presented two dif -\nferent comparisons either surgical or medical treatment \noptions.\nFig. 2 Live birth rate (surgical intervention vs. no treatment)\n\nPage 13 of 15\nKatta et al. Middle East Fertility Society Journal           (2024) 29:27 \n \nThere are contradictory observations regarding the \nimpact of endometriosis on ovarian responsiveness to \ngonadotropins during controlled ovarian stimulation and \nIVF. Some studies reported diminished ovarian response \nto COH in women with unilateral endometriomas [33, 34]. \nOn the other hand, a systematic review and meta-analy -\nsis of nine RCTs reported difference between the ovary \nwith endometrioma compared to the contralateral nonaf-\nfected ovary regarding the numbers of retrieved oocytes, \nMII oocytes, and obtained embryos. All were reported to \nbe lower from the affected ovaries. They suggested dif -\nferent mechanism for these findings including changes \nin immune markers as IL-6, VEGF, and oxidative stress \nmarkers with resultant decrease in density and diameters \nof primordial follicles. However, there was no differences \nregarding clinical pregnancy and live birth rates [35].\nThe impact of surgical treatment for endometrioma \nbefore IVF remains a controversy. In a retrospective trial \nthat involved 292 women with existing endometrioma, \nno history of surgery who were candidate for IVF, they \nreported lower numbers of antral follicles and required \nhigher doses of Gn in women with existing endometriomas \ncompared to those with previous surgery for endometrio-\nmas and absent endometrioma at time of IVF without any \nsignificant difference in live birth rate between them [36].\nIn a recent meta-analysis, there was a significantly \nlower number of retrieved oocytes and higher rate of \ncycle cancellation in women with existing endometrioma \nduring IVF cycle with similar clinical pregnancy and live \nbirth rates when compared to women without endome -\ntriomas [37, 38]. Hamadan and colleagues suggested that \nthe presence of ovarian endometrioma exerts a negative \neffect on the ovarian tissue with resultant decrease in \nnumber and quality of retrieved oocytes and increase in \nbaseline FSH level [37].\nOn the other hand, a retrospective study reported a signif-\nicantly higher clinical pregnancy and live birth rates trial in \nwomen who underwent laparoscopic cystectomy for endo-\nmetrioma when compared to those underwent diagnostic \nlaparoscopy without resection before IVF [39]. In a large \nFig. 3 Clinical pregnancy rate (surgical intervention vs. no treatment)\n\nPage 14 of 15Katta et al. Middle East Fertility Society Journal           (2024) 29:27 \nobservational study that involved 825 women diagnosed \nwith endometriosis-related infertility, there was a signifi -\ncantly higher overall pregnancy rates in women who under-\nwent endometrioma surgical resection followed by IVF \ncompared to those who underwent surgical resection with-\nout IVF, IVF without prior resection, or no treatment [40].\nFurthermore, several studies have reported the adverse \neffects of surgical treatment of endometrioma on ovar -\nian reserve markers as the reduction of serum AMH \nlevels after surgery [41]. After surgery, the level of AMH \nis reduced by 34% 1  week after surgery and gradually \nimproves to reach 65% of its preoperative level 3 months \nafter the operation. Measurement of AMH after 1  year \nof surgery revealed similar level to that reported after \n1 month of surgery. Bilateral ovarian cystectomy is asso -\nciated with more damage to ovarian reserve [42].\nRegarding the medical treatment before IVF, a sys -\ntematic review included 19 studies with 1709 partici -\npants compared with dydrogesterone to other hormonal \ntherapies. It concluded that dydrogesterone caused bet -\nter relieve of dysmenorrhea and improved the pregnancy \nrate compared to gestrinone with less side effects. They \nalso concluded that dydrogesterone decreased the recur -\nrence rate compared to with GnRH-a treatment. There \nare insufficient data to compare the efficacy of dydro -\ngesterone, letrozole and leuprolide acetate, and the tra -\nditional Chinese medicine remains [43]. A Cochrane \noverview concluded that a 3-month regimen with GnRH \nagonist before IVF improves the pregnancy rates [44].\nStrengths and limitations\nThis review is the first systematic review to study the \nclinical parameters of the effects of both surgical and \nmedical treatment of endometrioma before IVF cycles. \nWe included all the available studies that included all \ntypes of interventions. Adequate data extractions and \nproper meta-analysis when possible was done. The main \nlimitation of this review is the low quality of evidence \nbecause of the absence of adequate numbers of RCTs and \nthe marked heterogeneity among the included studies.\nConclusion\nIn conclusion, the optimal approach for treating endome-\ntrioma prior to IVF is not clear yet due to lack of well-\ndesigned randomized controlled trials.\nSupplementary Information\nThe online version contains supplementary material available at https:// doi. \norg/ 10. 1186/ s43043- 024- 00189-3.\nSupplementary Material 1.\nSupplementary Material 2.\nAcknowledgements\nNone.\nAuthors’ contributions\nStudy concept and design, MK and WSR. Analysis and interpretation of data, \nAM and AO. Drafting of the manuscript, MK. Critical revision of the manuscript \nfor important intellectual content, all authors.\nFunding\nNone.\nAvailability of data and materials\nAll data used are available within the manuscript itself.\nData used and/or analyzed during the study are available from the corre-\nsponding author upon request.\nDeclarations\nEthics approval and consent to participate\nNot applicable.\nConsent for publication\nAll authors give their consent for publication.\nCompeting interests\nThe authors declare that they have no competing interests.\nAuthor details\n1 Department of Obstetrics and Gynecology, Beni-Suef University, Beni Suef, \nEgypt. 2 Department of Obstetrics and Gynaecology, Kasr Al-Ainy Hospital, \nCairo University, Giza 12111, Egypt. 3 Department of Obstetrics and Gynecol-\nogy, Fayoum University, Fayoum, Egypt. \nReceived: 12 December 2023   Accepted: 21 May 2024\nReferences\n 1. 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