Ethanol Sclerotherapy for Primary and Recurrent Endometrioma Improves In Vitro Fertilization Pregnancy Outcomes: A Randomized Clinical Trial

Endometriosis affects approximately 10% of women of reproductive age and is among the most prevalent gynecological disorders ( 1 , 2 ). Its prevalence rises to 40 -60% in women with dysmenorrhea and 30-40% in those experiencing infertility. Ovarian endometriomas, present in 17-44% of women with endometriosis, consist of endometrial tissue and fluid resulting from the accumulation of menstrual debris. Endometriomas have been shown to adversely affect ovarian response to stimulation, oocyte yield, and embryo implantation. Women with endometriosis generally exhibit a reduced response to gonadotropins ( 3 , 4 ), often requiring substantially higher doses per cycle compared with women with tubal-factor infertility. Prior ovarian surgery may further contribute to diminished ovarian reserve and response in this population ( 5 ). Surgical intervention, particularly laparoscopic cystectomy, remains the most common treatment for endometriomas ( 6 - 8 ). Diagnosis and management traditionally rely on laparoscopy or laparotomy. Laparoscopic procedures require anesthesia and carry approximately a 3% risk of minor complications, including nausea, vomiting, and shoulder pain, and a 0.5% risk of major complications, such as intestinal perforation. Notably, over 90% of the excised endometrioma tissue often includes healthy ovarian tissue, potentially reducing ovarian reserve and increasing gonadotropin requirements in women under-going assisted reproductive techniques. Following bilateral ovarian cystectomy, 2.6% of women may experience premature ovarian failure or early menopause ( 9 ). Recurrence rates after conservative surgery range from 6.4% to 43.3, rising to 21.5% within two years and 40-50% within five years in the presence of adhesions ( 10 - 13 ). Given the potential complications of surgery, there has been growing interest in non-invasive approaches, including ultrasound-guided procedures. Cyst aspiration is a minimally invasive option; however, it is associated with a high recurrence rate and often requires repeated interventions. An alternative strategy involves cyst aspiration followed by sclerotherapy using sclerosing agents, such as ethanol, tetracycline, or methotrexate. This method induces protein denaturation in the cyst epithelium and promotes fibrosis of the cyst wall ( 14 - 16 ). The sclerotherapy procedure typically involves percutaneous puncture of the ovarian endometrioma to aspirate its contents, followed by ethanol instillation into the cyst cavity for a defined period before removal ( 17 ). Studies have demonstrated that alcohol sclerotherapy substantially reduces endometrioma recurrence and results in higher oocyte retrieval and antral follicle counts (AFCs) compared with ovarian cystectomy. The primary objective in managing endometriomas remains the preservation ovarian reserve and the improvement of pregnancy outcomes, particularly in women planning future conception ( 18 - 21 ). Current evidence on endometriosis and its subtypes is limited by imprecise prevalence data and a lack of quantified impact on ovarian response. Although surgical risks, particularly the inadvertent removal of healthy ovarian tissue, are recognized, supporting data remain sparse. Reported recurrence rates after surgery vary, and factors influencing recurrence require further clarification ( 22 , 23 ). While sclerotherapy has been suggested as an effective alternative, comparative data with traditional surgery are insufficient, particularly regarding long-term ovarian reserve and fertility outcomes. This study hypothesizes that ethanol sclerotherapy better preserves ovarian reserve and improved reproductive outcomes compared with laparoscopic cystectomy. The primary objectives are to assess whether sclerotherapy results in higher oocyte yield, increased AFCs, improved pregnancy rates, and fewer complications. Accordingly, we applied this approach to women with primary or recurrent endometriomas and diminished ovarian reserve to evaluate its impact on assisted reproductive outcomes.

A total of 80 participants were included in the study. The mean age was 32.85 ± 4.75 years in the intervention group and 31.68 ± 4.13 years in the control group, with no statistically significant difference (P=0.345). The mean duration of infertility was 6.05±1.45 years in the intervention group and 5.80 ± 1.20 years in the control group, also without significant difference. No significant differences were observed between groups regarding other baseline characteristics, including husband’s age, body mass index (BMI), FSH, LH, thyroid stimulating hormone (TSH), antral follicular count, CA125, and AMH. Detailed data are presented in Table 1. Baseline characteristics of participants in our groups Data are presented as men ± SD. P values were calculated using Independent t test. BMI; Body mass index, FSH; Follicle stimulating hormone, LH; Luteinizing hormone, TSH; Thyroid stimulating hormone, AMH; Anti-müllerian hormone, and CA125; Cancer Antigen 125. Pathological examination of the aspirated endometrioma fluid revealed no malignant cells. No procedural complications were reported in any patient. Endometrioma recurrence occurred in 8 patients (20%) within six months following sclerotherapy. No significant differences were observed between the groups regarding total gonadotropin dose (IU) (P=0.560), duration of gonadotropin administration (P=0.780), number of embryos (P=0.405), and number of transferred embryos (P=0.695). However, the intervention group demon-strated a statistically significant increase in the number of follicles (P=0.050) and total number of oocytes retrieved (P=0.042, Table 2 ). Comparison of IVF outcomes between the study groups Data are presented as mean ± SD. P values were calculated using the t test. D3; Day 3 embryos, and IU; International units. Detailed comparisons of embryo quality and pregnancy outcomes, including both significant and non-significant results, are summarized in Table 3. Comparison of pregnancy outcomes between the two study groups Data are presented as n/N (%). P values: *; Chi-square test and**; Fisher’s exact test.

This study evaluated the effects of ethanol sclerotherapy in women with primary endometriosis and diminished ovarian reserve, focusing on its impact on assisted reproductive outcomes. Our results demonstrated that ethanol sclerotherapy may be a safe and effective alternative for managing recurrent endometriomas. No significant differences in complication rates were observed between groups. However, the intervention group showed significantly higher embryo quality, as well as greater chemical and clinical pregnancy rates, whereas conception and implantation rates did not differ significantly between groups. These findings align with prior research ( 25 , 26 ). They reported 12% recurrence rate following ethanol sclerotherapy, with a mean follow-up of 17 months. No major complications were observed, although minor issues occurred, including mild abdominal pain in three patients (10.7%) and abdominal ethanol extravasation in two patients (7.1%). In a prospective study, Lee et al. ( 27 ) applied 20% ethanol for sclerotherapy and compared outcomes between surgical and conservative approaches. They reported that the number of retrieved, mature, and fertilized oocytes was significantly lower in the resection group compared with the other treatment groups. However, clinical pregnancy rates per initiated cycle, per embryo transfer, implantation rates, and miscarriage rates were similar across all groups. Follow-up for up to one year post-ethanol sclerotherapy indicated that the potential benefits of this method extend beyond initial treatment outcomes. Several studies have reported varying recurrence rates following ethanol sclerotherapy. Suzuki et al. ( 28 ) observed an 11.1% recurrence rate, while Aflatoonian et al. ( 29 ) using 98% ethanol, reported a 20% recurrence rate at six months. Yazbeck et al. ( 30 ) found a 12.9% recurrence rate over a 10 -month follow-up. A meta-analysis indicated that ethanol retention resulted in a lower recurrence rate compared to ethanol lavage ( 31 ). Furthermore, repeated monthly aspirations reduced recurrence from 91.5 to 27.9% over two years, and by the sixth aspirations, recurrence decreased to 5.4%. Variations in recurrence rates are likely due to differences in clinical characteristics (e.g., cyst size and primary vs. recurrent), procedural details (sclerosing agent type, dwell time, volume), and follow-up duration ( 27 ). In addition to recurrence, ethanol sclerotherapy has been associated with favorable IVF outcomes. Yazbeck et al. ( 30 ) reported that the ethanol sclerotherapy group had more mature oocytes and a higher cumulative clinical pregnancy rate compared to surgical cohorts. Similarly, Salem et al. ( 32 ) found improvements in ovarian responses to gonadotropin stimulation and an increased number and quality of embryos. Koike et al. ( 33 ) also observed a higher number of high-quality embryos in the ethanol-treated patients, consistent with our findings. Chang et al. ( 17 ) emphasized that ethanol retention was more effective than aspiration alone, reporting relapse rates of 13.3% versus 32.1% over one year. In contrast, Aflatoonian et al. ( 29 ) and Chang et al. ( 17 ) found no significant differences in chemical pregnancy, ongoing pregnancy, or live birth rates between retention and aspiration groups, likely due to larger cyst sizes in their studies. In the present study, ethanol was retained for ten minutes, resulting in a 20% recurrence rate, comparable to several previous reports. No significant differences in IVF outcomes were observed between the groups. Notably, overall recover defined as achieving pregnancy or absence of persistent symptoms or cysts was higher in patients receiving prolonged ethanol sclerotherapy (7-10 minutes). Patients with smaller cysts (≤5.05 cm), lower CA125 levels (≤62.03 IU/mL), and longer treatment durations exhibited the best recovery rates, suggesting that extended dwell time may enhance success, particularly in larger cysts and those with clear contents. The findings of the present study indicated that embryo quality, while generally good in both groups, was significantly higher in the intervention group, consistent with previous reports ( 27 - 29 ). Although endometriosis does not necessarily impair embryo quality per se, as noted by Yilmaz et al. ( 34 ), women with endometriomas may experience reduced fertility due to altered endometrial receptivity or the limitations of conventional morphological assessments in predicting embryo potential. This study on the efficacy of aspiration and ethanol sclerotherapy for primary and recurrent endometriomas carries important clinical implications for assisted reproductive technologies (ART). The observed improvements in embryo quality and pregnancy outcomes suggest that less invasive approach may serve as a viable alternative to conventional surgery, particularly in recurrent cases, and support a more patient-centered management strategy. The findings help clarify previously inconsistent results regarding endometrioma management in ART, providing evidence for the potential role of sclerotherapy in preserving ovarian reserve and optimizing reproductive outcomes. Further research is warranted to validate these results and to evaluate long-term reproductive and clinical outcomes. A potential limitation of this study is the relatively short follow-up period, as endometriosis may progress over time, and delayed ovarian stimulation could reduce pregnancy rates and increase recurrence. Additional limitations include a modest sample size, restrictive inclusion criteria that may limit generalizability, reliance on subjective outcome measures, and insufficient control for potential confounders. Potential sources of bias include selection bias from self-enrollment, investigator bias if outcome assessments are not blinded, and attrition bias due to loss to follow-up. Future studies should incorporate larger, welldefined cohorts and rigorous, standardized data collection to strengthen reliability and applicability of the findings.

The statistically significant improvements in clinical and chemical pregnancy rates observed in this study suggest that ethanol sclerotherapy may serve as a viable alternative to surgery for selected patients, particularly prior to IVF. This intervention appears to enhance both the quality and number of retrieved oocytes and to increase clinical pregnancy rates compared with conventional approaches. By effectively reducing endometrioma size and supporting ovarian function, ethanol sclerotherapy represents a valuable adjunct in assisted reproductive techniques, especially for women with endometriosis-related fertility challenges.

This a single-blind controlled clinical trial was conducted at Shariati Hospital, Tehran, Iran, following the CONSORT checklist ( Fig .1 ). The study was approved by the Tehran University of Medical Sciences (IR.TUMS.MEDICINE.REC.1398.019) and registered with the Iranian Registry of Clinical Trials (IRCT20191206045629N1). Written informed consent was obtained from all the participants prior to enrollment. Participants were infertile women aged 20-40 years with primary or recurrent endometriomas, whose male partners had normal semen parameters. Based on previous findings ( 24 ), the mean number of oocytes retrieved in groups with and without ovarian aspiration and ethanol sclerotherapy was 8.7 ± 4.1 and 6.0 ± 2.7, respectively. Assuming a significance level of 0.05 and a power of 80%, a sample size of 40 participants per group was calculated. Although clinical pregnancy was the primary outcome, sample size estimation was based on oocyte yield due to the absence of reliable prior data on clinical pregnancy rates in this specific population at the time of study design. Oocyte number was chosen as a validated surrogate marker with published variance, enabling a feasible power calculation. A post-hoc analysis using the observed clinical pregnancy rates confirmed that the achieved sample size would have been sufficient to detect a clinically meaningful difference. This limitation is acknowledged, and future studies are encouraged to power studies directly for clinical pregnancy. Women aged 20-40 years with recurrent endometriomas following prior ovarian surgery were eligible for inclusion. Additional criteria included baseline follicle-stimulating hormone (FSH) ≤10 IU/L, anti-Müllerian hormone (AMH) ≤1 ng/mL ( 24 , 25 ). Patients were excluded if they had a history of liver, kidney, or heart disease; endometriomas larger than 10 cm or smaller than 3 cm; cysts with a wall thickness >5 mm; or suspicion of malignancy. Pre-treatment evaluations included hormonal blood tests and transvaginal ultrasounds. Ovarian stimulation was performed using gonadotropins to promote the development of multiple follicles, followed by ovulation triggering with a human chorionic gonadotropin (hCG) agonist. CONSORT 2010 flow diagram. Oocyte retrieval was carried out under transvaginal ultrasound guidance. Semen samples were obtained from the patients’ male partners with normal semen parameters after 2-3 days of sexual abstinence on the day of oocyte retrieval. Sperm preparation was performed on the same day according to standard laboratory protocols. Fertilization was achieved via conventional insemination, and resulting embryos were cultured for several days. The highest-quality embryos were selected for transfer into the uterus. Luteal phase support was provided with progesterone, and a pregnancy test was performed 14 days after embryo transfer, followed by appropriate follow-up based on the results. Eligible patients underwent transvaginal ultrasound on the second or third day of menstruation to assess AFC, endometrioma size, and serum levels of luteinizing hormone (LH), FSH, AMH, estradiol, and CA125. These assessments were used to identify suitable candidates for the study. Following evaluation, participants were randomly assigned to either the intervention or the control group, comprising 39 and 40 patients. The control group received three ampoules of Dipherelin (triptorelin, Ipsen) at a dose of 3.75 mg every 28 days. The intervention group received intravenous prophylaxis with 1 g ceftriaxone and 0.5 g metronidazole two to three days after menstruation to prevent infection and manage endometriosis-related symptoms. Patients were placed in the lithotomy position under general anesthesia. After vaginal antiseptic preparation with betadine (Behvazan, Iran) and confirmation of sterile conditions, cyst contents were aspirated under transvaginal ultrasound guidance and sent for cytological analysis. The cyst cavity was irrigated with 0.5 cc of heparin (Caspian Tamin, Iran) in 500 cc of sterile normal saline (daropakhash, Iran) and subsequently aspirated. Approximately 80% of the cyst volume was filled with 98% ethanol, which was aspirated after 15 minutes. Patients were monitored for at least eight hours postoperatively and, if no complications occurred, were discharged with instructions to take 400 mg cefixime (Pharabi, Iran) and 500 mg of metronidazole (daropakhash, Iran) orally every 12 hours for one week. Additionally, patients received intramuscular injections of three ampoules of Dipherelin (3.75 mg, Ipsen, France) every 28 days. In both groups, ovulation stimulation with gonadotropin commenced ten days after the third Dipherelin injection, provided patients continued to meet eligibility criteria. Serum β-hCG levels were measured two weeks after embryo transfer. In cases of a positive β-hCG (baseline β-hCG >25 mIU/mL, taken approximately 12-14 days from expected conception), transvaginal ultrasound was performed three weeks later. Clinical pregnancy was confirmed upon detection of a fetal heartbeat. The proportion of women achieving clinical pregnancy following assisted reproductive techniques was considered a secondary outcome. The primary outcome was clinical pregnancy, defined as the presence of a fetal heartbeat on ultrasound. Secondary outcomes included chemical pregnancy rate (positive β-hCG 14 days post-transfer), number of retrieved oocytes, number of metaphase II oocytes, embryo number and quality, total gonadotropin dose administered, endometrioma recurrence rate at six months post-treatment, and implantation and conception rates. Eligible participants were allocated to the intervention (n=39) or control (n=40) group using balanced block randomization with blocks of four. Patients were blinded to the assigned intervention; however, double-blinding was not feasible, as the attending physicians were aware of the procedures. Data were analyzed using SPSS version 21.0 (IBM Corp., Chicago, IL, USA). The normality of continuous variables was assessed with the Kolmogorov-Smirnov test. Categorical variables were compared using the Chisquare and Fisher’s exact tests, while continuous variables were compared using independent t tests. A P<0.05 was considered statistically significant.