The effect of surgical management of endometrioma on the IVF/ICSI outcomes when compared with no treatment? A systematic review and meta-analysis

Objective To assess the impact of surgical management of endometrioma on the outcome of assisted reproduction treatment (ART). Design A systematic review and meta-analysis. Setting Department of reproductive medicine at teaching university hospital, UK. Patients Subfertile women with endometrioma undergoing ART. Interventions Surgical removal of endometrioma or expectant management. Main outcome measures Clinical pregnancy rate, pregnancy rate, live birth rate, number of oocytes retrieved and number of embryos available and ovarian response to gonadotrophins.

An extensive search of electronic databases for articles published from inception to September 2016 yielded 11 eligible studies for meta-analysis. Meta-analysis was conducted comparing surgery versus no treatment of endometrioma. There were no significant differences in pregnancy rate per cycle, clinical pregnancy rate and live birth rate between women who underwent surgery for endometrioma and those who did not.

Current evidence suggests that women with endometriosis-related infertility have similar cycle outcomes to other patients going through ART. It is pertinent for clinicians to assess the risks of surgical intervention on ovarian reserve prior to initiating therapy.

Endometrioma · Surgery · ART  · Pregnancy outcome

Endometriosis is a chronic-debilitating disease that affects 5–10% of fertile women [1]. It is characterised by the pres - ence of endometrial-like tissue (glands and stroma) outside the uterus, which induces a chronic inflammatory reaction, scar tissue, and adhesions that may distort a woman’s pelvic anatomy [2]. Around 25–50% of women with infertility may be affected by endometriosis, and 30–50% of women with endometriosis have infertility [3]. Women with endometriosis often require assisted repro - duction technology (ART) and the severity of endometrio - sis has been linked to ART outcome [ 4]. However, further research is necessary to understand this association. Multiple hypotheses have been suggested to explain the low fecundity observed with endometriosis. Most commonly, the associa- tion has been attributed to altered folliculogenesis resulting in reduced quality oocytes [5], mechanical interference with oocyte pickup and transportation [ 6], exposure to a hostile environment of macrophages, cytokines and vasoactive sub- stances in the peritoneal fluid [7, 8] and anatomical dysfunc- tion of the fallopian tube and ovary [9]. An endometrioma is the formation of a cyst within the ovary with ectopic endometrial tissue lining [ 10, 11]. An endometrioma is one of the most common manifestations of endometriosis. Endometriomas are found in 17–44% of patients with endometriosis [ 12]. The pathogenesis of an endometrioma is complex and different compared to that of * M. Nickkho-Amiry [email protected] 1 University Hospital of South Manchester, Southmoor Rd, Wythenshawe, Manchester M23 9LT, UK 2 Central Manchester Foundation Trust, Manchester, UK 1044 Archives of Gynecology and Obstetrics (2018) 297:1043–1057 1 3 other benign ovarian cysts. A majority of endometriomas are thought to be pseudocysts as described by Hughesdon rather than intra-ovarian cysts [10, 11]. Endometriomas are often associated with deep endome- triosis and often do not respond well to medical therapy. Medical therapy may relieve the symptoms and improve pain or reduce the size of the cyst but does not improve infertility [13]. Therefore, the focus has been on surgical treatment in an attempt to improve fertility. There has been much speculation as to the exact mecha- nism by which endometriomas cause infertility. Researchers have suggested that there is a decrease in ovarian reserve and follicular density in women with endometriomas pos- sibly due to an increase in oxidative stress [14]. However, surgical resection of these cysts has been shown to further decrease ovarian reserve [13]. This highlights that there is much debate regarding the treatment of endometriomas, and uncertainty with regards to infertility, particularly in women who are undergoing assisted reproductive technol- ogy (ART). The aim of this paper is to elucidate the effect of surgical management of ovarian endometriomas on fertility outcomes after ART.

Search strategy Related studies were identified after extensive search of PUBMED, Medline, EMBASE and Cochrane database from inception to September 2016. The following key - words and synonyms were used: ‘endometrioma’, ‘cystec- tomy’, ‘IVF’, ICSI’, ‘pregnancy’. The language of publi- cation was restricted to English. The European Society of Human Reproduction and Embryology guidelines were also reviewed. International standard randomised controlled trial number registry was checked for any trials registered with them. The reference lists of all publications and reviews were hand-searched to identify missing relevant publications. Two authors (RS and MA) independently conducted the search, and reviewed titles, abstracts and full manuscripts. Each article was independently assessed for inclusion and exclu- sion criteria. The review was registered with PROSPERO: International prospective register of systematic reviews. The ID number is CRD42015023914. Study selection The studies that were included in the meta-analysis met the following criteria: (1) an original paper; (2) a study of ovarian endometrioma; (3) a clinical study (including ran- domised controlled trials, case–control, prospective and retrospective cohort studies) that assessed the association of ovarian response, oocyte quality, embryo quality and IVF outcome with ovarian endometrioma. All controlled retrospective or prospective studies that studied the effect of surgery on endometrioma or aspira- tion of endometrioma on IVF/ICSI outcome and ovarian response to gonadotrophins and those with a defined com- parison group were included in the review. The major exclusion criteria were literature reviews, non-original articles; non-ovarian endometrioma; dupli- cation of a previous publication; and women who did not receive intervention on the endometrioma and women who had received medical or surgical treatment of their ovarian endometrioma before IVF cycles. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was used while writing this review (Fig.  1). Outcome measures The primary outcomes were live birth rate per cycle, clinical pregnancy rate per cycle (defined as visualisation of fetal heart activity on transvaginal ultrasound at ≥ 6 week) and pregnancy rate (positive pregnancy test after ART). Secondary measures included the ovarian response to gonadotropin stimulation by the total number of gonado- trophin ampoules required for ovarian stimulation, the peak E2 levels on the day of the hCG administration and the total number of oocytes retrieved with and number of embryos available for transfer. Statistical analysis Data analyses were carried out using RevMan, version 5.3 (Cochrane, Collaboration, Oxford, UK). Heterogeneity was evaluated graphically using forest plots and statistically using the I 2 statistic to quantify heterogeneity across stud- ies. An I 2 > 50% was considered to represent substantial heterogeneity between studies. A random-effect model was used for meta-analysis in cases of high heterogeneity, and a fixed- effect model was used in cases of low heterogeneity. Dichotomous outcome data were reported as odds ratios with 95% confidence intervals (CI). Continuous data were synthe- sized using weighted means with 95% CI for variables includ- ing number of gonadotrophin ampoules required for ovarian stimulation, the peak E2 level and the number of oocytes.

The search strategy yielded 721 articles, 91 of these were relevant to our review. 48 of these studies were found to be potentially eligible. 1045Archives of Gynecology and Obstetrics (2018) 297:1043–1057 1 3 Included studies The characteristics of the 28 studies included in the sys- tematic review and classified according to their controls are presented in Table  1. The majority were retrospective case–control studies. Ten studies were included for quanti- tative synthesis that compared surgical treatment versus no treatment (meta-analysis, Fig.  1). There were two prospec- tive cohort [15, 16] and three retrospective cohort studies [17–19]. Only one randomised control trial was available for study. Randomisation for aspiration of endometrioma was done in one study [15]. One prospective case–control study with randomisation for gonadotrophins was noted [20]. Laparoscopic excision of endometriomas by either ovar- ian cystectomy or stripping of the cyst wall was performed in the majority. Seven studies also involved laparotomies for endometrioma surgery [15, 18–23]. Ovarian stimulation was with the long protocol in the majority of the cases The size of the endometriomas, the duration from surgery to IVF and the laterality of the cyst are documented in Table 1. The control group varied and this has been classified in Table  1. Seven studied used multiple control groups [15, 18, 19, 22, 24–26]. There was no significant difference between the study and the control group with regards to the patient characteristics and the other confounding factors. We included a total of eleven studies in our meta-analysis. Ten studies compared surgical treatment for endometrioma with untreated endometrioma and four studies compared surgical treatment of endometrioma with aspiration of endometrioma. Among these, there were six retrospective case–control [19, 20, 26–29], two retrospective cohort [17, Fig. 1 Prisma flow diagram Records iden/g415fie d through database se archin g (n = 391 ) ScreeningIncluded Eligibility Iden/g415fica/g415on Addi/g415onal records ide n/g415 fied through other source s (n = 49 ) Records a/g332er duplicates removed (n =311) Records scr eene d (n = 96 ) Records exclude d (n = 44 ) Full-text ar/g415cles assessed for eligibilit y (n = 52) Full-text ar/g415cles excluded, with reasons (n = 24 ) Studies included in qualita/g415ve synthesi s (n =28 ) Studies included in quan/g415ta/g415ve sy nt hesis (meta-analysis ) (n=10 ) Comparison of types of st ud y (n =5 ) Control had no endometrioma ( n= 4) No surgery for endometrioma (n=4) No control (n=2) Compared second lin e surg ery (n =1 ) Did no t undergo IVF (n=1 ) Compared ovaria n re se rve with idiopathic d im inished ovar ia n reser ve ( n= 1) Compared side o f endometrioma (n=1 ) 1046 Archives of Gynecology and Obstetrics (2018) 297:1043–1057 1 3 Table 1 Characteristics of all studies included in the systematic review Study (reference) Design Intervention Study group Control group Type of surgery Cyst size (cm) Laterality Dt Outcomes Control group: non-treated endometrioma Tinkanen and Kujansuu [30] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Non-treated endome- trioma Endometrioma strip- ping 1.5–7 Either 1–7 years NOR, no. of embryos, FR, IR, PR, LBR Suganuma et al. [21] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Aspirated endome- trioma Non-treated endome- trioma Endometrioma strip- ping (laparoscopy or laparotomy) ND ND 31 ± 27 months NOR, FR, PR Garcia-Velasco et al. [29] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Non-treated endome- trioma Laparoscopic ovarian cystectomy > 3 Unilateral 12 months NOR, no. of embryos, FR, IR, CPR, MR, units, E2 peak Pabuccu et al. [24] Prospective cohort Randomised for aspiration IVF/ICSI long protocol Surgical treatment of endometrioma Non-treated endome- trioma Aspirated endome- trioma Tubal factor infertility Endometrioma strip- ping (laparoscopy or laparotomy) ND Either ≤ 4 years Mature follicles, FR, IR, CPR, MR, ampoules, E2 peak Wong et al. [19] Retrospective cohort IVF/ICSI long protocol Surgical treatment of endometrioma Non-treated endome- trioma Non-treated peritoneal endometriosis Laparoscopic cystec- tomy ND ND 3–48 months Mature follicles, FR, IR, PR, CPR, MR, ampoules, E2 peak Demirol et al. [31] RCT ICSI long protocol Surgical removal of endometrioma No treatment Endometrioma strip- ping (laparoscopy) 3–6 Unilateral 3 months NOR, FR, IR, CPR, E2 peak Pabuccu et al. [20] Prospective case control (Randomised for GnRh agonist/ antagonist) IVF/ICSI long protocol Surgical removal of endometrioma No treatment Non-treated peritoneal endometriosis Endometrioma (laparoscopy or laparotomy) Either < 4 years Ampoules, NOR, FR, no. of embryos, CPR Bongioanni et al. [27] Retrospective case– control IVF/ICSI long protocol Surgical treatment of endometrioma No Treatment Tubal factor infertility Endometrioma strip- ping (laparoscopy) < 6 Either < 5 years FR, NOR, PR, LBR Lee et al. [28] Retrospective case– control IVF/ICSI long protocol Surgical treatment of endometrioma No treatment Aspiration with ethanol sclerotherapy Laparoscopic cystec- tomy 4–7 ND 20 months NOR,CPR, LBR Dong et al. [18] Retrospective cohort IVF/ICSI long protocol Surgical treatment of endometrioma No treatment Laparoscopic cystec- tomy ND ND NOR, no. of embryos, CPR, LBR Control: aspirated endometrioma Suganuma et al. [21] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Aspirated endome- trioma Non-treated endome- trioma Endometrioma strip- ping (laparoscopy or laparotomy) ND ND 31 ± 27 months NOR, FR, PR Takuma et al. [22] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Aspirated endome- trioma Endometrioma strip- ping (laparoscopy or laparotomy ND ND 31 ± 27 months NOR, FR, PR Pabuccu et al. [15] Prospective cohort randomised for aspiration IVF/ICSI long protocol Surgical treatment of endometrioma Non-treated endome- trioma Aspirated endome- trioma Tubal factor infertility Endometrioma strip- ping (laparoscopy or laparotomy) ND Either ≤ 4 years Mature follicles, FR, IR, CPR, MR, ampoules, E2 peak Lee et al. [28] Retrospective case– control IVF/ICSI long protocol Surgical treatment of endometrioma No treatment Aspiration with ethanol sclerotherapy Laparoscopic cystec- tomy 4–7 ND 20 months NOR,CPR, LBR 1047Archives of Gynecology and Obstetrics (2018) 297:1043–1057 1 3Table 1 (continued) Study (reference) Design Intervention Study group Control group Type of surgery Cyst size (cm) Laterality Dt Outcomes Aflatoonian et al. [62] RCT IVF/ICSI long protocol Ethanol sclerotherapy No treatment N/A 3.5–5.5 ND 3 NOR, no. of embryos, ampoules, FR, CPR Control group: tubal factor infertility Marconi et al. [17] Retrospective cohort IVF-ET long protocol Surgical treatment of endometrioma Tubal factor infertility Endometrioma strip- ping (laparoscopy 4.8 ± 2.3 Either Either 12 ± 7 months Mature follicles, NOR, CPR, ampoules, E2 peak Wu et al. [69] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Contralateral normal ovary Laparoscopic cystec- tomy 3.9 ± 1.5 Unilateral 2.4 ± 1.7 months Mature follicles, NOR, no. of embryos, IR, CPR, ampoules, E2 peak Wyns and Donnez [25] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Tubal factor infertility Laparoscopically treated peritoneal endometriosis Idiopathic infertility Contralateral normal ovary Laparoscopic cyst wall laser vaporization ND ND ND Mature follicles, number of embryos, FR, IR, CPR, ampoules, E2 peak Pabuccu et al. [15] Prospective cohort IVF/ICSI long protocol Surgical treatment of endometrioma Non-treated endome- trioma Aspirated endome- trioma Tubal factor infertility Endometrioma strip- ping (laparoscopy or laparotomy) ND Either ≤ 4 years Mature follicles, FR, IR, CPR, MR, ampoules, E2 peak Loo et al. [66] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Tubal factor infertility Laparoscopic cystec- tomy > 3 ND 6 months NOR, no. of embryos, FR, IR, CPR, units, E2 peak Esinler et al. [63] Retrospective case– control ICSI long protocol Surgical treatment of endometrioma Tubal factor infertility Laparoscopic cystec- tomy > 3 Either ND Mature follicles, IR, CPR, MR, LBR, units, E2 peak Matalliotakis et al. [67] Retrospective case– control IVF/ICSI long protocol Surgical treatment of endometrioma Tubal factor infertility Laparoscopic cystec- tomy ND ND ND Mature follicles, NOR, no. of embryos, IR, FR, PR, CPR, MR, LBR, ampoules, E2 peak Bongioanni et al. [27] Retrospective case– control IVF/ICSI long protocol Surgical treatment of endometrioma No treatment tubal fac- tor infertility Endometrioma strip- ping (laparoscopy) < 6 Either 3 cm ND ND Ampoules, no. of embryos, FR, CPR, Control: laparoscopically treated peritoneal endometriosis Wyns and Donnez [25] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Tubal factor infertility Laparoscopically treated peritoneal endometriosis Idiopathic infertility Contralateral normal ovary Laparoscopic cyst wall laser vaporization ND ND ND Mature follicles, number of embryos, FR, IR, CPR, ampoules, E2 peak Duru et al. [41] Retrospective case– control IVF/ICSI Surgical treatment of endometrioma Laparoscopically treated peritoneal endometriosis Contralateral normal ovary Endometrioma strip- ping Laparoscopy Laparotomy ND Unilateral ≥ 1 year Mature follicles, CPR 1048 Archives of Gynecology and Obstetrics (2018) 297:1043–1057 1 3 Table 1 (continued) Study (reference) Design Intervention Study group Control group Type of surgery Cyst size (cm) Laterality Dt Outcomes Control: non-treated peritoneal endometriosis Wong et al. [19] Retrospective cohort IVF/ICSI long protocol Surgical treatment of endometrioma Non-treated endome- trioma Non-treated peritoneal endometriosis Laparoscopic cystec- tomy ND ND 3–48 months Mature follicles, FR, IR, PR, CPR, MR, ampoules, E2 peak Wyns and Donnez [25] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Tubal factor infertility Laparoscopically treated peritoneal endometriosis Idiopathic infertility Contralateral normal ovary Laparoscopic cyst wall laser vaporization ND ND ND Mature follicles, number of embryos, FR, IR, CPR, ampoules, E2 peak Control: idiopathic infertility Wyns and Donnez [25] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Tubal factor infertility Laparoscopically treated peritoneal endometriosis Idiopathic infertility Contralateral normal ovary Laparoscopic cyst wall laser vaporization ND ND ND Mature follicles, number of embryos, FR, IR, CPR, ampoules, E2 peak Wyns and Donnez [25] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Tubal factor infertility Laparoscopically treated peritoneal endometriosis Idiopathic infertility Contralateral normal ovary Laparoscopic cyst wall laser vaporization ND ND ND Mature follicles, number of embryos, FR, IR, CPR, ampoules, E2 peak Control group: non-endometriotic benign ovarian cyst. Nargund et al. [68] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Ovarian cystectomy for simple and dermoid cyst Cystectomy ND Unilateral ND Mature follicles, NOR Nargund et al. [68] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Ovarian cystectomy for simple and dermoid cyst Cystectomy ND Unilateral ND Mature follicles, NOR Control group: normal non-operated contralateral ovary Loh et al. [65] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Contralateral normal ovary Laparoscopic cystec- tomy 4.23 ± 2 Either ND Mature follicles Ho et al. [23] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Contralateral normal ovary Endometrioma strip- ping (laparoscopy or laparotomy) ND Unilateral 31 ± 27 months Mature follicles, ampoules, E2 peak Somigliana et al. [54] Retrospective case– control IVF/ICSI long protocol Surgical treatment of endometrioma Contralateral normal ovary Laparoscopic cystec- tomy 3.9 ± 1.5 Unilateral 2.4 ± 1.7 months Mature follicles, NOR, no. of embryos, IR, CPR, ampoules, E2 peak 1049Archives of Gynecology and Obstetrics (2018) 297:1043–1057 1 3Table 1 (continued) Study (reference) Design Intervention Study group Control group Type of surgery Cyst size (cm) Laterality Dt Outcomes Wyns and Donnez [25] Retrospective case– control IVF-ET long protocol Surgical treatment of endometrioma Tubal factor infertility Laparoscopically treated peritoneal endometriosis Idiopathic infertility Contralateral normal ovary Laparoscopic cyst wall laser vaporization ND ND ND Mature follicles, number of embryos, FR, IR, CPR, ampoules, E2 peak Ragni et al. [16] Prospective cohort IVF/ICSI long protocol Surgical treatment of endometrioma Contralateral normal ovary Endometrioma strip- ping (laparoscopy 4.0 ± 2.4 Unilateral 2.4 ± 2 years Mature follicles, OR, FR, IR, CPR, ampoules, E2 peak Duru et al. [41] Retrospective case– control IVF/ICSI long protocol Surgical treatment of endometrioma Laparoscopically treated peritoneal endometriosis Contralateral normal ovary Endometrioma strip- ping Laparoscopy Laparotomy ND Unilateral ≥ 1 years Mature follicles, CPR Somigliana et al. [26] Retrospective case control IVF/CSI long protocol Surgical treatment of endometrioma Normal ovaries Endometrioma strip- ping Laparoscopy Laparotomy 4 ± 1.6 Bilateral 3.9 ± 3.4 years NOR, no. of embryos, CPR Tang et al. [53] Retrospective case control IVF long protocol Surgical treatment of endometrioma Contralateral normal ovary Endometrioma strip- ping Laparoscopy  4 Unilateral ND NOR, CPR Dt interval between surgery and IVF/ICSI, ND not documented, NOR number of oocytes retrieved, FR fertilisation rate, IR implantation rate, PR pregnancy rate, CPR clinical pregnancy rate, LBR live birth rate, Ampoules ampoules/unit of gonadotrophins used for ovarian stimulation 1050 Archives of Gynecology and Obstetrics (2018) 297:1043–1057 1 3 25] and one prospective case–control studies [18]. One ran- domised control trial [30] and one prospective cohort study with randomisation for aspiration of endometrioma [15] were studied. The forest plots of the meta-analysis comparing surgi- cal treatment with no treatment and surgical treatment with aspiration of endometrioma are presented in Table  2 and Fig.  2. Main outcomes Surgical treatment compared to no treatment. There were ten studies that compared surgical treatment to no treatment included in this review. Meta-analysis of these results is as follows: Primary outcome Live birth rate. Surgery for endometrioma showed to favour live birth rate per cycle, but this was not statistically significant [4 studies, OR 0.75 (95% CI 0.54, 1.06)] (Fig.  2a1). Clinical pregnancy rate There were no significant differences in clinical pregnancy rate between women who underwent surgery for endome- trioma and those who did not per cycle 1.08 [7 studies, OR 1.08 (95% CI 0.80–1.45)] (Fig.  2a2). Pregnancy rate There were no significant differences in pregnancy rate per cycle between women who underwent surgery for endome- trioma and those who did not [5 studies, OR 0.88 (95% CI 0.60, 1.29)] (Fig.  2a3). Secondary outcomes Number of oocytes retrieved There was also no statistical difference in the number of oocytes retrieved [mean differ - ence—0.43 (95% CI − 1.67, 0.80)] and the total number of embryos created per cycle [mean difference 0.06 95% CI −  0.21 to 0.33)] in the group that underwent surgery for endometrioma compared to the control with no surgery (Fig. 2a5, a6). Gonadotropin usage There was no difference in between gonadotrophin ampoules used per cycle [mean difference 1.31 (95% CI (− 3.87, 6.50)] and the total gonadotrophin dose per cycle [mean difference 244.81 (95% CI − 525.43 to 1015.06)] between the two groups (Fig. 2 a6, a7). Table 2 Clinical outcomes and parameters of ovarian response assessed in the studies included in the systematic review S study group, underwent surgical removal or aspiration of endometrioma, C control group, ND not documented Study Cycles (n) Oocytes retrieved (n) Mature follicles (n) E2 peak (pg/ml) Implanta- tion rate (%) Fertilisation rate (%) Pregnancy rate (%) Clinical pregnancy rate (%) S C S C S C S C S C S C S C S C Tinkanen and Kujansuu [30] 55 45 6.1 6.5 ND ND 13 20 48 58 22 38 ND Suganuma et al. [21] 62 30 7.2 ± 6.2 9.7 ± 6.7 ND ND ND 56.8 56.5 29 36.6 ND Aspiration of endometrioma ± alcohol fixation 35 6.6 ± 5.5 ND ND ND 67.4 31.4 ND Takuma [22] 69 43 ND ND ND ND ND 26 9 ND Pabuccu et al. [15] 44 40 ND 5.3 ± 1.2 5.2 ± 1.1 1196 ± 445 946. ± 64 18 12 72 ± 13 68 ± 16 ND 25 20 Aspirated endometrioma 41 ND 5.9 ± 1.1 1632 ± 670 13 72 ± 10 ND 24 Garcia-Velasco et al. [29] 147 63 10.8 ± 7 11.8 ± 0.9 ND 191 ± 06 247 ± 61 12.8 14.1 76.5 69.9 30.2 28.8 25.4 22.7 Wong et al. [19] 36 38 10.3 ± 1.2 9.4 ± 0.9 ND 195 ± 15 192 ± 98 20 18 85 88 50 38 47 34 Demirol et al. [31] 49 50 ND ND 117 ± 17.14 16,80 ± 28.69 16.5 18.5 86.2 88.3 ND 34.4 38.2 Pabuccu et al. [20] 81 67 9.3 ± 5.2 7.4 ± 4 3.1 ± 0.9 4.2 ± 1.5 1716.7 ± 1163.5 1740.3 ± 829.5 19.3 13.6 67.5 ± 21.7 74.6 ± 19.6 33 22.3 Bongioanni et al. [27] 112 142 8.2 ± 5.3 9.4 ± 4.3 ND ND 24.6 24.2 73.4 67.7 36.6 41.5 ND Lee et al. [28] 36 36 8.2 ± 4.7 12. ± .5 3.3 ± 3.0 3.8 ± 2.0 ND ND ND ND 36.1 38.8 Aspiration with ethanol sclerotherapy 29 12.4 ± 7.6 3.1 ± 1.4 41.3 Dong et al. [18] 153 68 9.5 ± 5.0 9.0 ± 5.5 8.8 ± 4.2 9.0 ± 4.9 3623.5 ± 2175.3 3711 ± 2284.3 28.3 34.4 58.8 60.7 43.1 51.5 1051Archives of Gynecology and Obstetrics (2018) 297:1043–1057 1 3 1052 Archives of Gynecology and Obstetrics (2018) 297:1043–1057 1 3 Estradiol peak during ART There was no difference in the estradiol peak in the two groups. (mean difference − 159.349 (95% CI − 490.15, 171.46)] (Fig. 2a4). Surgical treatment compared to aspiration There were four studies included in the meta-analysis comparing surgical treatment with aspiration [15, 19, 20, 27]. There was no difference between the pregnancy rate per cycle [OR 1.66 (95% CI 0.44, 6.26)] and clinical pregnancy rate per cycle [OR 0.92 (95% CI − 1.43, 1.95)] between those women who underwent surgery for endometrioma and those who had aspiration of endometrioma (Fig.  2a1, b2). There were no live births reported. Excluded studies 19 studies from the potentially eligible studies were excluded (see Table  3). Four studies were excluded as the control did not have endometrioma and two of the studies did not have a control. Four studies did not have surgery for endome- triomas, five compared types of surgery and one compared second line surgery for endometriomas. Fig. 2 Forest plots examining outcome measures. a Surgical treat- ment versus no treatment (10 studies). 1. Live birth rate/cycle. 2. Clinical pregnancy/cycle. 3. Pregnancy/cycle. 4. Estradiol peak (pg/ ml). 5. Total oocytes retrieved/cycle (continuous data). 6. Total no. of embryos created/cycle. 7. Gonadotrophins ampoules/cycle. 8. Gon- adotrophins total dose/cycle. b Surgical treatment versus aspiration (4 studies). 1. Pregnancy/cycle. 2. Clinical pregnancy/cycle Fig. 2 (continued) ◂ 1053Archives of Gynecology and Obstetrics (2018) 297:1043–1057 1 3 One studies compared the effect of the side of endome- triomas, the subjects did not undergo IVF in another and one studied reduced ovarian reserve in comparison to idiopathic diminished ovarian reserve.

The aim of this systematic review and meta-analysis was to assess the impact of surgical management of endometrioma, on the outcome of assisted reproduction. Our main finding is that there was no significant difference in pregnancy rate per cycle, clinical pregnancy rate and live birth rate between women who underwent surgery for endometrioma and those who did not. Interestingly, there was a slight improvement in live birth rate but only four studies published live birth. The limitation of these data is that most of the studies on surgical management are retrospective in nature and very few publishing data on live birth rate. There is also the added

of variations in surgical techniques (i.e., ablation versus resection), completeness of removal of the disease, and differences in ART laboratories. There is much controversy regarding the surgical manage- ment of endometrioma on assisted reproduction outcome. Studies have suggested that the pathophysiologic process in endometrioma formation may be different to other manifes- tations of endometriosis [11, 14]. Pre-cycle surgical management of endometrioma has been suggested to be beneficial in specific circumstances and include [1] inability to access follicles at oocyte retrieval, [2] concern that oocytes may be exposed to endometrioma fluid, which may damage oocytes, and [3 ] the presumption that endometrioma resection would improve IVF outcome. These will be addressed individually. First, the inability to access follicles may indeed be true for endometriomas which are larger than 4–5 cm in mean diameter. With regards to expo- sure to endometrioma fluid, there is no evidence to suggest this is the case. Indeed, at least one investigative team has shown that exposure of oocytes to endometrioma fluid has no impact on rates of fertilisation on early embryo develop- ment [6]. Finally, with regards to improving IVF outcome, there are two meta-analyses that have assessed the impact of endometrioma resection on IVF outcomes. Tsoumpou et al. demonstrated no significant differences in response to gon- adotropin stimulation or in clinical pregnancy rates, when analyzing five studies which compared surgical resection of endometrioma to no treatment [50]. A Cochrane meta- analysis involving 312 patients by Benschop et al. confirmed that surgical management of endometrioma’s resulted in no benefits for a subsequent IVF cycle [51]. Importantly, these trials are limited as they are surgical in nature, and did not control for any confounding factors with regards to differ - ing surgical techniques (aspiration, stripping and total exci- sion, partial resection, and ablation), endometrioma size, or laterality. Indeed, this may mean that the only indication for removing an endometrioma greater than 3 cm in mean diameter before IVF, as suggested by Elter and Oral, would be to treat painful symptoms or to improve ovarian access [52]. Garcia-Velasco and Somigliana suggested indications for surgical intervention that may be beneficial for assisted reproduction. Proposed Indications for Resection of a Sus- pected Endometrioma prior to assisted reproduction [13]: 1. rapid growth, 2. suspicious features noted on ultrasound, 3. painful symptoms that can be attributed to the mass, 4. potential for rupture in pregnancy, 5. inability to access follicles in normal ovarian tissue. Fundamentally, it is crucial that if endometrioma resec- tion is indicated, one must proceed conservatively to mini- mize any compromise of ovarian blood supply and preserve normal ovarian tissue [53]. Needless to say, there are arguments against pre-cycle treatment of endometrioma. Evidence has suggested that not only has excision of endometriomas failed to be benefi- cial, but surgery may indeed, be detrimental. The evidence for this statement is based on excision of stable lesions at least 3 cm in diameter and without worrying features [54]. Somigliana et al. reported a 53% reduction in response to gonadotrophins in ovaries that had been operated upon regardless of size of the cyst with an absence in follicu- lar development in 13% of cases after excision of unilateral endometriomas [36, 54]. These data are supported by other studies. Furthermore, Somigliana et al. reviewed that nine of 11 studies showed a statistically significant postoperative decline in serum anti-Mullerian hormone (AMH) levels, which was exacerbated by excision of bilateral lesions [55]. Muzii et al., in a recent meta-analysis, extracted data on 597 patients from 13 evaluated studies, and demonstrated that despite heterogeneity amongst the studies, the antral follicle count was inherently lower in the affected ovary [56]. Table 3 Reason for exclusion of study Reason for exclusion References Control had no endometrioma [26], [31–34] No control [35, 36] No surgery for endometrioma [37–40] Types of surgery [41–45] Second-line surgery [46] Side of endometrioma [47] Did not undergo IVF [48] Compared ovarian reserve with idiopathic diminished ovarian reserve [49] 1054 Archives of Gynecology and Obstetrics (2018) 297:1043–1057 1 3 Harb et al. suggest from their systematic review that the implantation and clinical pregnancy rate are reduced in women with severe endometriosis although the most important clinical outcome was live birth rate, and although a reduction of 14% in live births (RR = 0.86, 95% CI 0.68–1.08) was observed with stage III/IV endometriosis, this did not reach statistical significance [57]. They suggest that this may be attributed to fewer reports of live birth rate in the literature, and hence weakening the power of their review to detect this outcome [57]. Furthermore, Hong et al. reported that IVF cycle out - comes including clinical pregnancy and live birth rate were not significantly different between the two groups of diminished ovarian reserve with surgery and without sur - gery [58]. They speculate that endometriosis-related infer - tility is attributed to diminished ovarian reserve and not the reduced endometrial receptivity, inferior oocyte and embryo quality [58]. Contrasting reports have shown that pre-cycle surgical intervention may be beneficial. Opøien et al. studied patients with stage I/II endometriosis from a single centre, in a retro- spective trial, who underwent surgical resection or controls who underwent diagnostic laparoscopy only before IVF/ ICSI [59]. They found significantly higher clinical preg- nancy (40.1 versus 29.4%, P  = 0.004), implantation (30.9 versus 23.9%; P  = 0.02) rates were achieved in those who underwent resection than those who underwent diagnostic laparoscopy, and live birth rate per ovum retrieval (27.7 versus 20.6%, P  = 0.04) [59]. Barri et al. evaluated 825 patients with endometriosis-related infertility over a seven- year period, and reported that overall pregnancy rates were significantly higher in patients undergoing surgical resec - tion and then IVF in comparison to those who underwent surgery alone, IVF alone, or no treatment (65.8, 54.2, 32.1, and 11.8%) [60]. Of note, it was unexpected that pregnancy rates from surgery alone would be so much higher than with IVF alone; however, this may be attributed to preg - nancy rates being reported as cumulative. The mean time to achieve pregnancy after surgery was 11.8 ± 12.1 months (range 1–66 months) [60]. The lack of randomised trials regarding pre-IVF cycle surgical management of endometriosis makes it difficult to recommend this approach unless symptom relief is the pri- mary goal. The current endometriosis guidelines by ESHRE 2013 recommend that “In infertile women with ovarian endome- trioma undergoing surgery, clinicians should perform exci- sion of the endometrioma capsule, instead of drainage and electrocoagulation of the endometrioma wall, to increase spontaneous pregnancy rates.” Hart et al. are the source quoted for this statement, but they did not examine within their study, if there is a favoured surgical approach, if any, to women undergoing fertility treatment [61]. These studies highlight that as clinicians, we need to bal- ance the risks and benefits of pre-IVF cycle endometrioma resection given that the bulk of evidence suggests that there is no significant difference in live pregnancy rate. Patients should be counseled with regard to outcome, as well as the risks to ovarian reserve and response particularly in those who already have evidence of compromise.

Current evidence suggests that women with endometrio- sis-related infertility have similar cycle outcomes to other patients going through ART. Pre-cycle surgical management of endometrioma does not appear to be beneficial aside from achieving symptom relief, although heterogeneity amongst studies make data analysis challenging. Endometriomas should not be resected to improve ART outcome and much evidence suggests a detrimental effect of surgery on ovarian reserve and response. The indications for surgical intervention should be limited to suspicious fea- tures, rapid growth, progressive symptoms, and an inability to aspirate follicles due to the size of the lesion. Conserva- tive surgical approaches taking great care to avoid compro- mise of normal ovarian tissue and blood supply are critical. Unfortunately, the evidence is largely based on retrospective data. It is pertinent for clinicians to assess the risks of surgical intervention on ovarian reserve prior to initiating therapy. The need for additional well-designed prospective ran- domised controlled trial is vital, as only one RCT had been done before. So we are relying on non-randomised data. In the world of evidence-based medicine, we should aim for the highest standard of evidence; there is a need for multi-centre RCT with live birth rate as the primary outcome to allow clinicians care for these patients. Author contributions MNA: Data extraction and analysis, manuscript writing and review. RS: Data extraction and analysis, and manuscript review. KM and EEOs: Project conception and manuscript review. MA: Project conception, data extraction and analysis, and manuscript review. Compliance with ethical standards Funding No funding was needed for this work. Conflict of interest There are no conflicts of interest. Ethical approval This article does not contain any studies with human participants performed by any of the authors. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http ://crea tive comm ons.org/lice nses /by/4.0/), which permits unrestricted use, distribution, 1055Archives of Gynecology and Obstetrics (2018) 297:1043–1057 1 3 and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

1. Giudice LC, Kao LC (2004) Endometriosis. Lancet. 364(9447):1789–1799 2. Kennedy S, Bergqvist A, Chapron C, D’Hooghe T, Dunselman G, Saridogan E et al (2005) ESHRE guideline on the diagnosis and management of endometriosis. Hum Reprod 20(10):2698–2704. http s://doi.org/10.1093 /humr ep/dei1 35 3. Macer ML, Taylor HS (2012) Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis- asso- ciated infertility. Obstet Gynecol Clin North Am 39:535–549 4. Olivennes F (2003) Results of IVF in women with endometriosis. J Gynecol Obstet Biol Reprod (Paris) 32:S45–S47 5. Cahill DJ, Wardle PG, Harlow CR, Hull MG (1996) Effect of progestogen therapy on follicular development, related hormone concentrations and fertilization in vitro in unstimulated cycles and unexplained and endometriosis-associated infertility. Hum Reprod 11:647–650 6. Khamsi F, Yavas Y, Lacanna IC, Roberge S, Endman M, Wong JC (2001) Exposure of human oocytes to endometrioma fluid does not alter fertilization or early embryo development. J Assist Reprod Genet 18:106–109 7. Dmowski WP, Rana N, Michalowska J, Friberg J, Papierniak C, el-Roeiy A (1995) The effect of endometriosis, its stage and activity, and of autoantibodies on in vitro fertilization and embryo transfer success rates. Fertil Steril 63:555–562 8. Pellicer A, Valbuena D, Bauset C, Albert C, Bonilla-Musoles F, Remohi J et al (1998) The follicular endocrine environment in stimulated cycles of women with endometriosis: steroid levels and embryo quality. Fertil Steril 69:1135–1141 9. Matalliotakis IM, Cakmak H, Mahutte N, Fragouli Y, Arici A, Sakkas D (2007) Women with advanced-stage endometriosis and previous surgery respond less well to gonadotropin stimu - lation, but have similar IVF implantation and delivery rates compared with women with tubal factor infertility. Fertil Steril 88:1568–1572 10. Hughesdon PE (1957) The structure of endometrial cysts of the ovary. J Obst Gynaecol Br Empire 64(4):481–487 11. Brosens I, Puttemans P, Gordts S, Campo R, Gordts S, Benagiano G (2013) Early stage management of ovarian endometrioma to prevent infertility. Facts Views Vis ObGyn 5(4):309–314 12. Alborzi S, Keramati P, Younesi M, Samsami A, Dadras N (2014) The impact of laparoscopic cystectomy on ovarian reserve in patients with unilateral and bilateral endometriomas. Fertil Steril 101(2):427–434 13. Garcia-Velasco A, Somigliana E (2009) Management of endome- triomas in women requiring IVF: to touch or not to touch. Hum Reprod 24(3):496–501 14. Sanchez AM, Viganò P, Somigliana E, Panina-Bordigno P, Vercel- lini P, Candiani M (2014) The distinguishing cellular and molecu- lar features of the endometriotic ovarian cyst: from pathophysiol- ogy to the potential endometrioma-mediated damage to the ovary. Human Reproduction Update 20(2):217–230 15. Pabuccu R, Onalan G, Goktolga U, Kucuk T, Orhon E, Ceyhan T (2004) Aspiration of ovarian endometriomas before intracyto- plasmic sperm injection. Fertil Steril 82:705–711 16. Ragni G, Somigliana E, Benedetti F, Paffoni A, Vegetti W, Restelli L et al (2005) Damage to ovarian reserve associated with lapa - roscopic excision of endometriomas: a quantitative rather than a qualitative injury. Am J Obstet Gynecol 193:1908–1914 17. Marconi G, Vilela M, Quintana R, Sueldo C (2002) Laparoscopic ovarian cystectomy of endometriomas does not affect the ovarian response to gonadotrophin stimulation. Fertil Steril 78:876–878 18. Dong X, Wang R, Zheng Y, Xiong T, Lian X, Huang B, Zhang H (2014) Surgical treatment of endometrioma does not increase clinical pregnancy rate or live birth/ongoing pregnancy rate after fresh IVF/IVSI treatment. Am J Transl Res 6(2):163–168 19. Wong BC, Gillman NC, Oehninger S, Gibbons WE, Stadtmauer LA (2004) Results of in vitro fertilization in patients with endo- metriomas: is surgical removal beneficial? Am J Obstet Gynecol 191:598–607 20. Pabuccu R, Onalan G, Kaya C (2007) GnRH agonist and antago- nist protocols for stage I–II endometriosis and endometrioma in in vitro fertilization/intracytoplasmic sperm injection cycles. Fer - til Steril 88:832–839 21. Suganuma N, Wakahara Y, Ishida D, Asano M, Kitagawa T, Katsumata Y et al (2002) Pretreatment for ovarian endometrial cyst before in vitro fertilization. Gynecol Obstet Invest 54(Suppl. 1):36–42 22. Takuma N, Sengoku K, Pan B, Wada K, Yamauchi T, Miyamoto T et al (2002) Laparoscopic treatment of endometrioma-associ- ated infertility and pregnancy outcome. Gynecol Obstet Invest 54:30–35 23. Ho HY, Lee RK, Hwu YM, Lin MH, Su JT, Tsai YC (2002) Poor response of ovaries with endometrioma previously treated with cystectomy to controlled ovarian hyperstimulation. J Assist Reprod Genet 19:507–511 24. Duru NK, Dede M, Acikel CH, Keskin U, Fidan U, Baser I (2007) Outcome of in vitro fertilization and ovarian response after endo- metrioma stripping at laparoscopy and laparotomy. J Reprod Med 52:805–809 25. Wyns C, Donnez J (2003) Laser vaporization of ovarian endome- triomas: the impact on the response to gonadotrophin stimulation. Gynecol Obstet Fertil 31:337–342 26. Somigliana E, Arnoldi M, Benaglia L, Iemmello R, Nicolosi AE, Ragni G (2008) IVF-ICSI outcome in women operated on for bilateral endometriomas. Hum Reprod 23(7):1526–1530 27. Bongioanni F, Revelli A, Gennarelli G, Guidetti D, Delle Piane LD, Holte J (2011) Ovarian endometriomas and IVF: a retrospec- tive case-control study. Reprod Biol Endocrinol 17(9):81 28. Lee KH, Kim CH, Lee YJ, Kim SH, Chae HD, Kang BM (2014) Surgical resection or aspiration with ethanol sclerotherapy of endometrioma before in vitro fertilization in infertilie women with endometrioma. Obstet Gynecol Sci 57(4):297–303 29. Garcia-Velasco JA, Mahutte NG, Corona J, Zuniga V, Giles J, Arici A et al (2004) Removal of endometriomas before in vitro fertilization does not improve fertility outcomes: a matched, case- control study. Fertil Steril 81:1194–1197 30. Tinkanen H, Kujansuu E (2000) In vitro fertilization in patients with ovarian endometriomas. Acta Obstet Gynecol Scand 79:119–122 31. Demirol A, Guven S, Baykal C, Gurgan T (2005) Effect of endo- metrioma cystectomy on IVF outcome: a prospective randomised study. Reprod Biomed Online 12:639–643 32. Harada M, Takahashi N, Hirata T, Koga K, Fujii T (2015) Osuga Y Laparoscopic excision of ovarian endometrioma does not exert a qualitative effect on ovarian function: insights from in vitro fer- tilization and single embryo transfer cycles. J Assist Reprod Genet 32(5):685–689 33. Benaglia L, Bermejo A, Somigliana E, Scarduelli C, Ragni G, Fedele L, Garcia-Velasco JA (2012) 9. Pregnancy outcome in women with endometriomas achieving pregnancy through IVF. Hum Reprod. 27(6):1663–1667 34. Nakagawa K, Ohgi S, Kojima R, Sugawara K, Ito M, Horikawa T, Irahara M, Saito H (2007) Impact of laparoscopic cystectomy 1056 Archives of Gynecology and Obstetrics (2018) 297:1043–1057 1 3 on fecundity of infertility patients with ovarian endometrioma. J Obstet Gynaecol Res 33(5):671–676 35. Shimizu Y, Takashima A, Takahashi K, Kita N, Fujiwara M, Murakami T (2010) Long-term outcome, including pregnancy rate, recurrence rate and ovarian reserve, after laparoscopic laser ablation surgery in infertile women with endometrioma. J Obstet Gynaecol Res 36(1):115–118 36. Benaglia L, Somigliana E, Vighi V, Ragni G, Vercellini P, Fedele L (2010) Rate of severe ovarian damage following surgery for endometriomas. Hum Reprod 25(3):678–682 37. Suzuki T, Izumi S, Matsubayashi H, Awaji H, Yoshikata K, Makino T (2005) Impact of ovarian endometrioma on oocytes and pregnancy outcome in in vitro fertilization. Fertil Steril 83(4):908–913 38. Oppenheimer A, Ballester M, Mathieu d’ Argent E, Morcel K, Antoine JM, Daraï E (2013) Pregnancy rate after first intra cyto- plasmic sperm injection—in vitro fertilisation cycle in patients with endometrioma with or without deep infiltrating endometrio- sis. Int J Fertil Steril 7(3):207–216 39. Ashrafi M, Fakheri T, Kiani K, Sadeghi M, Akhoond MR (2014) Impact of the endometrioma on ovarian response and pregnancy rate in in vitro fertilization cycles. Int J Fert Sterril 8(1):29–34 40. Almog B, Shehata F, Sheizaf B, Tan SL, Tulandi T (2011) Effects of ovarian endometrioma on the number of oocytes retrieved for in vitro fertilization. Fertil Steril 95(2):525–571 41. Duru NK, Dede M, Acikel CH, Keskin U, Fidan U, Baser I (2007) Outcome of in vitro fertilization and ovarian response after endo- metrioma stripping at laparoscopy and laparotomy. J Reprod Med 52(9):805–809 42. Alborzi S, Momtahan M, Parsanezhad ME, Dehbashi S, Zol- ghadri J, Alborzi S (2004) A prospective, randomised study comparing laparoscopic ovarian cystectomy versus fenestration and coagulation in patients with endometriomas. Fertil Steril 82(6):1633–1637 43. Takashima A, Takeshita N, Otaka K, Kinoshita T (2013) Effects of bipolar electrocoagulation versus suture after laparoscopic exci- sion of ovarian endometrioma on the ovarian reserve and outcome of in vitro fertilization. J Obstet Gynaecol Res 39(7):1246–1252 44. Alborzi S, Ravanbakhsh R, Parsanezhad ME, Alborzi M, Alborzi S, Dehbashi S (2007) A comparison of follicular response of ova- ries to ovulation induction after laparoscopic ovarian cystectomy or fenestration and coagulation versus normal ovaries in patients with endometrioma. Fertil Steril 88(2):507–509 45. Beretta P, Franchi M, Ghezzi F, Busacca M, Zupi E, Bolis P (1998) Randomised clinical trial of two laparoscopic treatments of endometriomas: cystectomy versus drainage and coagulation. Fertil Steril 70(6):1176–1180 46. Park H, Kim CH, Kim EY, Moon JW, Kim SH, Chae HD, Kang BM (2015) Effect of second-line surgery on in vitro fertilization outcome in infertile women with ovarian endometrioma recur - rence after primary conservative surgery for moderate to sever - eendometriosis. Obstet Gynecol Sci 58(6):481–486 47. Yu HT, Huang HY, Lee CL, Soong YK, Wang CJ (2015) Side of ovarian endometrioma does not affect the outcome of in vitro ferti- lization/intracytoplasmic sperm injection in infertile women after laparoscopic cystectomy. J Obstet Gynaecol Res 41(5):717–721 48. Li Z, Zhang HY, Zhu YJ, Hu YJ, Qu PP (2014) Randomised study comparing the side effects and hormonal status of triptorelin and leuprorelin following conservative laparoscopic surgery for ovarian endometriosis in Chinese women. Eur J Obstet Gynecol Reprod Biol 183:164–168 49. Roustan A, Perrin J, Debals-Gonthier M, Paulmyer-Lacroix O, Agostini A, Courbiere B (2015) Surgical diminished ovar - ian reserve after endometrioma cystectomy versus idiopathic DOR: comparison of in vitro fertilization outcome. Hum Reprod 30(4):840–847 50. Tsoumpou I, Kyrgiou M, Gelbaya TA, Nardo LG (2009) The effect of surgical treatment for endometrioma on in vitro fertilization outcomes: a systematic review and meta-analysis. Fertil Steril 92(1):75–87 51. Benschop L, Farquhar C, van der Poel N, Heineman MJ (2010) Interventions for women with endometrioma prior to assisted reproductive technology. Cochrane Database Syst Rev. 11:008571 52. Elter K, Oral E (2014) Surgical treatment before assisted repro- ductive technologies. Semin Reprod Med 32(4):253–261 53. Tang Y, Chen SL, Chen X, He YX, Ye DS, Guo W, Zheng HY, Yang XH (2013) Ovarian damage after laparoscopic endome- trioma excision might be related to the size of cyst. Fertil Steril 100(2):464–469 54. Somigliana E, Ragni G, Benedetti F, Borroni R, Vegetti W, Cro- signani PG (2003) Does laparoscopic excision of endometriotic ovarian cysts significantly affect ovarian reserve? Insights from IVF cycles. Hum Reprod 18:2450–2453 55. Somigliana E, Berlanda N, Benaglia L, Vigano P, Vercellini P, Fedele L (2012) Surgical excision of endometriomas and ovar - ian reserve: a systematic review on serum antimullerian hormone level modifications. Fertil Steril 98(6):1531–1538 56. Muzii L, di Tucci C, di Feliciantonio M, Marchetti C, Perniola G, Benedetti Panici P (2014) The effect of surgery for endometrioma on ovarian reserve evaluated by antral follicle count: a systematic review and meta-analysis. Hum Reprod 29(10):2190–2198 57. Harb HM, Gallos ID, Chu J, Harb M, Coomarasamy A (2013) The effect of endometriosis on in vitro fertilisation outcome: a systematic review and meta-analysis. BJOG 120(11):1308–1320 58. Hong SB, Lee NR, Kim SK, Kim H, Jee BC, Suh CS, Kim SH, Choi YM (2017) In vitro fertilization outcomes in women with surgery induced diminished ovarian reserve after endometrioma operation: comparison with diminished ovarian reserve without ovarian surgery. Obstet Gynecol Sci 60(1):63–68 59. Opøien HK, Fedorcsak P, Byholm T, Tanbo T (2011) Complete surgical removal of minimal and mild endometriosis improves outcome of subsequent IVF/ICSI treatment. Reprod BioMed Online 23(3):389–395 60. Barri PN, Coroleu B, Tur R, Barri-Soldevila PN, Rodríguez I (2010) Endometriosis-associated infertility: surgery and IVF, a comprehensive therapeutic approach. Reprod BioMed Online 21(2):179–185 61. Hart RJ, Hickey M, Maouris P, Buckett W (2008) Excisional surgery versus ablative surgery for ovarian endometriomata. Cochrane Database Syst Rev (2):CD004992. http s://doi. org/10.1002 /1465 1858 .CD00 4992 .pub3 Studies excluded from meta‑ analysis 62. Aflatoonian A, Rahmani E, Rahsepar M (2013) Assessing the efficacy of aspiration and ethanol injection in recurrent endome- trioma before IVF cycle: a randomised clinical trial. Iran J Reprod Med 11(3):179–184 63. Esinler I, Bozdag G, Aybar F, Bayar U, Yaradi H (2006) Out- come of in vitro fertilization/intracytoplasmic sperm injection after laparoscopic cystectomy for endometriomas. Fertil Steril 85:1730–1735 64. Kahyaoglu S, Ertas E, Kahyaoglu I, Mollamahmutoglu L, Batio- glu S (2008) Does laparoscopic cystectomy and cauterization of endometriomas greater than 3 cm diminish ovarian response to controlled ovarian hyperstimulation during IVF-ET? A case- control study. J Obstet Gynaecol Res 34(6):1010–1013 65. Loh FH, Tan AT, Kumar J, Ng SC (1999) Ovarian response after laparoscopic ovarian cystectomy for endometriotic cysts in 132 monitored cycles. Fertil Steril 72:316–321 1057Archives of Gynecology and Obstetrics (2018) 297:1043–1057 1 3 66. Loo TC, Lin M, Chen SH, Chung MT, Tang HH, Lin LY et al (2005) Endometrioma undergoing laparoscopic ovarian cystec- tomy: its influence on the outcome of in vitro fertilization and embryo transfer (IVF-ET). J Assist Reprod Genet 22:329–333 67. Matalliotakis I, Cakmak H, Mahutte N, Fragouli Y, Arici A, Sak- kas D (2007) Women with advanced-stage endometriosis and pre- vious surgery respond less well to gonadotrophin stimulation, but have similar IVF implantation and delivery rates compared with women with tubal factor infertility. Fertil Steril 88:1568–1572 68. Nargund G, Cheng WC, Parsons J (1995) The impact of ovar - ian cystectomy on ovarian response to stimulation during in vitro fertilization cycles. Hum Reprod 11:81–83 69. Wu MH, Tsai SJ, Pan HA, Hsiao KY, Chang FM (2003) Three- dimensional power Doppler imaging of ovarian stromal blood flow in women with endometriosis undergoing in vitro fertiliza- tion. Ultrasound Obstet Gynecol 21:480–485