Impact of treatment interventions of endometriomas prior to in vitro fertilization: a systematic review and meta-analysis

Background Treatment of endometrioma before in vitro fertilization (IVF) is challenging as it may affect ovarian response to induction.

A systematic review to search for the available optimal management of ovarian endometrioma before ovulation induction in IVF. Search strategy Screening of the MEDLINE, Web of Science, EMBASE, Cochrane database, and the clinical trial registration sites, covering the period from their inception up to June 2023 was done by two reviewers independently using the keywords ovarian endometrioma, ovarian endometriosis, endometrioma/surgery, endometrioma/hormonal treatment, randomized controlled trial(s), case-controlled studies, and cohort studies. Selection criteria All types of studies were included. Participants included were women with unilateral or bilateral ovarian endometriomas candidate for IVF/ICSI. We included 18 studies in the review. Three studies were randomized controlled parallel studies, six were prospective cohort, and nine were retrospective cohort studies. Data collection and analysis Data from all included studies were extracted by two authors (A. M., A. O.) indepen- dently. Data extracted included sample size, population characteristics including age, BMI, duration of infertility, ovar- ian reserve markers, cyst size, and bilaterality and induction protocol used. Main results We found 18 studies. Women with untreated endometrioma had significantly higher numbers of MII oocytes (the mean difference (MD) effect estimate was − 0.53 with [− 1.04, − 0.01] 95% CI and 0.04 P-value), higher number of obtained embryos (MD effect estimate was − 0.25 with [− 0.38, − 0.11] 95%CI and < 0.001 P-value), and required lower doses of gonadotropins for induction (MD effect estimate was 361.14 with [168.13, 5554.15] 95% CI and < 0.001 P-value) compared to those who had undergone surgical management of endometrioma. How- ever, live birth (OR effect estimate was 0.79 with [0.54, 1.18] 95% CI and 0.25 P-value), clinical pregnancy (OR effect estimate 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, 1.63] 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 P-value), and the duration of stimulation (MD effect estimate was 0.19 with [− 0.42, − 0.81] 95% CI and 0.54 P-value) did not show any significant difference between the two groups of women. Hormonal treatment of endome- trioma was associated with higher ongoing pregnancy rate (OR effect estimate was 3.39 with [1.83, 6.26] 95% CI and < 0.001 P-value), higher clinical pregnancy rate (OR effect estimate was 3.36 with [2.01, 5.63] 95% CI and < 0.001 P-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) *Correspondence: Ahmed M. Maged [email protected]; [email protected] Full list of author information is available at the end of the article Page 2 of 15Katta et al. Middle East Fertility Society Journal (2024) 29:27 when compared to women who did not receive such therapy. These effects were evident in treatment with GnRH agonists, OCPs (oral contraceptive pills), and dienogest, while the miscarriage and cycle cancellation rates did not show these differences.

The optimal approach for treating endometrioma prior to IVF is not clear yet due to lack of well- designed randomized controlled trials. Registration number CRD42020151736.

Ovarian endometrioma, Ovarian endometriosis, Endometrioma/surgery, Endometrioma/hormonal treatment, Endometrioma/GnRH agonist, Endometrioma/aspiration, Endometrioma/laparoscopy, IVF outcome

Endometriosis is a benign gynecological pathology char - acterized by the existence of endometrium outside the uterine cavity and was commonly diagnosed by surgery [1]. Recently, ESHRE in 2022 stated that diagnosis of endometriosis with laparoscopy showed to be restricted to only to those with negative different imaging find - ings, and women with failed empirical treatment and the group stated that laparoscopy is no longer considered as the gold standard for diagnosis of endometriosis [2]. Endometriosis is an estrogen-dependent chronic inflam - matory pathology that affects between 10 and 15% of women during their childbearing period. It is commonly associated with pain, infertility [3, 4], chronic stress, and anxiety [5]. Difficult conception is observed in 30 to 50% of women diagnosed with endometriosis [6], and many of them are trying to conceive through different assisted reproductive techniques [7]. Unfortunately, the pathogenesis of endometriosis associated with infertility remains unclear. Endome - triosis causes infertility through various mechanisms: distortion of the normal pelvic anatomy, scarring of the fallopian tubes, inflammation of different pelvic organs with adhesion formation, alteration of immune response and hormonal environment of ova, impair - ment of implantation of a pregnancy, and alteration of oocytes quality [8]. Various inflammatory changes have been proposed to be the reasons behind endometriosis- associated infertility including alteration of macrophages proliferation and its phagocytic activity, increasing the numbers of malfunctioning natural killer cells and T lymphocytes with enhancement of proinflammatory and angiogenic cytokines release [9, 10]. Ovarian endo - metrioma decreases the volume of functioning ovarian tissue through its space-occupying action and/or the local inflammatory and immune reactions or both. This reduction in functioning ovarian tissue is aggravated by surgery. Clinical examination has low sensitivity and specificity for diagnosis of endometriosis, and laparos - copy remains the gold standard for diagnosis; however, recent studies look promising for new sonographic and magnetic resonance imaging (MRI) techniques [11]. Endometrioma could be managed by either medical or surgical modalities, and both affect the reproductive potential of the women. Women should be counselled about behavioral changes that creates optimum patients’ characteristics and healthy lifestyle before they started medical and/or surgical treatments. One of these is the maintenance of ideal body weight to decrease the endo - metriosis cancer risk and to improve the success of IVF [2]. The best management of endometriomas before starting IVF/ICSI trial is unknown. Medical treatment for endometrioma includes mainly hormonal therapy with progestogens, combined oral contraceptives, aro - matase enzyme inhibitors, and gonadotropin-releasing hormone analogues. Their mode of action depends on their ability to decrease ovarian activity [12]. Surgical treatment includes cyst aspiration, laparoscopic ovar - ian cystectomy, ovarian cystectomy via laparotomy, or robotic surgery. Laparoscopic management is currently the most accepted approach being associated with lower costs and faster recovery compared to other approaches [13]. The aim of current review is to evaluate the impact of medical and surgical interventions to endometriomas prior to IVF-ET as there was no similar review to assess the effects of different treatment modalities of ovarian endometriomas on IVF outcomes. Methodology This study protocol was prospectively registered follow - ing the guidelines of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) with CRD42020151736 number. Research question • Population: Women with unilateral or bilateral ovar - ian endometrioma • Intervention: Surgical (including cystectomy and aspiration) and medical (including GnRH, progester - Page 3 of 15 Katta et al. Middle East Fertility Society Journal (2024) 29:27 one, and aromatase inhibitors) management of endo- metrioma before IVF • Comparison: Surgical treatment and medical treat - ment compared to no intervention • Outcome: Outcomes of IVF cycles In this systematic review, the following databases: MEDLINE, Web of Science, Embase, Cochrane Library, and the clinical trial registry were searched from incep - tion up to June 2023. The search used the keywords as follows: endometriosis; endometrioma, ovarian endometriosis, and ovarian endometrioma; ovarian endometriosis; endometriotic ovarian cyst; endome - trioma/surgery; endometrioma/hormonal treatment, GnRH agonist, letrozole, aromatase inhibitors, OCPs (oral contraceptive pills)), IVF/ICSI, and in  vitro fer - tilization; intracytoplasmic sperm injection; assisted reproductive technologies; ART; oocytes; live birth; fertilization; and live birth rate, pregnancy rate, miscar - riage rate, number of oocytes, cancellation rate, rand - omized controlled trial(s), case-controlled studies, and cohort studies. As only few randomized controlled tri - als were available, the authors agreed to include other types of studies as case controlled and cohort studies whether prospective or retrospective. Review articles and case reports, editorial opinion, and commentary were excluded. We analyzed the references and cita - tions of all available studies (both primary and sec - ondary), narrative and systematic reviews, abstracts of gynecology, and infertility seminars. We emailed the authors directly for any missing or unclear informa - tion. If necessary, all studies written in English compar - ing different surgical and medical modalities against no treatment or other modalities were included. Surgical modalities include laparoscopic cystectomy, open cys - tectomy, or cyst aspiration. Medical modalities include progestogens, aromatase inhibitors, GnRH agonists, or oral contraceptive pills (OCPs). Cystectomy is the stripping of the cyst wall away from the healthy ovarian tissues through either laparoscopy or laparotomy. Aspiration procedure is the transvaginal aspiration of the cyst content guided by ultrasound. Med- ical treatment acts through antagonizing estrogen secre - tion and/or action. Two authors (A. O. and A. M.) independently assessed the titles, abstracts, and the full articles and then extracted the data of the included studies, and disa - greements were discussed further with other authors. Extracted data included study type, settings, participants characteristics, details of intervention, and outcome parameters. The risk of bias was assessed using the Cochrane Hand- book of Systematic Reviews recommendations for the 3 RCTs [14]. These recommendations include random sequence generation, allocation concealment, partici - pants and outcome assessors blinding, incomplete data of outcomes, selective reporting, and other biases. The outcome parameters of this review included live birth, clinical pregnancy, miscarriage, cancellation rates, number of MII follicles, duration of stimulation, total dose of gonadotropin used for induction, and number of obtained embryos. Statistical analysis For analysis of continuous and dichotomous data, the mean difference and odd ratio with 95% confidence inter- val (CI) analysis were used, respectively. The random effect model was used to calculate the effect size, and I 2 statistic and Cochran’s Q test were calculated to evalu - ate the studies heterogeneity. Significant P-value was considered when 40%. Analyses were done using the Review Manager (RevMan) version 5.4.1 (The Nordic Cochrane Centre, Cochrane Collaboration, 2020, Copenhagen, Denmark).

The PRISMA flow chart is shown in Fig. 1. Study characteristics Table  1 describes the characteristics of the included studies. Eighteen studies were included in this review [15–32]. Five were conducted in Turkey [15, 16, 18, 25, 26], 3 in Japan [19, 27, 28], and 1 in each of the following coun - tries: Canada [31], China [21], Denmark [22], Egypt [23], France [32], Italy [30], Russia [24], Spain [17], South Korea [20], and the USA [29]. Three studies were RCTs [16, 23, 26], six were prospective cohort [21, 22, 24, 25, 30, 32], and nine were retrospective cohort studies [15, 17–20, 27–29, 31]. All were single center except three tri- als [17, 31, 32] that were conducted in two centers. Six studies compared laparoscopic surgery to no treatment [16–19, 21, 27], five compared surgery to no treatment [15, 20, 25, 26, 29], and three compared cyst aspiration to no treatment [20, 25, 27]. Medical treatment was GnRH in two studies [23, 24], OCPs in one study [15], and dien - ogest in one study [24], while aromatase inhibitors were studied in two trials [22, 31]. Risk of bias of included studies Risk of bias in the three RCTs is described in Table 2. The risk of bias for non-RCTs was evaluated using the New - castle–Ottawa scale (Table 3). Page 4 of 15Katta et al. Middle East Fertility Society Journal (2024) 29:27 Synthesis of results Eighteen studies with 3063 participants were included in our review. Surgical intervention versus no treatment Live birth rate was evaluated in 4 studies (565 par - ticipants). The OR effect estimate was 0.79 with [0.54, 1.18] 95% CI and 0.25 P -value (Fig. 2 ). Clinical pregnancy rate was evaluated in 11 studies (1447 participants). The OR effect estimate was 0.95 with [0.72, 1.26] 95% CI and 0.73 P -value (Fig. 3 ). Miscarriage rate was evaluated in 6 studies (333 par - ticipants). The OR effect estimate was 0.74 with [0.33, 1.63] 95% CI and 0.45 P -value (Figure S1). Cycle cancellation rate was evaluated in 4 studies (551 participants). The OR effect estimate was 1.62 with [0.57, 4.66] 95% CI and 0.37 P -value (Figure S2). Number of MII oocytes was evaluated in 11 studies (1475 participants). The mean difference (MD) effect estimate was − 0.53 with [− 1.04, − 0.01] 95% CI and 0.04 P-value (Figure S3). Number of obtained embryos was evaluated in 4 stud - ies (569 participants). The MD effect estimate was − 0.25 with [− 0.38, − 0.11] 95% CI and < 0.001 P-value (Figure S4). Duration of stimulation was evaluated in 6 studies (881 participants). The MD effect estimate was 0.19 with [− 0.42, 0.81] 95% CI and 0.54 P-value (Figure S5). The total dose of gonadotropins was evaluated in 9 studies (1255 participants). The MD effect estimate was 361.14 with [168.13, 554.15] 95% CI and < 0.001 P-value (Figure S6). Fig. 1 Prisma flow chart Page 5 of 15 Katta et al. Middle East Fertility Society Journal (2024) 29:27 Table 1 Characteristics of the included studies Study Settings Design Size Participants Intervention Outcome Candiani (2020) Single center, Italy Prospective cohort 142 Inclusion criteria ○ Previous surgery for unilateral or bilateral endometriomas > 3 cm Exclusion criteria • Age ≥ 40 years • Previous bilateral ovarian surgery or more at the time of surgery • Previous salpingectomy or hysterectomy • Follow-up < 12 months 2 arms group 1: patients underwent a standardized laparoscopic stripping technique group 2: patients underwent cyst co2 laser vaporization Postoperative pregnancy rate (sponta- neous or assisted) Identification of independent predic- tors of pregnancy Canton (2018) 2 centers, Canada Retrospective cohort 126 Inclusion criteria • Age 21–39 years • Ground-glass cysts persistent for at least 3 months and not enlarg- ing • Previous IVF failed cycle with frozen embryo transfers Exclusion criteria • Hydrosalpinges • Intracavitary lesion • Severe male factor • Previous surgery for endometriosis • First IVF cycle • Lack of an endometrioma 2 arms • Group 1 received 3.75-mg intramus- cular depo-leuprolide treatment alone for 60 days • Group 2 received 5 mg of oral letrozole daily beside leuprolide with the same regimen and duration CPR LBR AFC Largest mean endometrioma diameter Total Gn dose No. of mature oocytes retrieved No. of pronuclear (2PN) embryos No. of blastocysts Demirdag (2021) [15] Single center, Turkey Retrospective cohort 179 P 259 C Inclusion criteria • History of ovarian endometrioma before the IVF/ICSI cycle Exclusion criteria • Polycystic ovarian syndrome • Male factor infertility • Thaw cycles 3 arms • Group 1 (n = 81): Previous endome- trioma surgery • Group 2 (n = 98): Non-operated endometrioma • Group 3 (n = 1757): Other infertility causes as unexplained and tubal fac- tor infertility without endometrioma CPR LBR AFC, NOR E2 levels on the day of hCG trigger Total Gn dose Cancellation rates Demirol (2006) [16] Single center, Turkey RCT 99 Inclusion criteria • Single or multiple • Unilateral ovarian endometriomas between • 3 and 6 cm referred to ICSI Exclusion criteria • Bilateral endometrioma • Patients with laparoscopic suturing 2 arms ○ Group 1 (n = 49) underwent con- servative ○ ovarian surgery before ICSI • Group 2 (n = 50) underwent ICSI directly Stimulation duration Peak E2 level No. of mature oocytes retrieved FR IR CPR Page 6 of 15Katta et al. Middle East Fertility Society Journal (2024) 29:27 Table 1 (continued) Study Settings Design Size Participants Intervention Outcome DeZiegler (2010) 2 centers, France Prospective cohort 60 Endometriosis was diagnosed either surgically or by ultrasound 4 arms • Group 1 (n = 540) received OCP0 .03 mg of EE and 0.125 mg of LNG before ART for 6 to 8 weeks subdi- vided to endometriosis (n = 114, 29 endometrioma) and control (n = 426) • Group 1 (n = 255) received no OC pretreatment subdivided to endo- metriosis (n = 172, 31 endometrioma) and control (n = 83) CPR No. of mature oocytes retrieved No. of embryos Garcia-Velasco (2004) [17] 2 centers, Spain Retrospective cohort 189 P 210 C Inclusion criteria • Ovarian endometriomas underwent IVF-ET cycles Exclusion criteria • Any other known infertility factor besides endometriosis 2 arms • Study group (n = 133 women, 147 cycles): Previous laparoscopic cystec- tomy for an ovarian endometrioma • Control group (n = 56 women, 63 cycles): Non-operated ovarian endometrioma(s) No. of oocytes retrieved No. of mature oocytes No. of embryos FR IR CPR MPR ChPR Miscarriage rate Cancellation rate Guler (2017) [18] Single center, Turkey Retrospective ohort 150 P 257 C Exclusion criteria Unexplained infertility without endo- metriosis, endometriosis-related tubal factor, male factor infertility • Previous laparotomy or oophorec- tomy for endometrioma • Recurrent endometrioma 4 arms 257 ICSI cycles of 150 patients • Group 1 (n = 84 women, 91 cycles): Minimal endometriosis • Group 2 (n = 25 women, 57 cycles): Endometrioma removal • Group 3 (n = 53 women, 65 cycles): Non-operated endometrioma Group 4 (n = 24 women, 44 cycles): Tubal factor infertility CPR LBR Total Gn dose No. of oocytes retrieved Stimulation duration Kuroda (2009)[19] Single center, Japan Retrospective cohort 61 P 97 C Inclusion criteria • Women with endometriosis or endo- metrioma Exclusion criteria Women with more than 4 IVF/ICSI cycles 4 arms • Group A (n = 31 cycles): Unoperated endometrioma • Group B (n = 51 cycles): Postoperative • endometrioma • Group C (n = 15 cycles): No endo- metrioma Group D (n = 27 cycles): Tubal infertil- ity No. of oocytes retrieved FR Cancellation rate IR CPR LBR Miscarriage rate Page 7 of 15 Katta et al. Middle East Fertility Society Journal (2024) 29:27 Table 1 (continued) Study Settings Design Size Participants Intervention Outcome Lee (2014) [20] Single center, Korea Retrospective cohort 101 Inclusion criteria • Women with pathologically confirmed previous or current endometrioma(s) > 3 cm • Age: 20–45 years • Normal: 24–35-day ovulatory cycles • BMI: 18–25 kg/m2 Exclusion criteria • Endocrine abnormalities as diabetes mellitus, PCOS, hyperprolactinemia • Previous severe OHSS • Abnormalities interfering with stimu- lation Previous (within 12 months) or current drug or alcohol abuse 3 arms • Resection group (n = 36): Surgical resection of endometrioma • Aspiration group (n = 29): Transvagi- nal endometrioma aspiration Control group (n = 36): No surgical intervention No. of oocytes retrieved No. of mature oocytes No. of embryos Total Gn dose CPR LBR MPR Miscarriage rate Liang (2019) [21] Single center, China Prospective cohort 41 Inclusion criteria ○ Infertility due to stages III or IV endometriosis • Normal semen analysis Exclusion criteria • Age: ≥ 40 years • BMI: ≥ 30 kg/m2 • FSH: ≥ 12 mIU/mL • PCOS • Endocrinal disorders (thyroiddisease, diabetes mellitus, and Cushing’s syndrome) Cycles with contaminated dominant FF with blood cycles with the domi- nant FF not yielding oocytes 2 arms • Surgery group (n = 13): Surgery to remove the endometrioma Surgery group (n = 28): Untreated before IVF Total Gn dose No. of oocytes retrieved No. of MII oocytes FR IR CPR Page 8 of 15Katta et al. Middle East Fertility Society Journal (2024) 29:27 Table 1 (continued) Study Settings Design Size Participants Intervention Outcome Lossl (2009) [22] Single center, Denmark Prospective ohort 20 Inclusion criteria ○ Ultrasonographic diagnosedendometrioma(s) persisting for three or more cycles between 20 and 70 mm and indicated for IVF or ICSI • Age: 20–39 years • Regular: 21–35-day menstrual cycle • BMI: 18–30 kg/m2 • Negative urinary pregnancy test on treatment day 1 Exclusion criteria ○ GnRH-agonist treatment withinthe last 3 months History of osteopenia, hepatic, renal,cardiovascular, or thromboem- bolic disorder 1 arm received goserelin 3.6 mg s on treatment days 1, 28, and 56 and 1 mg of anastrozole from day 1 to day 69. COH initiated from day 70ncompared to a standard IVF/ ICSI treatment in 15 women who underwent a previous or subse- quent standard cycle, with present endometrioma(s) Endometrioma volume changes Serum CA125 changes Stimulation duration Total Gn dose No. of oocytes retrieved No. of embryos Total Gn dose FR IR CPR LBR Miscarriage rate Maged (2018) [23] Single center, Egypt RCT 90 Inclusion criteria ○ Subfertile women indicated for ICSI and having a single endometrioma of 2–5 cm • Normal uterine cavity Exclusion criteria • Bilateral or multiple endometriomas, • FSH > 10 • BMI > 30 kg/m2 • Age > 40 years • Cases who received GnRH within 12 months of the study • Patients who received OCPs or other hormones within 3 months • Previous surgical resection of endo- metrioma Severe male factor 2 arms • Group A (n = 45): Received standard long protocol Group B (n = 45): Received Intramus- cular injections of 3.75-mg triptorelin every 28 days for 3 doses followed by thestandard long protocol 28 days after the last injection Ch PR CPR Ongoing PR Miscarriage rate ectopic pregnancy MPR Page 9 of 15 Katta et al. Middle East Fertility Society Journal (2024) 29:27 Table 1 (continued) Study Settings Design Size Participants Intervention Outcome Muller (2017) [24] Single center, Russia Prospective cohort 144 Inclusion criteria: • Age 23–42 years • Infertility • Surgical treatment of endometrioma • ≤ 4 months before enrollment • No endometriomas or other ovarian cysts at thestart of stimulation • FSH < 12.0 IU/L and AMH ≥ 0.5 ng/mL Exclusion criteria • BMI ≥ 30 kg/m2 • Uterine fibroids ≥ 2 cm in diameter and/or deforming the uterine cavity • III/IV stage ofadenomyosis Contraindications to COS or gestation 3 arms ○ Group 1 (n = 38): Received 2-mg dienogest daily for 6 months before IVF • Group 2 (n = 70): Received 3.75-mg triptorelin every 28 days for six doses before IVF • Group 3 (n = 38): Without any hor- mone therapy before IVF CPR LBR Total Gn dose Stimulation duration No oocyte retrieved Cancellation rate Pabuccu (2004) [25] Single center, Turkey Prospective cohort 171 Inclusion criteria • Women candidate for ICSI • Normal uterine cavity Exclusion criteria • Thaw cycles 4 arms • Group 1 (n = 41): Aspiration of endo- metriomas and no history of previous surgery • Group 2 (n = 40): Nonaspirated endometriomas • Group 3 (n = 44): History of ovarian surgery for endometriomas in patients without ovarian endometriomas at the beginning of COH Group 4 (n = 46): Tubal factor infertility Total Gn dose Stimulation duration No MII oocytes FR IR CPR Miscarriage rate Pabuccu (2007) [26] Single center, Turkey RCT 246 Inclusion criteria • Women candidate for ICSI • Normal uterine cavity Exclusion criteria • Patients with recurrent endometri- oma or with advanced endometriosis (stages III–IV) without endometrioma were excluded from group 1 • Hydrosalpinx • Tuberculosis • Male factor infertility • Thaw cycles 3 arms ○ Group 1 (n = 98): Mild-to-moderate endometriosis • Group 2 (n = 81): Ovarian surgery for endometrioma • Group 3 (n = 67): Non-operated endometrioma Total Gn dose Stimulation duration E2 levels on the day of hCG trigger No oocytes retrieved No MII oocytes FR ChPR CPR Page 10 of 15Katta et al. Middle East Fertility Society Journal (2024) 29:27 Table 1 (continued) Study Settings Design Size Participants Intervention Outcome Suganuma (2002) [27] Single center, Japan Retrospective cohort 79 P 127 C Inclusion: Infertile women with endo- metrioma who underwent IVF-ET 3 arms • Surgery group (n = 36 women, 62 cycles) underwent laparotomy or laparoscopy • Cyst-aspirated group (n = 23 women, 35 cycles): Endometrioma content aspirated under transvagi- nal ultrasonic imaging andtreated with or without alcohol fixation No treatment group (n = 20 women, 30 cycles): Nontreated endometrioma Retrieved oocytes, no. of mature oocytes, fertilization, and pregnancy Takashima (2013)[28] Single center, Japan Retrospective cohort 44 Inclusion criteria ○ Patients who had undergone laparoscopic excision of ovarian endo- metrioma followed by IVF treatment • Age 32–40 years • BMI 18–25 kg/m2 • Both ovaries present • Menstrual cycle length between 25 and 35 days Exclusion criteria • Hormonal treatment within 1 year prior to the laparoscopy • Previous adnexal surgery Clinical hyperandrogenism 2 arms Women who had laparoscopic exci- sion for unilateral endometrioma among infertile women • Group 1 (n = 21): Hemostasis dur- ing the surgery achieved by coagula- tion • Group 2 (n = 23): Hemostasis dur- ing the surgery achieved by suture No. of mature oocytes retrieved No. of embryos Total Gn dose Stimulation duration CPR Wong (2004) [29] Single center, USA Retrospective cohort 204 Inclusion criteria • Women candidate for ICSI • Couples with male factor infertility treated by ICSI Exclusion criteria • Tubal factor infertility • Ovulatory dysfunction 3 arms • Group 1A (n = 36 cycles): Previous laparoscopic ovarian cystectomy for endometrioma • Group 1B (n = 38 cycles): Nontreated endometrioma • Group 2 (n = 183 cycles): Endome- triosis without endometrioma CPR Cancellation rate No mature oocytes FR IR Miscarriage rate MPR C cycles, ChPR chemical pregnancy rate, CPR clinical pregnancy rate, FR fertilization rate, IR Implantation rate, LBR Live birth rate, P Participants Page 11 of 15 Katta et al. Middle East Fertility Society Journal (2024) 29:27 Medical intervention versus no treatment Ongoing rate was evaluated in 2 studies (270 partici - pants). The OR effect estimate was 3.39 with [1.83, 6.26] 95% CI and < 0.001 P-value (Figure S7). Clinical pregnancy rate was evaluated in 3 studies (330 participants). The OR effect estimate was 3.36 with [2.01, 5.63] 95% CI and < 0.001 P-value (Figure S8). Miscarriage rate was evaluated in 2 studies (270 partic - ipants). The OR effect estimate was 1.31 with [0.46, 3.72] 95% CI and 0.61 P-value (Figure S9). Cancellation rate was evaluated in 2 studies (270 par - ticipants). The OR effect estimate was 0.48 with [0.21, 1.10] 95% CI and 0.08 P-value (Figure S10). Number of MII oocytes was evaluated in 3 studies (330 participants). The mean difference (MD) effect estimate was 2.04 with [0.72, 3.36] 95% CI and 0.003 P-value (Fig - ure S11). Subgroup analysis of all outcomes based on the type of surgical and medical intervention is shown in supple - mentary Table S1. Candiani and colleagues (2020) [30] conducted a ret - rospective study on 142 women diagnosed with sympto - matic endometrioma who were subjected to laparoscopic cyst stripping or CO2 cyst vaporization and then tried to conceive spontaneously and if failed through IVF. They reported pregnancy rates of 72.2% vs 74.3% (55.6% vs. 35.9% spontaneously;16.7% vs.38.5% through IVF) in stripping vs. laser respectively (P = 0.83), and 26.7% do not achieve pregnancy. They identified age and duration of infertility as independent indicators for pregnancy. They concluded that the pregnancy rate was not differ - ent between the two groups and suggest that CO2 laser one-step technique could be a good alternative to con - ventional cystectomy. Cantor et  al. in 2019 [31] conducted a retrospective study on 126 women with endometrioma and had a his - tory of previous IVF cycle. Participants were subjected to either two doses of intramuscular 3.75-mg intramuscu - lar depo-leuprolide with 1-month interval or daily 5-mg oral letrozole for 60 days along with the same leuprolide Table 2 Risk of bias H High riskm L Low risk, U Unclear risk Random sequence generation Allocation concealment Participants blinding Outcome assessor blinding Incomplete data Selective reporting Other bias Demirol (2006) [16] U U H H L L L Maged (2018) [23] L L H H L L L Pabuccu (2007) [26] L U H H L L L Table 3 Risk-of-bias assessment of non-RCTs Study Selection Comparability Outcome/exposure Total score Case cohort Control Design Analysis Ascertainment of exposure Outcome negative at start Outcome assessment Follow-up duration Candiani (2020) * * ** * * * * * 9 Canton (2018) * * ** * * * * * 9 Demirdag (2021) [15] * * * * * * * * 8 DeZiegler (2010) * * * * * * * X 7 Garcia-Velasco (2004) [17] * * * * * * * * 8 Guler (2017) [18] * * * * * * * X 7 Kuroda (2009) [19] * * ** * * * * * 9 Lee (2014) [20] * * * * * * * * 8 Liang (2019) [21] * * * * * * * X 7 Lossl (2009) [22] * * * * * * * * 8 Muller (2017) [24] * * * * * * * X 7 Pabuccu (2004)[25] * * ** * * * * * 9 Suganuma (2002) [27] * * * * * * * * 8 Takashima (2013) [28] * * * * * * * * 8 Wong (2004) [29] * * * * * * * * 8 Page 12 of 15Katta et al. Middle East Fertility Society Journal (2024) 29:27 treatment before fresh IVF cycle. They reported a sig - nificantly higher AFC (10.3 ± 2.0 vs. 6.4 ± 2.5; P = 0.0001), lower required total doses of Gn (2079 ± 1119 ver - sus 3716 ± 1314; P = 0.0001), higher number of mature oocytes (9.1 ± 2.4 versus 4.0 ± 1.7; P = 0.0001), clinical pregnancy rate (50% versus 22%, P = 0.003), and live birth rate (40% versus 17%, P = 0.008) in letrozole GnRH group compared to GnRH only group, respectively. Lossl et al. in 2009 [22] conducted a prospective single arm study on 20 women candidate for IVF and diagnosed with endometrioma. They were subjected to three subcu- taneous injections of 3.6 goserelin every 28 days in addi - tion to daily oral tablet of 1-mg anastrozole for 70 days. They reported a significant decrease in endometriomal volume by 29% (P = 0.007) and serum CA125 by 61% (P = 0.001).

In this review, women with untreated endometrioma had significantly higher numbers of MII oocytes (P = 0.04), higher number of obtained embryos (P < 0.001), and required lower doses of gonadotropins for induction (P < 0.001) compared to those who had undergone sur - gical management of endometrioma. However live birth (P = 0.25), clinical pregnancy (P = 0.73), miscarriage (P = 0.45), cancellation rates (P = 0.37), and the duration of stimulation (P = 0.54) did not show any significant dif - ference between the two groups of women. Our systematic review also confirmed that hormo - nal treatment of endometrioma was associated with higher ongoing pregnancy rate (P < 0.001), higher clini - cal pregnancy rate (P < 0.001), and higher numbers of MII oocytes (P = 0.003) when compared to women who did not receive such therapy. These effects were evident in treatment with GnRH agonists, OCPs, and dienogest, while the miscarriage (P = 0.61) and cycle cancellation rates (P = 0.08) did not show these differences. Given the thorough search strategy and clear inclusion and exclusion criteria, this review provides a comprehen- sive overview of the current scientific evidence regarding surgical and medical treatment of endometriomas prior to IVF/ICSI. All 18 included studies included various comparisons, different study designs, and heterogenous reporting of data. This marked heterogeneity in study design, sample size, included population characteristics, intervention differences in type and timing, and differ - ent treatment modalities after intervention completion prevents the proper meta-analysis reporting of differ - ent outcome parameters. The review presented two dif - ferent comparisons either surgical or medical treatment options. Fig. 2 Live birth rate (surgical intervention vs. no treatment) Page 13 of 15 Katta et al. Middle East Fertility Society Journal (2024) 29:27 There are contradictory observations regarding the impact of endometriosis on ovarian responsiveness to gonadotropins during controlled ovarian stimulation and IVF. Some studies reported diminished ovarian response to COH in women with unilateral endometriomas [33, 34]. On the other hand, a systematic review and meta-analy - sis of nine RCTs reported difference between the ovary with endometrioma compared to the contralateral nonaf- fected ovary regarding the numbers of retrieved oocytes, MII oocytes, and obtained embryos. All were reported to be lower from the affected ovaries. They suggested dif - ferent mechanism for these findings including changes in immune markers as IL-6, VEGF, and oxidative stress markers with resultant decrease in density and diameters of primordial follicles. However, there was no differences regarding clinical pregnancy and live birth rates [35]. The impact of surgical treatment for endometrioma before IVF remains a controversy. In a retrospective trial that involved 292 women with existing endometrioma, no history of surgery who were candidate for IVF, they reported lower numbers of antral follicles and required higher doses of Gn in women with existing endometriomas compared to those with previous surgery for endometrio- mas and absent endometrioma at time of IVF without any significant difference in live birth rate between them [36]. In a recent meta-analysis, there was a significantly lower number of retrieved oocytes and higher rate of cycle cancellation in women with existing endometrioma during IVF cycle with similar clinical pregnancy and live birth rates when compared to women without endome - triomas [37, 38]. Hamadan and colleagues suggested that the presence of ovarian endometrioma exerts a negative effect on the ovarian tissue with resultant decrease in number and quality of retrieved oocytes and increase in baseline FSH level [37]. On the other hand, a retrospective study reported a signif- icantly higher clinical pregnancy and live birth rates trial in women who underwent laparoscopic cystectomy for endo- metrioma when compared to those underwent diagnostic laparoscopy without resection before IVF [39]. In a large Fig. 3 Clinical pregnancy rate (surgical intervention vs. no treatment) Page 14 of 15Katta et al. Middle East Fertility Society Journal (2024) 29:27 observational study that involved 825 women diagnosed with endometriosis-related infertility, there was a signifi - cantly higher overall pregnancy rates in women who under- went endometrioma surgical resection followed by IVF compared to those who underwent surgical resection with- out IVF, IVF without prior resection, or no treatment [40]. Furthermore, several studies have reported the adverse effects of surgical treatment of endometrioma on ovar - ian reserve markers as the reduction of serum AMH levels after surgery [41]. After surgery, the level of AMH is reduced by 34% 1  week after surgery and gradually improves to reach 65% of its preoperative level 3 months after the operation. Measurement of AMH after 1  year of surgery revealed similar level to that reported after 1 month of surgery. Bilateral ovarian cystectomy is asso - ciated with more damage to ovarian reserve [42]. Regarding the medical treatment before IVF, a sys - tematic review included 19 studies with 1709 partici - pants compared with dydrogesterone to other hormonal therapies. It concluded that dydrogesterone caused bet - ter relieve of dysmenorrhea and improved the pregnancy rate compared to gestrinone with less side effects. They also concluded that dydrogesterone decreased the recur - rence rate compared to with GnRH-a treatment. There are insufficient data to compare the efficacy of dydro - gesterone, letrozole and leuprolide acetate, and the tra - ditional Chinese medicine remains [43]. A Cochrane overview concluded that a 3-month regimen with GnRH agonist before IVF improves the pregnancy rates [44]. Strengths and limitations This review is the first systematic review to study the clinical parameters of the effects of both surgical and medical treatment of endometrioma before IVF cycles. We included all the available studies that included all types of interventions. Adequate data extractions and proper meta-analysis when possible was done. The main

of this review is the low quality of evidence because of the absence of adequate numbers of RCTs and the marked heterogeneity among the included studies.

In conclusion, the optimal approach for treating endome- trioma prior to IVF is not clear yet due to lack of well- designed randomized controlled trials. Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s43043- 024- 00189-3. Supplementary Material 1. Supplementary Material 2.

None. Authors’ contributions Study concept and design, MK and WSR. Analysis and interpretation of data, AM and AO. Drafting of the manuscript, MK. Critical revision of the manuscript for important intellectual content, all authors. Funding None. Availability of data and materials All data used are available within the manuscript itself. Data used and/or analyzed during the study are available from the corre- sponding author upon request. Declarations Ethics approval and consent to participate Not applicable. Consent for publication All authors give their consent for publication. Competing interests The authors declare that they have no competing interests. Author details 1 Department of Obstetrics and Gynecology, Beni-Suef University, Beni Suef, Egypt. 2 Department of Obstetrics and Gynaecology, Kasr Al-Ainy Hospital, Cairo University, Giza 12111, Egypt. 3 Department of Obstetrics and Gynecol- ogy, Fayoum University, Fayoum, Egypt. Received: 12 December 2023 Accepted: 21 May 2024

1. Acién P , Velasco I (2013) Endometriosis: a disease that remains enigmatic. ISRN Obstet Gynecol 17(2013):242149 2. Becker CM, Bokor A, Heikinheimo O, Horne A, Jansen F, Kiesel L, King K, Kvaskoff M, Nap A, Petersen K, Saridogan E, Tomassetti C, van Hanegem N, Vulliemoz N, Vermeulen N (2022) ESHRE Endometriosis Guideline Group ESHRE guideline: endometriosis. Hum Reprod Open 2022(2):hoac009 3. Fauconnier A, Chapron C (2005) Endometriosis and pelvic pain: epide- miological evidence of the relationship and implications. Hum Reprod Update 11(6):595–606 4. Giudice LC (2010) Clinical practice Endometriosis. N Engl J Med 362(25):2389–2398 5. Garalejić E, Bojović-Jović D, Damjanović A, Arsić B, Pantić I, Turjacanin- Pantelić D, Perović M (2010) Hamilton Anxiety Scale (HAMA) in infertile women with endometriosis and its correlation with magnesium levels in peritoneal fluid. Psychiatr Danub 22(1):64–67 6. Macer ML, Taylor HS (2012) Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin North Am 39(4):535–549 7. Stephansson O, Kieler H, Granath F, Falconer H (2009) Endometriosis, assisted reproduction technology, and risk of adverse pregnancy out- come. Hum Reprod 24(9):2341–2347. https:// doi. org/ 10. 1093/ humrep/ dep186. (Epub 2009 May 12 PMID: 19439428) 8. Pellicer A, Oliveira N, Ruiz A, Remohi J, Simon C (1995) Exploring the mechanism(s) of endometriosis-related infertility: an analysis of embryo development and implantation in assisted reproduction. Hum Reprod 10(Suppl 2):91–97 9. SukhikhG T, Sotnikova NY, Antsiferova YS, Posiseeva LV, Veryasov VN, Vanko LV (2004) Cytokine production by immunocompetent cells of peritoneal fluid in women with external genital endometriosis. Bull Exp Biol Med 137(6):568 Page 15 of 15 Katta et al. Middle East Fertility Society Journal (2024) 29:27 10. de Ziegler D, Borghese B, Chapron C (2010) Endometriosis and infertility: pathophysiology and management. Lancet 376(9742):730–738 11. Bazot M, Daraï E (2017) Diagnosis of deep endometriosis: clinical examina- tion, ultrasonography, magnetic resonance imaging, and other techniques. Fertil Steril 108(6):886–894 12. Hughes E, Brown J, Collins JJ, Farquhar C, Fedorkow DM, Vandekerckhove P (2007) Ovulation suppression for endometriosis. Cochrane Database Syst Rev 3:CD000155 13. Ahmad G, O’Flynn H, Duffy JM, Phillips K, Watson A (2012) Laparoscopic entry techniques. Cochrane Database Syst Rev 2:CD006583 14. Higgins, J.P .T. and Green, S. (2011) Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. The Cochrane Collaboration. http:// handb ook-5- 1. cochr ane. org 15. Demirdag E, Guler I, Selvi I, Cevher Akdulum MF, Canan S, Erdem A, Erdem M (2021) Analysis of 2438 cycles for the impact of endometrioma and its surgery on the IVF outcomes. Eur J Obstet Gynecol Reprod Biol 263:233– 238. https:// doi. org/ 10. 1016/j. ejogrb. 2021. 06. 034. (Epub 2021 Jun 29 PMID: 34242932) 16. Demirol A, Guven S, Baykal C, Gurgan T (2006) Effect of endometrioma cys- tectomy on IVF outcome: a prospective randomized study. Reprod Biomed Online 12(5):639–643. https:// doi. org/ 10. 1016/ s1472- 6483(10) 61192-3. (PMID: 16790114) 17. Garcia-Velasco JA, Arici A (2004) Surgery for the removal of endometriomas before in vitro fertilization does not increase implantation and pregnancy rates. Fertil Steril 81(5):1206. https:// doi. org/ 10. 1016/j. fertn stert. 2003. 10. 032. (PMID: 15136078) 18. Guler I, Erdem A, Oguz Y, Cevher F, Mutlu MF, Bozkurt N, Oktem M, Erdem M (2017) The impact of laparoscopic surgery of peritoneal endometriosis and endometrioma on the outcome of ICSI cycles. Syst Biol Reprod Med 63(5):324–330. https:// doi. org/ 10. 1080/ 19396 368. 2017. 13321 14. (Epub 2017 Jun 13 PMID: 28609124) 19. Kuroda K, Kitade M, Kikuchi I, Kumakiri J, Matsuoka S, Kuroda M, Takeda S (2009) The impact of endometriosis, endometrioma and ovarian cystec- tomy on assisted reproductive technology. Reprod Med Biol 8(3):113–118. https:// doi. org/ 10. 1007/ s12522- 009- 0021-1. (Erratum.In:ReprodMedBiol.200 9Sep19;8(4):181.PMID:29699316;PMCID:PMC5907135) 20. 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. https:// doi. org/ 10. 5468/ ogs. 2014. 57.4. 297. (Epub 2014 Jul 15. PMID: 25105103; PMCID: PMC4124091) 21. Liang Y, Yang X, Lan Y, Lei L, Li Y, Wang S (2019) Effect of endometrioma cystectomy on cytokines of follicular fluid and IVF outcomes. J Ovarian Res 12(1):98. https:// doi. org/ 10. 1186/ s13048- 019- 0572-7. (PMID:31639028;PMCI D:PMC6802315) 22. Lossl K, Loft A, Freiesleben NL, Bangsbøll S, Andersen CY, Pedersen AT, Hartwell D, Andersen AN (2009) Combined down-regulation by aromatase inhibitor and GnRH-agonist in IVF patients with endometriomas-a pilot study. Eur J Obstet Gynecol Reprod Biol 144(1):48–53. https:// doi. org/ 10. 1016/j. ejogrb. 2009. 02. 001. (Epub 2009 Mar 3 PMID: 19261371) 23. Maged AM, Rashwan H, Mahmoud M, El-Mazny A, Farouk M, Belal DS, Marie HM (2018) Effect of prolonged GnRH agonist downregulation on ICSI outcome in patients with endometriomas of less than 5 cm: a randomized controlled trial. Reprod Sci 25(10):1509–1514. https:// doi. org/ 10. 1177/ 19337 19118 756753. (Epub 2018 Feb 13 PMID: 29439618) 24. Muller V, Kogan I, Yarmolinskaya M, Niauri D, Gzgzyan A, Aylamazyan E (2017) Dienogest treatment after ovarian endometrioma removal in infertile women prior to IVF. Gynecol Endocrinol 33(sup1):18–21. https:// doi. org/ 10. 1080/ 09513 590. 2017. 14156 76. (PMID: 29264985) 25. Pabuccu R, Onalan G, Goktolga U, Kucuk T, Orhon E, Ceyhan T (2004) Aspira- tion of ovarian endometriomas before intracytoplasmic sperm injection. Fertil Steril 82(3):705–711. https:// doi. org/ 10. 1016/j. fertn stert. 2004. 02. 117. (PMID: 15374718) 26. Pabuccu R, Onalan G, Kaya C (2007) GnRH agonist and antagonist protocols for stage I-II endometriosis and endometrioma in in vitro fertilization/intra- cytoplasmic sperm injection cycles. Fertil Steril 88(4):832–839. https:// doi. org/ 10. 1016/j. fertn stert. 2006. 12. 046. (Epub 2007 Apr 10 PMID: 17428479) 27. Suganuma N, Wakahara Y, Ishida D, Asano M, Kitagawa T, Katsumata Y, Moriwaki T, Furuhashi M (2002) Pretreatment for ovarian endometrial cyst before in vitro fertilization. Gynecol Obstet Invest 54(Suppl 1):36–40. https:// doi. org/ 10. 1159/ 00006 6293. (discussion 41-2 PMID: 12441659) 28. Takashima A, Takeshita N, Otaka K, Kinoshita T (2013) Effects of bipolar electro- coagulation versus suture after laparoscopic excision of ovarian endometrioma on the ovarian reserve and outcome of in vitro fertilization. J Obstet Gynaecol Res 39(7):1246–1252. https:// doi. org/ 10. 1111/ jog. 12056. (PMID: 23803008) 29. Wong BC, Gillman NC, Oehninger S, Gibbons WE, Stadtmauer LA (2004)

of in vitro fertilization in patients with endometriomas: is surgical removal beneficial? Am J Obstet Gynecol 191(2):597–606. https:// doi. org/ 10. 1016/j. ajog. 2004. 05. 079. (discussion 606-7 PMID: 15343246) 30. Candiani M, Ferrari S, Bartiromo L, Schimberni M, Tandoi I, Ottolina J (2021) Fertility outcome after CO2 laser vaporization versus cystectomy in women with ovarian endometrioma: a comparative study. J Minim Invasive Gynecol 28(1):34–41. https:// doi. org/ 10. 1016/j. jmig. 2020. 07. 014. (Epub 2020 Jul 24. PMID: 32712323) 31. Cantor A, Tannus S, Son WY, Tan SL, Dahan MH (2019) A comparison of two months pretreatment with GnRH agonists with or without an aromatase inhibitor in women with ultrasound-diagnosed ovarian endometriomas undergoing IVF. Reprod Biomed Online 38(4):520–527. https:// doi. org/ 10. 1016/j. rbmo. 2018. 12. 028. (Epub 2018 Dec 22 PMID: 30935663) 32. de Ziegler D, Gayet V, Aubriot FX, Fauque P , Streuli I, Wolf JP , de Mouzon J, Chapron C (2010) Use of oral contraceptives in women with endometriosis before assisted reproduction treatment improves outcomes. Fertil Steril 94(7):2796–2799. https:// doi. org/ 10. 1016/j. fertn stert. 2010. 05. 056. (Epub 2010 Jul 21 PMID: 20663495) 33. Somigliana E, Infantino M, Benedetti F, Arnoldi M, Calanna G, Ragni G (2006) The presence of ovarian endometriomas is associated with a reduced responsiveness to gonadotropins. Fertil Steril 86:192–196 34. Benaglia L, Somigliana E, Santi G, Scarduelli C, Ragni G, Fedele L (2011) IVF and endometriosis-related symptom progression: insights from a prospec- tive study. Hum Reprod 26:2368–2372 35. Yang C, Geng Y, Li Y, Chen C, Gao Y (2015) Impact of ovarian endometrioma on ovarian responsiveness and IVF: a systematic review and meta-analysis. Reprod Biomed Online 31(1):9–19. https:// doi. org/ 10. 1016/j. rbmo. 2015. 03. 005. (Epub 2015 Mar 19) 36. Dong X, Wang R, Zheng Y, Xiong T, Liao X, Huang B, Zhang H (2014) Surgical treatment for endometrioma does not increase clinical pregnancy rate or live birth/ongoing pregnancy rate after fresh IVF/ICSI treatment. Am J Transl Res 6(2):163–168 37. Hamdan M, Dunselman G, Li TC, Cheong Y (2015) The impact of endome- trioma on IVF/ICSI outcomes: a systematic review and metaanalysis. Hum Reprod Update 21:809–825 38. Hong SB, Lee NR, Kim SK, Kim H, Jee BC, Suh CS et al (2017) In vitro fertiliza- tion outcomes in women with surgery induced diminished ovarian reserve after endometrioma operation: comparison with diminished ovarian reserve without ovarian surgery. Obstet Gynecol Sci 60:63–68 39. Opøien HK, Fedorcsak P , Byholm T, Tanbo T (2011) Complete surgical removal of minimal and mild endometriosis improves outcome of subse- quent IVF/ICSI treatment. Reprod BioMed Online 23(3):389–395 40. Barri PN, Coroleu B, Tur R, Barri-Soldevila PN, Rodríguez I (2010) Endome- triosis-associated infertility: surgery and IVF, a comprehensive therapeutic approach. Reprod BioMed Online 21(2):179–185 41. Iwase A, Hirokawa W, Goto M (2010) Serum anti-Müllerian hormone level is a useful marker for evaluating the impact of laparoscopic cystectomy on ovarian reserve. Fertil Steril 94(7):2846–49 42. Sugita A, Iwase A, Goto M, Nakahara T, Nakamura T, Kondo M, Osuka S, Mori M, Saito A, Kikkawa F (2013) One-year follow-up of serum antimüllerian hor- mone levels in patients with cystectomy: are different sequential changes due to different mechanisms causing damage to the ovarian reserve? Fertil Steril 100(2):516–22.e3 43. Peng C, Huang Y, Zhou Y. Dydrogesterone in the treatment of endometriosis: evidence mapping and meta-analysis. Arch Gynecol Obstet. 2021 Jan 4. https:// doi. org/ 10. 1007/ s00404- 020- 05900-z. Epub ahead of print. PMID: 33398505. 44. Brown J, Farquhar C (2014) Endometriosis: an overview of Cochrane reviews. Cochrane Database Syst Rev 2014(3):D009590. https:// doi. org/ 10. 1002/ 14651 858. (PMID:24610050;PMCID:PMC6984415) Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.