The study protocol was designed a priori and agreed upon by all authors. We conducted an overview (systematic review) of systematic reviews following the recommendations of Smith et al. (18) and the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (19, 20). The overview was registered in advance on the International Prospective Register of Systematic Reviews (PROSPERO—CRD42024595209).

We conducted an extensive database search on PubMed, Medline (Web of Science platform), Epistemonikos, the Cochrane Library, and PROSPERO. The search in these databases focused on publications in the English literature from their inception until March 31, 2025. The search terms (including their MeSH) used were endometriosis OR endometrioma AND sclerotherapy. The investigation was limited to manuscripts published in peer-reviewed journals and human studies. After the selection process, we screened the bibliographies of eligible manuscripts for other potentially suitable papers. All sclerosing agents were considered for inclusion in the search strategy.

Systematic reviews (with or without meta-analysis) that examined the safety and efficacy of sclerotherapy in women with ovarian endometrioma at reproductive age were applicable for evaluation. Specifically, reviews that explored the procedure efficacy, pain relief, the recurrence rate of endometrioma, the impact on ovarian reserve, the ART outcome, and the pregnancy outcome were eligible. Furthermore, systematic reviews that compared sclerotherapy safety and efficacy to endometriotic cystectomy were qualified.

Narrative reviews and opinion papers were excluded from the evaluation. Systematic reviews targeting only women with non-endometriotic ovarian cysts, gonadal or non-gonadal malignancies, and polycystic ovary syndrome were also excluded. Additionally, systematic reviews focused on females in adolescence, perimenopause, or postmenopause were excluded from the evaluation. Moreover, papers assessing women undergoing other minimally invasive approaches, such as endometrioma ablation using electrocoagulation or plasma energy and laser vaporization, were excluded. Data presented exclusively as abstracts at scientific meetings were discounted. Furthermore, reviews with discernible sampling bias or inappropriate design were excluded.

All studies relevant to the research question were retrieved. Two reviewers (JSY and NS) independently screened, reviewed, and selected relevant publications for this overview. The screening process for systematic reviews consisted of two stages, e.g., title/abstract, followed by full-text. We resolved disagreements regarding inclusion, quality assessment, and data extraction through discussion, consensus, or mediation with a third reviewer (HST).

Two independent reviewers (JSY and NS) utilized the AMSTAR2 tool to assess the quality of eligible systematic reviews (17). This tool was selected because current meta-analyses often include both randomized and non-randomized intervention studies in their evaluations. AMSTAR2 helps decision-makers identify high-quality systematic reviews that cover both types of studies.

The evaluation of eligible systematic reviews was conducted using the sixteen domains of AMSTAR2. Each domain was categorized as “yes,” “partial yes,” or “no” based on whether it was fully implemented (and documented), partially applied, or not implemented, respectively, in each systematic review. Based on the critical and non-critical domains defined by AMSTAR2, the overall evidence was rated as high, moderate, low, or critically low (17).

We utilized a citation matrix to evaluate the overlap among studies analyzed in the included systematic reviews. This allowed us to calculate the corrected cover area (CCA) according to Pieper et al. (21).

To properly evaluate the use of sclerotherapy for managing endometriomas, we first looked at whether it was used as a primary treatment (without previous surgery) or as a secondary treatment (after recurrence). We focused on assessing the technical efficacy of the procedure, its impact on pain relief, and the occurrence of any adverse events. Additionally, we studied the likelihood of endometrioma recurrence after the procedure and the effect of sclerotherapy on measures of ovarian reserve. We also examined how sclerotherapy affected pregnancy rates and assisted reproductive technology (ART) outcomes. Furthermore, we compared the outcome measures of sclerotherapy with those of endometriotic cystectomy.

For consistency, outcomes were defined as follows: technical success = successful aspiration and instillation/retention of ethanol without procedural failure; recurrence = reappearance of an endometrioma in the treated ovary on follow-up imaging; pain improvement = reduction or resolution of endometriosis-related pelvic pain as reported by individual studies; pregnancy outcomes = any reported conception, unless specifically defined as spontaneous or ART-related. Where reviews distinguished a clinical pregnancy (ultrasound-confirmed gestational sac) or live birth, this is stated explicitly.

Two reviewers, JSY and NS, independently performed the data extraction. We created a descriptive table summarizing all systematic reviews on sclerotherapy for managing endometrioma during the reproductive years. For each eligible review, we documented the first author, publication year, the study aims, detailed review objectives, sclerosing agent used, number of studies included in the review, total number of women, number of studies that exclusively used ethanol, the tool used for evaluating the risk of bias in the included studies, and whether a meta-analysis was conducted.

We have created a second descriptive table that inclusively summarizes the results of the outcome measures of all eligible reviews. We collected pooled estimates of the outcome measures from the systematic reviews and meta-analyses and organized them into the table. The remaining results were either calculated or summarized from the data within the systematic reviews. Additionally, we included a comparison of sclerotherapy and endometriotic cystectomy.

In systematic reviews that predominantly employed ethanol and performed pooled estimates, we meticulously assessed the strength of evidence for each outcome measure following the GRADE recommendations (22, 23). Two review authors (JSY, NS) independently and thoroughly assessed the certainty of the evidence using GRADE. The level of evidence was evaluated using the five recommended domains of GRADE scoring, which include study limitations (risk of bias), inconsistency, indirectness, imprecision, and publication bias. The overall grading was adversely affected by these factors. To enhance the application of the GRADE scoring tool, we utilized the checklist of questions that was published in 2014 (24).

Since the current systematic reviews include many observational studies, we assessed the possibility of increasing the level of evidence by considering three additional factors in the GRADE system. These factors are a large magnitude of effect, a dose-response gradient, and residual confounders (24). Finally, we classified the levels and certainty of the evidence for each outcome studied on a four-level scale: very low, low, moderate, or high (22, 23).

Database and manual searching identified two hundred seventy-six manuscripts (Figure 1). Following exclusions of duplicates and elimination of publications by reading the title and abstract, thirty reviews were qualified for full-text assessment. Among these publications, twenty-one were excluded from the final evaluation; fourteen were narrative reviews (25–38), five did not discuss sclerotherapy (39–43), and two were not in English (44, 45). The remaining nine systematic reviews were eligible for final analysis (14, 15, 46–52).

As summarized in Table 1, nine systematic reviews were eligible for critical appraisal: seven with meta-analysis (14, 15, 47–51) and two without (46, 52). According to the Journal Citation Reports 2023, all of these systematic reviews, except one (15), were published in a Journal with an established impact factor. Six systematic reviews evaluated multiple sclerosing agents, including Ethanol, Methotrexate, Tetracycline, and Lauromacrogol, and three targeted solely Ethanol (15, 49, 52). In five systematic reviews, ethanol was the predominant sclerosing agent (14, 15, 47, 51, 52).

Additionally, all but one systematic review evaluated only women with endometrioma, while another review evaluated other benign pelvic cystic masses, including simple cysts, hydrosalpinx, and other lesions, in addition to endometrioma (50). Furthermore, all systematic reviews evaluated endometrioma aspiration and sclerotherapy; seven compared sclerotherapy with surgery (14, 15, 47–49, 51, 52), and one evaluated other endometrioma management modalities (48).

The quality of eligible systematic reviews per the AMSTAR2 tool ranged between moderate to critically low (Table 2). The AMSTAR2 sixteen domains were scored as yes, partial yes, or no based on whether it was fully implemented, partially applied, or not implemented, respectively. Following the AMSTAR2 critical and non-critical defined domains (17), the quality appraisal was critically low in three (15, 46, 48), low in four (47, 49, 50, 52), and moderate in two (14, 51) systematic reviews.

An overlap analysis using a citation index revealed that the nine eligible systematic reviews included 67 studies, with 31 of them analyzed more than once. Using the citation matrix proposed by Pieper et al. (21), the corrected covered area was calculated to be 14.1%. This overlap prevented the conduct of a random-effects meta-analysis for the primary outcomes.

Only seven studies were included in four systematic reviews that compared ethanol sclerotherapy to endometriotic cystectomy and examined pregnancy rates. One study was analyzed four times, while another four were analyzed three times, precluding a random-effects meta-analysis to combine the effect measures for this outcome.

The practice of ethanol sclerotherapy varied among the studies in each systematic review (Table 3). In most cases, aspiration and sclerotherapy were conducted trans-vaginally under ultrasound guidance. In some cases, the trans-abdominal approach was chosen depending on the exact location of the endometrioma. In one of the largest systematic reviews, among the 21 studies that employed ethanol as the sclerosing agent, only six employed the trans-abdominal approach guided by ultrasound or laparoscopy (14).

The procedure was typically carried out under sterile conditions. The endometrioma was usually punctured and aspirated using a needle ranging from 17 to 20 gauge and 20 to 25 cm long. In some cases, an 8.5-F pigtail catheter was utilized instead. Generally, the endometrioma was aspirated to remove its contents and then flushed with a saline solution before introducing ethanol.

The concentration of ethanol used in the studies ranged from 20% to 100%, with most studies employing 95% to 100% dosing (about two-thirds of studies). The volume of ethanol injected depended on the endometrioma size and varied between 20% and 100% of the endometrioma volume. In numerous studies, the maximal volume of ethanol used was below 60–100 ml to prevent spillage and rupture.

The duration of ethanol sclerotherapy varied across different studies. Some studies utilized irrigation, while others retained the ethanol, with approximately two-thirds of cases involving irrigation and one-third retaining the ethanol. In the irrigation cases, the duration of ethanol contact varied widely, ranging from one to 30 minutes. In most instances, the duration fell between 5 and 20 minutes.

Nine eligible reviews focused on various safety and efficacy aspects of sclerotherapy for endometrioma management in women of reproductive age. The results are summarized in Table 4. Seven systematic reviews also compared sclerotherapy with the surgical approach, specifically endometriotic cystectomy. The main findings are focused on accumulated evidence of these aspects, specifically when employing ethanol as the sclerosing agent and when data was pooled for quantitative estimates.

It is essential to note that all eligible systematic reviews included combined studies that evaluated women with endometrioma undergoing sclerotherapy as a primary (intact endometrioma) and secondary (endometrioma recurrence) treatment option.

Table 5 summarizes the strength of evidence for the main outcome measures in eligible systematic reviews primarily focusing on ethanol sclerotherapy that attained quantitative estimates. The strength of evidence of these outcome measures was evaluated using the GRADE tool. The eligible systematic reviews included both experimental (RCT) and observational studies. As most cases involved observational studies, the evidence initially in our overview started with low quality following the GRADE approach (23). Furthermore, a serious limitation was present in all eligible systematic reviews, specifically in the ‘limitations’ domain (risk of bias). Therefore, since serious limitations preclude upgrading the level of evidence according to the GRADE recommendations (23), we decided not to consider the magnitude of effect, dose-response gradients, and residual confounders to promote the primary evaluation’s results.

The strength of evidence regarding the technical efficacy and adverse events of ethanol sclerotherapy in managing endometrioma was low. The pooled estimate of technical efficacy was 98.3%, and the minor and major adverse events were 11.0% and 1.7%, respectively (14). Despite the low strength of evidence, the large number of women involved in the evaluation (650 and 1,117) and the short-term effect on these outcomes increase the evidence, may suggest that this minimally invasive approach could be a feasible option for treating endometrioma.

Moreover, there was a low level of evidence to show that ethanol retention is superior to irrigation, and ethanol exposure of > 10 minutes is more efficient than ≤ 10 minutes in preventing endometrioma recurrence (14, 47).

Conversely, sclerotherapy’s impact on pain relief, ovarian reserve, pregnancy rates, and IVF results had a very low level of evidence, suggesting that the estimated effects are very uncertain.

Four systematic reviews have compared ethanol sclerotherapy to endometriotic cystectomy, focusing on adverse events, recurrence rate, pregnancy rates, number of oocytes, and clinical pregnancy rates in the context of IVF (14, 15, 47, 51). The strength of evidence varied from low to very low and, at times, was controversial, making it difficult to draw definitive conclusions. Of note, two systematic reviews reported similar pregnancy rates between sclerotherapy and endometriotic cystectomy (n = 370 and 235, respectively) (15, 51), whereas a third review showed an advantage for sclerotherapy (n = 189) (14). However, the level of evidence was low in the first two reviews and very low in the third, precluding a definitive conclusion.

Our comprehensive critical overview of systematic reviews indicates that sclerotherapy, specifically with ethanol, is a feasible and readily applicable management modality for women with endometrioma during their reproductive years. This finding supports its application as a minimally invasive management approach for women facing infertility or those who have not yet achieved their reproductive goals. Sclerotherapy appears to preserve ovarian reserve better than ovarian cystectomy.

Although each primary outcome measure had only one estimate among the nine systematic reviews (which precluded the pooling of effect measures), our overview shows that sclerotherapy has a high technical efficacy of 95.0-98.3%. Additionally, the rates of adverse events were low, with minor events reported at 11.0-12.0% and major adverse events at 1.0-1.7%. Although the strength of the evidence was assessed as low, the analysis involved a large number of women, and the effect was observed over a short time, supporting the feasibility of this minimally invasive approach for managing endometrioma in women of reproductive age.

Furthermore, there is low-strength evidence that ethanol retention is more effective than irrigation, and sclerotherapy for more than 10 minutes is better than less than 10 minutes in preventing endometrioma recurrence.

The impact of ethanol sclerotherapy on pain relief, ovarian reserve, pregnancy rate, and IVF results are based on very low evidence strength, suggesting uncertainty and precluding definitive conclusions. In addition, systematic reviews that compared sclerotherapy to endometriotic cystectomy, although showing comparable pregnancy rates, had low to very low evidence strength and sometimes provided controversial estimates, making reliable conclusions at this stage challenging to reach.

Sclerotherapy is the controlled, therapeutic use of sclerosants to destroy undesired target tissues. Ethanol sclerotherapy was first applied in 1980 and was used to manage endometrioma in 1988 (53, 54). Since then, it has gained popularity worldwide. Its mechanism of action involves cytotoxic damage induced by the denaturation and extraction of surface proteins, hypertonic dehydration of cells, and coagulation and thrombosis in the presence of blood products, leading to fibrinoid necrosis (55). Dosing should not exceed 1 mL/kg because this dose can lead to systemic blood alcohol concentrations of up to 0.07%, posing the risk of alcohol intoxication. The risk of alcohol intoxication in our overview, under these regulations, was negligible. Furthermore, the rates of other minor and major adverse events were reasonable in our overview, supporting the feasibility of this management modality for endometrioma.

Extensive literature continuously discusses whether endometrioma could reduce ovarian reserve by itself. Evidence exists on both sides, but the proof seems inconclusive (56, 57). A recent systematic review of prospective studies (n = 1,272) found that intact bilateral endometrioma, compared to unilateral endometrioma, a surrogate measure of more advanced disease, did not significantly affect preoperative serum AMH levels, challenging that endometrioma per se reduces functional ovarian reserve (6). Conversely, there is convincing evidence that ovarian cystectomy significantly harms ovarian reserve in a non-reversible way (5, 6), and may lead to ovarian insufficiency and early menopause (11–13). Our overview implies that ethanol sclerotherapy did not impair ovarian reserve; however, the strength of evidence was low. Additionally, future research on this matter may be beneficial in refining ethanol dosage, volume, and sclerosing duration to optimize its effect on ovarian reserve and endometrioma recurrence.

Endometrioma recurrence after endometriotic cystectomy is also a primary concern. Based on short-term and long-term follow-up studies, the reported recurrence rate after endometriotic cystectomy is high, estimated at 21.5% at two years and 40-50% at five years (58, 59). Furthermore, there is a high rate of repeat surgeries (60, 61). In a recent large-scale, population-based, long-term study on women who underwent surgery for endometriosis, it was found that 1 in 4 individuals following minor surgery and 1 in 5 following major conservative surgery (with ovarian preservation) required additional endometriosis surgery (61).

In our overview, the recurrence rate varied considerably, ranging from 16% to 67%. However, our overview of eligible systematic reviews of ethanol sclerotherapy was assessed in combined primary and secondary treatment cases based on short-term follow-up. Future studies should focus on sclerotherapy as a primary management tool with long-term follow-up. In this regard, identifying biomarkers for the diagnosis or recurrence of endometriosis would help track disease progression (62, 63).

In the IVF setting, various systematic reviews have shown that an intact endometrioma reduces the number of retrieved oocytes compared to normal ovaries, but clinical and live birth rates are comparable (64–66). Furthermore, several systematic reviews have shown that endometriotic cystectomy, compared to expectant management, does not improve clinical pregnancy and live birth rates (64, 67–71).

In our overview, we found that using ethanol sclerotherapy to treat endometriomas did not show significant differences in pregnancy rates when compared to expectant management or endometriotic cystectomy. However, it was unclear whether the pregnancies occurred naturally or as a result of IVF treatment. Additionally, the evidence supporting these findings was of low to very low quality. Future studies should investigate whether sclerotherapy offers any advantages over expectant management or endometriotic cystectomy in terms of pregnancy and live birth rates.

Our overview of systematic reviews did not assess the cost-effectiveness of ethanol sclerotherapy. In recent small-scale studies (n = 33-71), ethanol sclerotherapy, compared to endometriotic cystectomy, avoided or reduced hospitalization stays, decreasing health costs substantially (72, 73). One study performed the procedure on outpatients without anesthesia, sedation, or prophylactic antibiotics, reducing health costs eightfold (73). Future studies should pursue ethanol sclerotherapy costs, achieving the best outcome measures at the lowest possible cost.

Ethanol sclerotherapy has its limitations. It cannot be performed when an endometrioma ruptures during the procedure or when there is a risk of malignancy. However, the occurrence of endometrioma rupture and the risk of malignant transformation are both uncommon and sporadic. Among women with gonadal endometriosis-associated ovarian cancer, only 0.028% are under the age of 40, with a calculated risk of 3 to 1000 (74). Utilizing magnetic resonance imaging (MRI) for atypical endometriomas diagnosed by trans-vaginal ultrasound prior to sclerotherapy may aid in distinguishing between benign endometriomas and malignant transformations (75). Furthermore, when other subtypes of endometriosis, such as superficial, deep infiltrating, or adenomyosis, are present, a comprehensive multidisciplinary evaluation is recommended to determine optimal management and treatment planning.

Our overview of the systematic reviews has numerous strengths. It is the first contemporary overview that rigorously evaluates systematic reviews focusing on sclerotherapy, particularly with ethanol, as a minimally invasive treatment for women of reproductive age with ovarian endometriosis. We developed a study protocol that all the review authors agreed upon and registered on PROSPERO beforehand.

The safety and efficacy of endometrioma sclerotherapy management were evaluated by examining various outcome measures. These measures included technical efficacy, pain relief, endometrioma recurrence, impact on ovarian reserve, adverse events, pregnancy rate, and IVF results. Additionally, comparisons with endometriotic cystectomy were also analyzed.

We used five search engines to systematically maximize our results by searching for eligible papers and looking for published and ongoing reviews. Previous publications were narrative and only briefly précised the procedure without delving into the various aspects of sclerotherapy’s safety and effectiveness. Additionally, they did not include details of the search methodology.

We applied the AMSTAR2 tool to evaluate the quality of eligible systematic reviews, incorporating randomized and non-randomized intervention studies. Additionally, we rated each systematic review’s overall evidence according to the critical and non-critical domains defined by AMSTA2 guidelines.

The strength of evidence for each outcome measure in all eligible systematic reviews was evaluated using the GRADE scoring system. Furthermore, the levels and certainty of the evidence for each outcome studied were categorized on a four-level scale: very low, low, moderate, or high, as recommended (22, 23).

In contrast, the overview of systematic reviews we conducted has several limitations. All eligible systematic reviews included an assessment of sclerotherapy as a combined primary and secondary treatment for endometrioma. The reviews pooled cases of endometrioma recurrence after endometriotic cystectomy and others who received sclerotherapy as their initial treatment. This made it challenging to genuinely assess sclerotherapy as a primary management modality in women with endometrioma.

Additionally, the inclusion of both investigational randomized and observational non-randomized (largely retrospective) studies of intervention influenced the quality of systematic reviews. This was assessed using the MASTAR2 tool, which ranged from moderate to critically low. Moreover, it influenced the level of evidence of the outcome measures, as assessed by the GRADE tool, and the strength of recommendations.

As demonstrated in Table 5, the primary outcome measures in the included systematic reviews had only one estimate each. Thus, a random-effects meta-analysis was not performed to pool together effect measures for these outcomes. Furthermore, while four systematic reviews comparing ethanol sclerotherapy to endometriotic cystectomy had more than three estimates for two of the primary outcome measures (endometrioma recurrence and pregnancy rates), the overlap between the included studies was high, which precluded pooling the effect measures.

Also, endometrioma laterality (uni- or bilateral) and diameter were not considered when assessing sclerotherapy safety and efficacy. In cases following endometriotic cystectomy, laterality significantly influences the decline in ovarian reserve measures following surgery (6). Furthermore, endometrioma size may impact ovarian reserve since it has been suggested to affect ovarian responsiveness during IVF treatment (76). These endometrioma characteristics are essential when assessing the efficacy and safety of sclerotherapy and should be considered in future research.

Furthermore, the available systematic reviews did not adequately address the impact of sclerotherapy on ovarian reserve. While some reviews touched on this topic using AMH or AFC, none did so proficiently. The rationale for employing sclerotherapy, particularly with ethanol, aimed to avoid the significant decline of ovarian reserve caused by endometriotic cystectomy. Notably, none of the eligible systematic reviews assessed ovarian reserve measures following sclerotherapy over time. Additionally, it is essential to note that AMH is a more sensitive measure of ovarian reserve in this setting, and AFC is not recommended in women with endometrioma (77).